beta-endorphin and Disease-Models--Animal

Long known for its anti-nociceptive effects, the opioid beta-endorphin is also reported to have rewarding and reinforcing properties and to be involved in stress response. In this manuscript we summarize the present neurobiological and behavioral evidence regarding the role of beta-endorphin in stress-related psychiatric disorders, depression and PTSD. There is existing data that support the importance of beta-endorphin neurotransmission in mediating depression. As for PTSD, however, the data is thus far circumstantial. The studies described herein used diverse techniques, such as biochemical measurements of beta-endorphin in various brain sites and behavioral monitoring, in two animal models of depression and PTSD. We suggest that the pathways for stress-related psychiatric disorders, depression and PTSD, converge to a common pathway in which beta-endorphin is a modulating element of distress. This may occur via its interaction with the mesolimbic monoaminergic system and also by its interesting effects on learning and memory. The possible involvement of beta-endorphin in the process of stress-related psychiatric disorders, depression and PTSD, is discussed.

Topics: Animals; beta-Endorphin; Disease Models, Animal; Memory; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic

In the present study, we demonstrated that repeated treatment with fentanyl, but not morphine or oxycodone, causes a rapid desensitization to its ability to block the hyperalgesia associated with the attenuation of mu-opioid receptor resensitization in mice in a chronic pain-like state. In contrast, no such effect was noted in beta-endorphin knockout mice under the chronic pain-like conditions. On the assumption that beta-endorphin might be released within the spinal cord under pain-like conditions, we further examined whether beta-endorphin could be responsible for a desensitization and resensitization of fentanyl under the chronic pain. In cultured cells, unlike morphine, fentanyl and oxycodone induced a robust mu-opioid receptor internalization and, in turn, its resensitization. In the presence of beta-endorphin, the internalized mu-opioid receptor induced by fentanyl, but not oxycodone, remained within the cytosolic component even after washing out. The findings suggest that beta-endorphin could attenuate the resensitization of mu-opioid receptors. This phenomenon may explain the high degree of tolerance to fentanyl that develops with hyperalgesia caused by a chronic pain-like state.

Topics: Analgesics, Opioid; Animals; beta-Endorphin; Chronic Disease; Disease Models, Animal; Drug Tolerance; Fentanyl; Humans; Mice; Morphine; Oxycodone; Pain; Receptors, Opioid, mu

Human and animal studies suggest that there is a correlation between endogenous opioid peptides, especially beta-endorphin, and alcohol abuse. It has been proven that the consumption of alcohol activates the endogenous opioid system. Consumption of alcohol results in an increase in beta-endorphin level in those regions of the human brain, which are associated with a reward system. However, it has also been observed that habitual alcohol consumption leads to a beta-endorphin deficiency. It is a well-documented phenomenon that people with a genetic deficit of beta-endorphin peptide are particularly susceptible to alcoholism. The plasma level of beta-endorphin in subjects genetically at high risk of excessive alcohol consumption shows lower basal activity of this peptide. Its release increases significantly after alcohol consumption. Clinical and laboratory studies confirm that certain genetically determined factors might increase the individual's vulnerability to alcohol abuse.

Topics: Alcoholism; Animals; beta-Endorphin; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Mice; Rats

Topics: Animals; Antibodies; beta-Endorphin; Disease Models, Animal; Endorphins; Immunity, Cellular; Inflammation; Naloxone; Neuroimmunomodulation; Neurons, Afferent; Pain; Pain Threshold; Rats; Receptors, Opioid

Many New World primate species have greatly increased plasma cortisol concentrations, decreased plasma cortisol binding globulin capacity and affinity, marked resistance of the hypothalamic-pituitary-adrenal axis to suppression by dexamethasone, and no biological evidence of glucocorticoid excess. These primates also have high levels of circulating progesterone, estrogen, mineralocorticoid, androgen and vitamin D. The glucocorticoid target tissues that have been examined (circulating mononuclear lymphocytes and cultured skin fibroblasts) have normal concentrations of glucocorticoid receptors with decreased affinity for dexamethasone. Transformation of B-lymphocytes with the Epstein-Barr virus leads to glucocorticoid receptor induction that is less than that observed with cells from Old World primates. The receptor in these cells has a low affinity for dexamethasone. The low affinity leads to an increased loss of specific bound ligand during thermal activation. Meroreceptor generation is normal. The molecular weight of the receptor, determined by SDS-PAGE, is similar to that of Old World primates (approximately 92,000) and the activation pattern per se, examined in vitro by heating cytosol and performing phosphocellulose chromatography, appears similar to that of human controls. The ratios of nuclear to cytosolic hormone-receptor-complexes and of cytosolic activated to unactivated receptor complexes in intact cells are similar to Old World primates. Results from mixing studies do not support the hypothesis that a binding inhibitor(s) or a deficient cytosolic positive modifier(s) of binding underlies the findings in these primates. The New World primates, unlike men with the syndrome of primary cortisol resistance, have compensated for their condition with intra-adrenal and mineralocorticoid receptor adaptations. Thus, unlike Old World primates, cortisol in New World primates has only weak sodium-retaining potency because the aldosterone receptor has a low affinity for cortisol. The common element that would explain the apparent resistance to six steroid hormones in New World primates remains unknown.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Aldehyde-Lyases; Aldosterone; Animals; Aotus trivirgatus; beta-Endorphin; Cebidae; Dexamethasone; Disease Models, Animal; Drug Resistance; Endorphins; Glucocorticoids; Humans; Hypothalamo-Hypophyseal System; Kidney; Macaca fascicularis; Macaca mulatta; Monocytes; Pituitary-Adrenal System; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Saimiri; Steroid 11-beta-Hydroxylase; Steroid 17-alpha-Hydroxylase; Steroid 21-Hydroxylase

Asthma, a chronic respiratory disease is characterized by airway inflammation, remodelling, airflow limitation and hyperresponsiveness. At present, it is considered as an umbrella diagnosis consisting several variable clinical presentations (phenotypes) and distinct pathophysiological mechanisms (endotypes). Recent evidence suggests that oxidative stress participates in airway inflammation and remodelling in chronic asthma. Opioids resembled by group of regulatory peptides have proven to act as an immunomodulator. β-Endorphin a natural and potent endogenous morphine produced in the anterior pituitary gland play role in pain modulation. Therapeutic strategy of many opioids including β-Endorphin as an anti‑inflammatory and antioxidative agent has not been yet explored despite its promising analgesic effects. This is the first study to reveal the role of β-Endorphin in regulating airway inflammation, cellular apoptosis, and oxidative stress via Nrf-2 in an experimental asthmatic model. Asthma was generated in balb/c mice by sensitizing with 1% Toulene Diisocyanate on day 0, 7, 14 and 21 and challenging with 2.5% Toulene Diisocyanate from day 22 to 51 (on every alternate day) through intranasal route. β-Endorphin (5 µg/kg) was administered through the nasal route 1 h prior to sensitization and challenge. The effect of β-Endorphin on pulmonary inflammation and redox status along with parameters of oxidative stress were evaluated. We found that pre-treatment of β-Endorphin significantly reduced inflammatory infiltration in lung tissue and cell counts in bronchoalveolar lavage fluid. Also, pre-treatment of β-Endorphin reduced reactive oxygen species, Myeloperoxidase, Nitric Oxide, Protein and protein carbonylation, Glutathione Reductase, Malondialdehyde, IFN-γ, and TNF-α. Reversely, β-Endorphin significantly increased Superoxide dismutase, Catalase, glutathione, Glutathione-S-Transferase, and activation of NF-E2-related factor 2 (Nrf-2) via Kelch-like ECH-associated protein 1 (Keap1), independent pathway in the lung restoring architectural alveolar and bronchial changes. The present findings reveal the therapeutic potency of β-END in regulating asthma by Keap-1 independent regulation of Nrf-2 activity. The present findings reveal the therapeutic potency of β-Endorphin in regulating asthma.

Topics: Analgesics, Opioid; Animals; Apoptosis; Asthma; beta-Endorphin; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Glutathione; Inflammation; Kelch-Like ECH-Associated Protein 1; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Oxidative Stress

The study aimed to investigate the significance of serum biomarkers in the severity grading of traumatic brain injury (TBI). For this purpose, mice underwent fluid percussion injury (FPI) at three discrete severity levels, mild, moderate, and severe. The severity of trauma was verified by the qualitative and quantitative histopathology of the brain. The serum samples were analyzed for the potential changes in ubiquitin C‑terminal hydrolase‑1 (UCHL‑1), S100β, interleukin‑6 (IL‑6), corticosterone, and β‑endorphin at 24 and 72 h post injury. A multifold increase in the values of UCHL‑1 was reported at all severity extents of FPI. However, TBI severity‑dependent increase in UCHL‑1 was reported on 72 h following FPI but not at 24 h. S100β values were significantly augmented in the mild and moderate group at both the time point but not in the severe group. Serum level of IL‑6 was significantly increased in the mild injury group at 24 h but not in the moderate and severe. At 72 h, IL‑6 showed a reverse trend. β‑endorphin and corticosterone were sensitive at an early stage only. Such unique dynamics of each biomarker enable us to propose TBI severity scale in the term of biomarkers codes to predict the extent of neurotrauma. Our preclinical study presents a predictive model for further clinical validation.

Topics: Animals; beta-Endorphin; Biomarkers; Brain Injuries, Traumatic; Corticosterone; Disease Models, Animal; Interleukin-6; Mice; Percussion

Benefits of phototherapy were characterized in multiple diseases including depression, circadian rhythm disruptions, and neurodegeneration. Studies on migraine and fibromyalgia patients revealed that green light-emitting diodes (GLED) exposure provides a pragmatic and safe therapy to manage chronic pain. In rodents, GLED reversed hypersensitivity related to neuropathic pain. However, little is known about the underlying mechanisms of GLED efficacy. Here, we sought to understand how green light modulates the endogenous opioid system. We first characterized how exposure to GLED stimulates release of β-endorphin and proenkephalin in the central nervous system of male rats. Moreover, by individually editing each of the receptors, we found that µ- and δ-opioid receptors are required for green light's antinociceptive effect in naïve rats and a model of HIV-induced peripheral neuropathy. We investigated how GLED could increase pain thresholds, and explored its potential in reversing hypersensitivity in a model of HIV-related neuropathy. Through behavioral and gene editing approaches, we identified that green light provides antinociception via modulation of the endogenous opioid system in the spinal cord. This work identifies a previously unknown mechanism by which GLED can improve pain management. Clinical translation of these results will advance the development of an innovative therapy devoid of adverse effects. PERSPECTIVE: Development of new pain management therapies, especially for HIV patients, is crucial as long-term opioid prescription is not recommended due to adverse side effects. Green light addresses this necessity. Characterizing the underlying mechanisms of this potentially groundbreaking and safe antinociceptive therapy will advance its clinical translation.

Topics: Animals; beta-Endorphin; Disease Models, Animal; Enkephalins; Male; Neuralgia; Phototherapy; Protein Precursors; Rats; Spinal Cord

Traditional Chinese medicine detoxification prescription Chaihu-jia-Longgu-Muli decoction (CLMD) relieves depressive symptoms in patients withdrawing from methamphetamine. In the present study, we assessed the effects of CLMD on methamphetamine withdrawal in rats. A methamphetamine-intoxicated rat model was established. Rats were randomly divided into the control, model, high-dosage, medium-dosage, and low-dosage groups, receiving high, medium, and low doses of CLMD, respectively. Weekly body weight measurements revealed that rats treated with methamphetamine had the lowest body weight. The conditioned place preference (CPP) experiment revealed that methamphetamine-intoxicated rats stayed significantly longer in the drug-paired chamber than the control rats. However, after administering high-dosage CLMD, the amount of time the rats spent in the drug-paired chamber was significantly less than that of the model rats. Our open-field test revealed that the model group had lower crossing and rearing scores than the control group. Additionally, rats that received CLMD treatment exhibited higher crossing and rearing scores than the model rats. Striatal dopamine (DA), 5-hydroxytryptamine (5-HT), and endorphins (β-EP) and serum interleukin (IL)-1α and IL-2 concentrations were estimated. Rats in the model group had lower striatal DA, 5-HT, and β-EP and higher serum IL-1α and IL-2 concentrations than those in the control group. High-dosage CLMD administration significantly changed the concentrations of these molecules, such that they approached normal concentrations. In general, CLMD could prevent the development of methamphetamine-induced withdrawal symptoms in rats by increasing the DA, 5-HT, and β-EP and lowering the IL-1α and IL-2 concentrations.

Topics: Animals; Behavior, Animal; beta-Endorphin; Central Nervous System Stimulants; Conditioning, Psychological; Corpus Striatum; Disease Models, Animal; Dopamine; Drugs, Chinese Herbal; Interleukin-1alpha; Interleukin-2; Male; Methamphetamine; Open Field Test; Rats, Sprague-Dawley; Serotonin; Substance Withdrawal Syndrome

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Pain caused by soft tissue injury (STI) is always intractable and will eventually result in physical and psychological problems. This experiment aimed to assess the efficacy and mechanisms of low-intensity focused ultrasound (LIFU) for pain-related STI.. Rabbits (n = 30) with STI were given fixed treatment for 20 seconds and then mobile treatment for 60 seconds daily for 10 consecutive days by an LIFU device with a power output of 5 to 6 W and a frequency of 0.8 MHz. To evaluate the degree of pain, the levels of β-endorphin in serum were measured by an enzyme-linked immunosorbent assay before and 5 to 10 minutes after the 1st, 3rd, 7th, and 10th treatments. The pain threshold was measured by an electronic analgesy meter on the 1st, 3rd, 7th, 10th, 17th, and 24th days after the start of the treatment. To investigate inflammation, prostaglandin E. Compared with non-LIFU groups, β-endorphin levels and pain thresholds were significantly increased (P < .05), whereas nuclear factor- κB messenger RNA, prostaglandin E. Low-intensity focused ultrasound can alleviate pain induced by STI and could have further clinical applications.

Topics: Animals; beta-Endorphin; Disease Models, Animal; Pain; Pain Management; Pain Measurement; Rabbits; Soft Tissue Injuries; Treatment Outcome; Ultrasonic Therapy

Chronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under-diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD.. Unilateral OA pain was induced chemically, via an intra-articular injection of monosodium iodoacetate (MIA) in the left knee joint of AD-mice (TASTPM) and age- and gender-matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue.. MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28 days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re-established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD-mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of β-endorphin post-MIA which correlated with impaired allodynia.. These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re-evaluation of opioid analgesic use for management of pain in AD.. This study shows attenuated pain-like behaviour in a transgenic mouse model of Alzheimer's disease due to alterations in the opioidergic system and central plasticity mechanisms of persistent pain.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Analgesics; Analgesics, Opioid; Animals; Arthralgia; Behavior, Animal; beta-Endorphin; Chronic Pain; Disease Models, Animal; Enzyme Inhibitors; Gabapentin; Humans; Hyperalgesia; Injections, Intra-Articular; Iodoacetic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphine; Naloxone; Narcotic Antagonists; Osteoarthritis; Pain Measurement; Pain Threshold; Quality of Life; Spinal Cord

Endogenous β-endorphin is delivered exclusively from the pituitary gland in various stressful conditions and plays an essential role in the nervous system. Recently, a few studies demonstrated peripheral endogenous opioid secretion from immune cells at inflammatory sites. Here, we investigated the expression of β-endorphin, the most powerful endogenous opioid peptide, in peripheral tissues in response to systemic administration of lipopolysaccharide in mice.. Male C57BL/6N mice received intravenously administered lipopolysaccharide to induce an endotoxic shock-like condition. mRNA for proopiomelanocortin, a precursor of β-endorphin, was quantified in peripheral blood cells, liver and spleen. β-endorphin peptide was measured in the liver and spleen.. Expression of proopiomelanocortin mRNA was detected in peripheral tissues after systemic administration of lipopolysaccharide. Lipopolysaccharide also induced β-endorphin expression in the liver and spleen.. Expression of proopiomelanocortin mRNA and β-endorphin was detected in peripheral tissues after systemic administration of lipopolysaccharide. These results provide new evidence that peripheral endogenous opioids can be produced not only as a result of local inflammation but also by severe systemic stress such as endotoxic shock. Further study is required to clarify the role of peripheral β-endorphin during endotoxic shock.

Topics: Animals; beta-Endorphin; Blood Cells; Disease Models, Animal; Gene Expression; Inflammation; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Pro-Opiomelanocortin; Shock, Septic; Spleen; Tissue Distribution

Bone cancer metastasis is extremely painful and decreases the quality of life of the affected patients. Available pharmacological treatments are not able to sufficiently ameliorate the pain, and as patients with cancer are living longer, new treatments for pain management are needed. Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferases inhibitor, has analgesic properties in preclinical models of postsurgical and soft-tissue oral cancer pain by inducing an upregulation of endogenous opioids. In this study, we report that daily treatment with decitabine (2 µg/g, intraperitoneally) attenuated nociceptive behavior in the 4T1-luc2 mouse model of bone cancer pain. We hypothesized that the analgesic mechanism of decitabine involved activation of the endogenous opioid system through demethylation and reexpression of the transcriptionally silenced endothelin B receptor gene, Ednrb. Indeed, Ednrb was hypermethylated and transcriptionally silenced in the mouse model of bone cancer pain. We demonstrated that expression of Ednrb in the cancer cells lead to release of β-endorphin in the cell supernatant, which reduced the number of responsive dorsal root ganglia neurons in an opioid-dependent manner. Our study supports a role of demethylating drugs, such as decitabine, as unique pharmacological agents targeting the pain in the cancer microenvironment.

Topics: Animals; Antimetabolites, Antineoplastic; beta-Endorphin; Bone Density; Bone Neoplasms; Cancer Pain; Cell Line, Tumor; Culture Media, Conditioned; Decitabine; Disease Models, Animal; Endothelin-1; Female; Ganglia, Spinal; Locomotion; Mice; Mice, Inbred BALB C; Naloxone; Neurons; Quaternary Ammonium Compounds; Receptor, Endothelin B; Weight-Bearing

The G protein-coupled receptor 40 (GPR40), broadly expressed in various tissues such as the spinal cord, exerts multiple physiological functions including pain regulation. This study aimed to elucidate the mechanisms underlying GPR40 activation-induced antinociception in neuropathic pain, particularly related to the spinal glial expression of IL-10 and subsequent β-endorphin.. Spinal nerve ligation-induced neuropathic pain model was used in this study. β-Endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Double immunofluorescence staining of β-endorphin with glial and neuronal cellular biomarkers was also detected in the spinal cord and cultured primary microglia, astrocytes, and neurons.. GPR40 was expressed on microglia, astrocytes, and neurons in the spinal cords and upregulated by spinal nerve ligation. Intrathecal injection of the GPR40 agonist GW9508 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in neuropathic rats, with E. Our results illustrate that GPR40 activation produces antinociception via the spinal glial IL-10/β-endorphin antinociceptive pathway.

Topics: Animals; Animals, Newborn; beta-Endorphin; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Hyperalgesia; Interleukin-10; Male; Methylamines; Nerve Tissue Proteins; Neuralgia; Neuroglia; Pain Measurement; Propionates; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; RNA, Messenger; Signal Transduction

Alcohol is one of the leading threats to health worldwide. Craving for alcohol makes abstinence a difficult challenge by maintaining alcohol dependence. Many studies suppose the hypothalamic-pituitary-adrenal axis, especially the proopiomelanocortin (POMC)-derived neuropeptides, to mediate craving during withdrawal in alcohol dependence. Evidence is available that the two POMC proteins, α-melanocyte-stimulating hormone (α-MSH) and β-endorphin (β-END) are altered by alcohol consumption and influence alcohol consumption, respectively.. We investigated the dynamics of α-MSH and β-END during alcohol withdrawal and the influence of intraperitoneal administration of either α-MSH or β-END in an established rodent model (Wistar rats) for alcohol dependence.. After long-term alcohol self-administration over 12 months and repeated deprivation periods for 3 days, we found a significant decrease in α-MSH levels during withdrawal in rodents (p = 0.006) compared to controls, while β-END levels remained unchanged. Treatment with intraperitoneally administered α-MSH and β-END did not affect alcohol drinking behavior after deprivation.. We demonstrate the effects of alcohol deprivation on α-MSH in alcohol-dependent rodents, which appear to mimic α-MSH alteration found after fasting periods during appetite regulation. Therefore, low α-MSH levels are a possible indicator for craving in alcohol-dependent individuals and hence would be a potential target for anti-craving treatment.

Topics: Alcohol Drinking; Alcoholism; alpha-MSH; Animals; beta-Endorphin; Disease Models, Animal; Ethanol; Male; Rats, Wistar

The opioid system modulates the central reinforcing effects of ethanol and participates in the etiology of addiction. However, the pharmacotherapy of ethanol dependence targeted on the opioid system is little effective and varies due to individual patients' sensitivity. In the present study, we used two mouse lines with high (HA) and low (LA) activity of the endogenous opioid system to analyze the effect of opioid receptor blockade on ethanol drinking behavior. We found that LA and HA lines characterized by divergent magnitudes of swim stress-induced analgesia also differ in ethanol intake and preference. Downregulation of the opioid system in LA mice was associated with increased ethanol consumption. Treatment with a non-selective opioid receptor antagonist (naloxone) had no effect on ethanol intake in this line. Surprisingly, in HA mice, the blockage of opioid receptors led to excessive ethanol consumption. Moreover, naloxone selectively induced high levels of anxiety- and depressive-like behaviors in HA mice which was attenuated by ethanol. With the use of specific opioid receptor antagonists we showed that the naloxone-induced increase in ethanol drinking in HA mice is mediated mainly by δ and to a lower extent by μ opioid receptors. The effect of δ-opioid receptor antagonism was abolished in HA mice carrying a C320T transition in the δ-opioid receptor gene (EU446125.1), which impairs this receptor's function. Our results indicate that high activity of the opioid system plays a protective role against ethanol dependence. Therefore, its blockage with opioid receptor antagonists may lead to a profound increase in ethanol consumption.

Topics: Alcohol Drinking; Analgesia; Analysis of Variance; Animals; beta-Endorphin; Central Nervous System Depressants; Disease Models, Animal; Ethanol; Genotype; Maze Learning; Mice; Mood Disorders; Morphinans; Naloxone; Narcotic Antagonists; Receptors, Opioid, delta; Stress, Psychological; Swimming

To investigate the mechanism of cinobufagin-reduced cancer pain in mouse cancer pain model and in vitro cell co-culture system.. Female Kunming mice were randomly divided into 4 groups. One group of animals was set as normal control without any treatment. Other three groups of animals received H22 hepatoma cell inoculation in right hind paw. At day 9 after inoculation, mice in other three groups were injected intraperitoneally once a day for 8 days with the solvent, morphine or cinobufagin, respectively. The pain behavior was recorded daily. On the last day, all mice were sacrificed and xenograft tissues homogenate and plasma levels of β-endorphin (β-END), corticotropin-releasing factor (CRF) and interleukin-1β (IL-1β) were assessed by ELISA assay. Immunohistochemistry was performed to determine the expression of β-END, pro-opiomelanocortin (POMC) and the μ-opioid receptor (μ-OR) in the xenograft tissues. Immunofluorescence was used to localize lymphocytes with expression of CD3+, CD4+ and CD8+ in xenograft tumors and adjacent tissues. Mice splenic lymphocytes and H22 hepatoma carcinoma ascites cells were prepared for co-culture. β-END and CRF were detected in co-culture supernatants. The MTT assay and cytometry were used to assess cell proliferation. RT-PCR was conducted to determine the gene expression of POMC and Cathepsin L (CTSL). Chemotaxis was examined using a transwell-based migration assay.. Compared to the model group, the thermal and mechanical pain thresholds were increased in mice after cinobufagin treatment. The expression of β-END and CRF in the plasma and tumor tissues of cinobufagin group were much higher than that of the model group mice, but the expression of IL-1β in the plasma and tumor tissues was much lower than that in the model group mice. Meanwhile, the expression of β-END, POMC and μ-OR proteins was significantly increased in the xenograft tissues from cinobufagin group. Lymphocyte population of CD3+, CD4+, CD8+ were also elevated in xenograft tumors and adjacent tissues. In the cell co-culture assays, the content of β-END in the supernatant was significantly increased by cinobufagin in a dose-dependent manner. Cinobufagin also largely increased the proliferation of immune cells and inhibited H22 hepatoma carcinoma cell proliferation in single or co-culture cell assays. Gene expression of POMC and CTSL in cinobufagin group was significantly up-regulated comparing to the control group. Finally, cinobufagin addition enhanced the migration of immune cells in transwell assay.. Cinobufagin-induced local analgesic effect might be associated with increased activity of POMC/β-END/μ-OR pathway released from invaded CD3/4/8 lymphocytes in cancer tissues.

Topics: Analgesics; Animals; beta-Endorphin; Bufanolides; Carcinoma, Hepatocellular; Cell Line, Tumor; Coculture Techniques; Corticotropin-Releasing Hormone; Disease Models, Animal; Drugs, Chinese Herbal; Enzyme-Linked Immunosorbent Assay; Female; Immunohistochemistry; Interleukin-1beta; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Mice; Neoplasms, Experimental; Pain; Pain Threshold; Polymerase Chain Reaction; Random Allocation

Lamiophlomis rotata (L. rotata, Duyiwei) is an orally available Tibetan analgesic herb widely prescribed in China. Shanzhiside methylester (SM) is a principle effective iridoid glycoside of L. rotata and serves as a small molecule glucagon-like peptide-1 (GLP-1) receptor agonist. This study aims to evaluate the signal mechanisms underlying SM anti-allodynia, determine the ability of SM to induce anti-allodynic tolerance, and illustrate the interactions between SM and morphine, or SM and β-endorphin, in anti-allodynia and anti-allodynic tolerance. Intrathecal SM exerted dose-dependent and long-lasting (>4 h) anti-allodynic effects in spinal nerve injury-induced neuropathic rats, with a maximal inhibition of 49% and a projected ED50 of 40.4 μg. SM and the peptidic GLP-1 receptor agonist exenatide treatments over 7 days did not induce self-tolerance to anti-allodynia or cross-tolerance to morphine or β-endorphin. In contrast, morphine and β-endorphin induced self-tolerance and cross-tolerance to SM and exenatide. In the spinal dorsal horn and primary microglia, SM significantly evoked β-endorphin expression, which was completely prevented by the microglial inhibitor minocycline and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. SM anti-allodynia was totally inhibited by the GLP-1 receptor antagonist exendin(9-39), minocycline, β-endorphin antiserum, μ-opioid receptor antagonist CTAP, and SB203580. SM and exenatide specifically activated spinal p38 MAPK phosphorylation. These results indicate that SM reduces neuropathic pain by activating spinal GLP-1 receptors and subsequently stimulating microglial β-endorphin expression via the p38 MAPK signaling. Stimulation of the endogenous β-endorphin expression may be a novel and effective strategy for the discovery and development of analgesics for the long-term treatment of chronic pain.

Topics: Analgesics; Animals; Animals, Newborn; beta-Endorphin; Cells, Cultured; Disease Models, Animal; Drugs, Chinese Herbal; Functional Laterality; Gene Expression Regulation; Glucagon-Like Peptide 1; Hyperalgesia; Male; Microglia; Minocycline; Neuralgia; Neurons; Pain Measurement; Plant Preparations; Rats; Rats, Wistar; Spinal Cord; Spinal Nerves

Acute alcohol intoxication (AAI) is a frequent emergency, but therapeutic drugs with superior efficacy and safety are lacking. Panax ginseng (PG) and Hippophae rhamnoides (HR) respectively has a wide application as a complementary therapeutic agent in China for the treatment of AAI and liver injury induced by alcohol. We investigated the effects of aqueous extracts from PG and HR (AEPH) on AAI mice and identified its underlying mechanisms.. Models of AAI were induced by intragastric administration of ethanol (8g/kg). Seventy-two Specific pathogen-free (SPF) male Kunming mice were randomly divided into six groups: normal group, positive control group, AEPH of low dosage (100mg/kg) group, AEPH of medium dose (200mg/kg) group, AEPH of high dosage (400mg/kg) group and model group. The mice were treated with metadoxine (MTD, 500mg/kg) and AEPH. Thirty minutes later, the normal group was given normal saline, while the other groups were given ethanol (i.g., 8g/kg). The impact of AEPH was observed. In the same way, another seventy-two Kunming mice were randomly divided into six groups equally. The blood ethanol concentration at 0.5, 1, 1.5, 2, 3 and 6h after ethanol intake was determined by way of gas chromatography. The activity of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and microsomal ethanol oxidase (EO) in liver, and the concentration of β-endorphin (β-EP), leucine-enkephalin (LENK) in the brain were determined by enzyme-linked-immunosorbent serologic assay (ELISA).. AEPH markedly prolonged alcohol tolerance time and shortened sober-up time after acute ethanol administration. AEPH decreased blood ethanol levels in six tests after ethanol intake. The 7-day survival rate of AEPH group was obviously superior to model group. AEPH increased the activities of ADH, ALDH, and decreased EO activity in liver. The crucial find was that AEPH markedly decreased β-EP and LENK concentration in the brain.. AEPH can markedly increase the levels of ADH, ALDH, decrease EO activity in liver and decrease the concentration of β-EP and LENK in the brain to against acute alcohol intoxication in mice.

Topics: Alcohol Dehydrogenase; Alcohol Oxidoreductases; Alcoholic Intoxication; Aldehyde Dehydrogenase; Animals; beta-Endorphin; Blood Alcohol Content; Brain; Cytochrome P-450 Enzyme System; Disease Models, Animal; Dose-Response Relationship, Drug; Enkephalin, Leucine; Ethanol; Gas Chromatography-Mass Spectrometry; Hippophae; Liver; Male; Mice; Panax; Phytotherapy; Plant Extracts; Plants, Medicinal; Solvents; Time Factors; Water

During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain.. Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4. The macrophage phenotypes were verified using flow cytometry for surface marker analysis and cytokine bead array for cytokine profile assessment. Opioid peptide levels were measured by radioimmunoassay and enzyme immunoassay. As a model of neuropathic pain, a chronic constriction injury (CCI) of the sciatic nerve was employed. Polarized M0, M1, and M2 macrophages (5 × 10. Compared to M0 and M1 cells, M2 macrophages contained and released higher amounts of opioid peptides, including Met-enkephalin, dynorphin A (1-17), and β-endorphin. M2 cells transferred perineurally at the nerve injury site reduced mechanical, but not heat hypersensitivity following the second injection. The analgesic effect was reversed by the perineurally applied opioid receptor antagonist naloxone methiodide. M2 cells did not affect sensitivity following sham surgery. Neither M0 nor M1 cells altered mechanical and heat sensitivity in CCI or sham-operated animals. Tracing the fluorescently labeled M0, M1, and M2 cells ex vivo showed that they remained in the nerve and preserved their phenotype.. Perineural transplantation of M2 macrophages resulted in opioid-mediated amelioration of neuropathy-induced mechanical hypersensitivity, while M1 macrophages did not exacerbate pain. Therefore, rather than focusing on macrophage-induced pain generation, promoting opioid-mediated M2 actions may be more relevant for pain control.

Topics: Acyltransferases; Adoptive Transfer; Animals; beta-Endorphin; Cell Polarity; Cytokines; Disease Models, Animal; Dynorphins; Flow Cytometry; Histocompatibility Antigens Class II; Hyperalgesia; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Neuralgia; Opioid Peptides; Pain Threshold; Physical Stimulation

β-Endorphin (BEP)-producing neuron in the hypothalamus plays a key role in bringing the stress axis to a state of homeostasis and maintaining body immune defense system. Long-term delivery of BEP to obtain beneficial effect on chemoprevention is challenging, as the peptides rapidly develop tolerance. Using rats as animal models, we show here that transplantation of BEP neurons into the hypothalamus suppressed carcinogens- and hormone-induced cancers in various tissues and prevented growth and metastasis of established tumors via activation of innate immune functions. In addition, we show that intracerebroventricular administration of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) increased the number of BEP neurons in the hypothalamus, reduced the stress response, enhanced the innate immune function, and prevented tumor cell growth, progression, and metastasis. BEP neuronal supplementation did not produce any deleterious effects on general health but was beneficial in suppressing age-induced alterations in physical activity, metabolic, and immune functions. We conclude that the neuroimmune system has significant control over cancer growth and progression, and that activation of the neuroimmune system via BEP neuronal supplementation/induction may have therapeutic value for cancer prevention and improvement of general health.

Topics: Animals; Anticarcinogenic Agents; beta-Endorphin; Bucladesine; Carcinogens; Cell Differentiation; Disease Models, Animal; Female; Glucose Tolerance Test; Hypothalamus; Immune System; Immunohistochemistry; Killer Cells, Natural; Male; Neoplasm Metastasis; Neoplasms; Neurons; Rats; Rats, Inbred F344; Rats, Nude; Rats, Sprague-Dawley

Several recent studies have indicated that lamotrigine, similarly to other antiepileptic drugs, may be useful in the therapy of alcohol dependence. The rationale for using lamotrigine in the treatment of alcohol addiction is based on its multiple mechanisms of action which include inhibition of voltage-sensitive sodium channels, modulation voltage-gated calcium currents and transient potassium outward current. However, the known mechanism of lamotrigine does not fully explain its efficacy in alcohol addiction therapy. For this reason we have decided to examine the effect of lamotrigine on the opioid system. Our previous studies showed that topiramate and levetiracetam (antiepileptic drugs) as well as the most effective drugs in alcohol addiction therapy i.e. naltrexone and acamprosate, when given repeatedly, all increased plasma beta endorphin (an endogenous opioid peptide) level, despite operating through different pharmacological mechanisms. It is known that low beta-endorphin level is often associated with alcohol addiction and also that alcohol consumption elevates the level of this peptide. This study aims to assess the effect of repeated treatment with lamotrigine on voluntary alcohol intake and beta-endorphin plasma level in alcohol preferring rats (Warsaw high preferring (WHP) rats). We observed a decrease in alcohol consumption in rats treated with lamotrigine. However we didn't observe significant changes in beta-endorphin level during withdrawal of alcohol, which may indicate that the drug does not affect the opioid system. We suppose that lamotrigine may be useful in alcohol dependence therapy and presents a potential area for further study.

Topics: Alcohol Drinking; Analysis of Variance; Animals; beta-Endorphin; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Ethanol; Female; Lamotrigine; Rats; Triazines

Topics: Animals; beta-Endorphin; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Ethanol; Female; Hypothalamus; Liver Neoplasms; Male; Neurons; Pregnancy

Studies implicate opioid transmission in hedonic and metabolic control of feeding, although roles for specific endogenous opioid peptides have barely been addressed. Here, we studied palatable liquid consumption in proenkephalin knockout (PENK KO) and β-endorphin-deficient (BEND KO) mice, and how the body weight of these mice changed during consumption of an energy-dense highly palatable 'cafeteria diet'. When given access to sucrose solution, PENK KOs exhibited fewer bouts of licking than wild types, even though the length of bouts was similar to that of wild types, a pattern that suggests diminished food motivation. Conversely, BEND KOs did not differ from wild types in the number of licking bouts, even though these bouts were shorter in length, suggesting that they experienced the sucrose as being less palatable. In addition, licking responses in BEND, but not PENK, KO mice were insensitive to shifts in sucrose concentration or hunger. PENK, but not BEND, KOs exhibited lower baseline body weights compared with wild types on chow diet and attenuated weight gain when fed cafeteria diet. Based on this and related findings, we suggest endogenous enkephalins primarily set a background motivational tone regulating feeding behavior, whereas β-endorphin underlies orosensory reward in high need states or when the stimulus is especially valuable. Overall, these studies emphasize complex interplays between endogenous opioid peptides targeting μ-receptors, such as enkephalins and endorphins, underlying the regulation of feeding and body weight that might explain the poor efficacy of drugs that generally target μ-opioid receptors in the long-term control of appetite and body weight.

Topics: Animals; Appetite; beta-Endorphin; Body Weight; Case-Control Studies; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking Behavior; Enkephalins; Feeding Behavior; Female; Food Deprivation; Male; Mice; Mice, Knockout; Obesity; Protein Precursors; Sucrose

This study is aimed at examining the long-term effects of chronic pain during early life (postnatal day 0 to 8weeks), and intervention using sucrose, on cognitive functions during adulthood in rats. Pain was induced in rat pups via needle pricks of the paws. Sucrose solution or paracetamol was administered for analgesia before the paw prick. Control groups include tactile stimulation to account for handling and touching the paws, and sucrose alone was used. All treatments were started on day one of birth and continued for 8weeks. At the end of the treatments, behavioral studies were conducted to test the spatial learning and memory using radial arm water maze (RAWM), as well as pain threshold via foot-withdrawal response to a hot plate apparatus. Additionally, the hippocampus was dissected, and blood was collected. Levels of neurotrophins (BDNF, IGF-1 and NT-3) and endorphins were assessed using ELISA. The results show that chronic noxious stimulation resulted in comparable foot-withdrawal latency between noxious and tactile groups. On the other hand, pretreatment with sucrose or paracetamol increased pain threshold significantly both in naive rats and noxiously stimulated rats (P<0.05). Chronic pain during early life impaired short-term memory, and sucrose treatment prevented such impairment (P<0.05). Sucrose significantly increased serum levels of endorphin and enkephalin. Chronic pain decreased levels of BDNF in the hippocampus and this decrease was prevented by sucrose and paracetamol treatments. Hippocampal levels of NT-3 and IGF-1 were not affected by any treatment. In conclusion, chronic pain induction during early life induced short memory impairment, and pretreatment with sucrose prevented this impairment via mechanisms that seem to involve BDNF. As evident in the results, sucrose, whether alone or in the presence of pre-noxious stimulation, increases pain threshold in such circumstances; most likely via a mechanism that involves an increase in endogenous opioids.

Topics: Acetaminophen; Analgesics; Animals; Animals, Newborn; beta-Endorphin; Chronic Pain; Disease Models, Animal; Female; Hippocampus; Intercellular Signaling Peptides and Proteins; Learning; Male; Maze Learning; Memory; Pain Measurement; Pain Threshold; Physical Stimulation; Pregnancy; Rats; Sucrose

This study investigated whether and how electroacupuncture (EA) attenuates cold hypersensitivity (allodynia) in a rat model of oxaliplatin-induced neuropathic pain. Cold allodynia [evaluated by immersing the tail into cold water (4 °C) and measuring the withdrawal latency] was induced 3 days after an oxaliplatin administration (6 mg/kg, i.p.). EA stimulation (2/100 Hz, 0.3-ms pulse duration, 0.2-0.3 mA) was delivered to ST36 acupoint or non-acupoint for 20 min. Low-frequency (2 Hz) EA at ST36 relieved cold allodynia more effectively than high-frequency EA at ST36 or low-frequency EA at non-acupoint. Naloxone (opioid antagonist, 2 mg/kg, i.p.) completely blocked such EA-induced anti-allodynia, whereas phentolamine (α-adrenergic antagonist, 2 mg/kg, i.p.) did not. Moreover, plasma β-endorphin levels significantly increased right after the end of EA and subsequently decreased. These results indicate that low-frequency EA at ST36 in rats has a marked relieving effect on oxaliplatin-induced cold allodynia that is mediated by the endogenous opioid, but not noradrenergic, system.

Topics: Adrenergic alpha-Antagonists; Animals; Behavior, Animal; beta-Endorphin; Cold Temperature; Disease Models, Animal; Electroacupuncture; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Organoplatinum Compounds; Oxaliplatin; Pain Threshold; Phentolamine; Rats; Rats, Sprague-Dawley; Reaction Time; Time Factors

A large body of evidence now exists for the immune cell expression, production, and the release of beta-endorphin (BE 1-31) within inflamed tissue. The inflammatory milieu is characterised by increased acidity, temperature and metabolic activity. Within these harsh conditions BE 1-31 is even more susceptible to increased enzymatic degradation over that of plasma or other non-injured tissue. To elucidate the biotransformation pathways of BE 1-31 and provide an insight to the impact of inflamed tissue environments, BE 1-31 and three of its major N-terminal fragments (BE 1-11, BE 1-13 and BE 1-17) were incubated in inflamed tissue homogenates at pH 5.5 for 2 hrs. In addition, the potency of BE 1-31 and five main N--terminal fragments (BE 1-9, BE 1-11, BE 1-13, BE 1-17, BE 1-20) was assessed at mu-opioid receptors (MOR), delta-opioid receptors (DOR), and kappa-opioid receptors (KOR). Opioid receptor potency was investigated by examining the modulation of forskolin induced cAMP accumulation. The majority of the N-terminal fragment of BE 1-31 had similar efficacy to BE 1-31 at MOR. The shortest of the major N-terminal fragments (BE 1-9), had partial agonist activity at MOR but possessed the highest potency of all tested peptides at DOR. There was limited effect for BE 1-31 and the biotransformed peptides at KOR. Major N-terminal fragments produced within inflamed tissue have increased presence within inflamed tissue over that of the parent molecule BE 1-31 and may therefore contribute to BE 1-31 efficacy within disease states that involve inflammation.

Topics: Animals; beta-Endorphin; Cell Line; Colforsin; Cyclic AMP; Disease Models, Animal; Gene Expression; Humans; Hydrogen-Ion Concentration; Inflammation; Male; Metabolic Networks and Pathways; Peptides; Rats; Receptors, Opioid; Receptors, Opioid, kappa

Interleukin-17 (IL-17) is involved in a wide range of inflammatory disorders and in recruitment of inflammatory cells to injury sites. A recent study of IL-17 knock-out mice revealed that IL-17 contributes to neuroinflammation and neuropathic pain after peripheral nerve injury. Surprisingly, little is known of micro-environment modulation by IL-17 in injured sites and in pathologically related neuroinflammation and chronic neuropathic pain. Therefore, we investigated nociceptive sensitization, immune cell infiltration, myeloperoxidase (MPO) activity, and expression of multiple cytokines and opioid peptides in damaged nerves of wild-type (IL-17(+/+)) and IL-17 knock-out (IL-17(-/-)) mice after partial sciatic nerve ligation. Our results demonstrated that the IL-17(-/-) mice had less behavioral hypersensitivity after partial sciatic nerve ligation, and inflammatory cell infiltration and pro-inflammatory cytokine (tumor necrosis factor-α, IL-6, and interferon-γ) levels in damaged nerves were significantly decreased, with the levels of anti-inflammatory cytokines IL-10 and IL-13, and expressions of enkephalin, β-endorphin, and dynorphin were also decreased compared to those in wild-type control mice. In conclusion, we provided evidence that IL-17 modulates the micro-environment at the level of the peripheral injured nerve site and regulates progression of behavioral hypersensitivity in a murine chronic neuropathic pain model. The attenuated behavioral hypersensitivity in IL-17(-/-) mice could be a result of decreased inflammatory cell infiltration to the injured site, resulting in modulation of the pro- and anti-inflammatory cytokine milieu within the injured nerve. Therefore, IL-17 may be a critical component for neuropathic pain pathogenesis and a novel target for therapeutic intervention for this and other chronic pain states.

Topics: Animals; Behavior, Animal; beta-Endorphin; Central Nervous System Sensitization; Cytokines; Disease Models, Animal; Dynorphins; Enkephalins; Hyperalgesia; Inflammation; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-1beta; Interleukin-2; Interleukin-6; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Neutrophils; Nociception; Peripheral Nerve Injuries; Peroxidase; Sciatic Nerve; T-Lymphocytes; Tumor Necrosis Factor-alpha

To study the effect of Qilongtoutong granule (QLTT) on plasma calcitonin gene-related peptide (CGRP), beta-endorphin (beta-EP), 5-HT, dopamine (DA), noradrenalin (NE), and blood viscosity in migraine model rats and mice.. Both the acute blood stasis model group and nitroglycerin-induced migraine model group included 60 Sprague-Dawley rats. The reserpine-reduced model group had 60 Kunming mice. Rats from each test were grouped into normal control group, model group, Zhengtian pill (ZTP) group, and high, moderate, or low-dose QLTT groups. In the acute blood stasis model test, after gavage for 7 days, rats were given 0.8 mL/kg adrenaline hydrochloride subcutaneously twice, and kept in ice water for 5 min. After fasting for 12 h, rats were anesthetized and blood samples were collected for detection of blood viscosity. In the nitroglycerin-induced migraine group, after gavage for 7 days, rats were intraperitoneally injected nitroglycerin (10 mg/kg), and 4 h later, blood samples were collected from postcava for measuring the plasma CGRP and beta-EP levels. In the reserpine-reduced model test, except the normal control group, mice were administered reserpine (0.25 mg/ kg, i.h.) for 9 days. Mice received intragastric administration from the third day to the ninth day. One hour after the last gavage, blood and brain tissue samples were obtained. Then, blood clotting time and the contents of neurotransmitters were determined.. QLTT- (3.6, 1.8, and 0.9 g/kg) and ZTP-treated rats had lower blood viscosity than that in model rats under different shear rates (P < 0.01). QLTT- (3.6, 1.8 g/kg) and ZTP-treated rats had significantly lower plasma CGRP levels and higher plasma beta-EP levels than those in model rats (P < 0.01). QLTT treatment at dose of 0.9 g/kg had lower plasma CGRP levels as well (P < 0.05). QLTT- (5.2, 2.6 g/kg) and ZTP-treated mice had longer blood clotting time than that in model mice (P < 0.01). QLTT- (2.6 g/kg) and ZTP-treated mice had higher plasma serotonin (5-HT) levels than those in model mice (P < 0.05).. QLTT-treated animals had lower plasma CGRP level, higher plasma beta-EP, 5-HT, higher brain tissue 5-HT, NE, DA levels, and lower blood viscosity than those in the migraine model animals.

Topics: Animals; beta-Endorphin; Calcitonin Gene-Related Peptide; Disease Models, Animal; Dopamine; Drugs, Chinese Herbal; Female; Humans; Male; Mice; Migraine Disorders; Norepinephrine; Rats; Rats, Sprague-Dawley; Serotonin

To observe the influence of different moxibustion durations on hypothalamic pro-opiomelanocortin (POMC) and prodynorphin (PDYN) mRNA expressions and plasma beta-endorphin (beta-EP) content in rheumatoid arthritis (RA) rats, to understand the mechanism of moxibustion analgesia and its dose-effect relationship.. Twelve male Wistar rats were randomly selected from 48 male Wistar rats as a normal control group. The RA model was created by raising rats in a windy (blowing with electric fan), cold (6 degrees C +/- 2 degrees C), and wet (80%-90% humidity) environment for 20 days, 12 h each day. This was followed by injection of Freund's complete adjuvant (0.15 mL) into the ankle. Then, rats were randomly divided into a model group, moxibustion group I, and moxibustion group II, with 12 rats in each group. In moxibustion groups I and II, moxibustion was given at Shenshu (BL 23) and Zusanli (ST 36) for 20 and 40 min, respectively, once daily for 15 days. Hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content were determined.. Compared with the normal group, the pressure pain threshold decreased, while the hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content increased in the moxibustion groups (P < 0.01). Compared with the model group, the pressure pain threshold, hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content in the moxibustion groups increased significantly (P < 0.01). Compared the moxibustion group I, the pain threshold, hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content in moxibustion group II significantly increased (P < 0.01).. Moxibustion has an analgesic effect and increases hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content in RA rats.The analgesic effect in moxibustion group II is betterthan that in moxibustion group I.

Topics: Acupuncture Points; Analgesia; Animals; Arthralgia; Arthritis, Rheumatoid; beta-Endorphin; Disease Models, Animal; Enkephalins; Humans; Hypothalamus; Male; Moxibustion; Pain Threshold; Pro-Opiomelanocortin; Protein Precursors; Rats; Rats, Wistar

Recently, retrograde tracing has provided evidence for an influence of hypothalamic β-endorphin (BEP) neurons on the liver, but functions of these neurons are not known. We evaluated the effect of BEP neuronal activation on alcohol-induced liver injury and hepatocellular cancer.. Male rats received either BEP neuron transplants or control transplants in the hypothalamus and were randomly assigned to feeding alcohol-containing liquid diet or control liquid diet for 8 weeks or to treatment of a carcinogen diethylnitrosamine (DEN). Liver tissues of these animals were analyzed histochemically and biochemically for tissue injuries or cancer.. Alcohol feeding increased liver weight and induced several histopathological changes such as prominent microvesicular steatosis and hepatic fibrosis. Alcohol feeding also increased the levels of triglyceride, hepatic stellate cell (HSC) activation factors, and catecholamines in the liver and endotoxin levels in the plasma. However, these effects of alcohol on the liver were reduced in animals with BEP neuron transplants. BEP neuron transplants also suppressed carcinogen-induced liver histopathologies such as extensive fibrosis, large focus of inflammatory infiltration, hepatocellular carcinoma (HCC), collagen deposition, numbers of preneoplastic foci, levels of HSC activation factors and catecholamines, as well as inflammatory milieu and increased the levels of natural killer cell cytotoxic factors in the liver.. These findings are the first evidence for a role of hypothalamic BEP neurons in influencing liver functions. Additionally, the data identify that BEP neuron transplantation prevents hepatocellular injury and HCC formation possibly via influencing the immune function.

Topics: Animals; beta-Endorphin; Cells, Cultured; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Ethanol; Female; Hypothalamus; Liver Neoplasms; Male; Neurons; Pregnancy; Random Allocation; Rats; Rats, Inbred F344; Rats, Sprague-Dawley

GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 µg) and GW9508 (1.0 µg), a GPR40-selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 µg), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of β-endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 µg) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that hypothalamic GPR40 activated by free long chain fatty acids might have an important role in this pain control system.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Astrocytes; Benzoates; beta-Endorphin; Chronic Pain; Disease Models, Animal; DNA-Binding Proteins; Docosahexaenoic Acids; Flavonoids; Freund's Adjuvant; Gene Expression; Glial Fibrillary Acidic Protein; Hyperalgesia; Injections, Intraventricular; Male; Methylamines; Mice; Nerve Tissue Proteins; Neuroglia; Nuclear Proteins; Pain Management; Piperidines; Pro-Opiomelanocortin; Propionates; Pyrimidines; Receptors, G-Protein-Coupled; Signal Transduction; Time Factors

Endogenous opioids are implicated in pain-regulation in chronic inflammatory bowel disease (IBD). We sought to examine whether endogenous opioids suppress the excitability of colonic nociceptive dorsal root ganglia (DRG) neurons during chronic IBD, and if so, whether modulation of underlying voltage-gated K(+) currents was involved.. The effects of chronic dextran sulfate sodium (DSS) colitis on afferent signaling in mice was studied using patch clamp recordings. Colonic DRG neurons were identified using Fast Blue retrograde labeling and recordings obtained from small DRG neurons (<40 pF).. In current-clamp recordings, the rheobase of neurons was increased 47% (P < 0.01) and action potential discharge at twice rheobase decreased 23% (P < 0.05) following incubation in colonic supernatants from chronic DSS mice. β-endorphin increased 14-fold, and tissue opioid immunoreactivity and expression in CD4+ cells observed by flow cytometry increased in chronic DSS colons. Incubation of naïve neurons in the μ-opioid receptor agonist D-Ala(2), N- MePhe(4), Gly-ol (DAMGO) (10 nM) partially recapitulated the effects of supernatants from DSS mice on rheobase. Supernatant effects were blocked by the μ-opioid receptor antagonist naloxone. In voltage clamp, chronic DSS supernatants and DAMGO increased I(A) K(+) currents.. The release of endogenous opioids during chronic inflammation in mice suppresses the excitability of nociceptive DRG neurons. Targeting immune cells may provide a novel means of modulating IBD pain.

Topics: Action Potentials; Animals; beta-Endorphin; Cell Separation; Chronic Disease; Colon; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Ganglia, Spinal; Immunohistochemistry; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques

Reactivity to traumatic stress varies between individuals and only a minority of those exposed to trauma develops stress-induced psychopathologies. Currently extensive effort is made to unravel the specific mechanisms predisposing to vulnerability vs. resilience to stress. We investigated in rats the role of β-endorphin metabolism in vulnerability to acute traumatic stress. Responders (showing extreme anxiety; n=7) and resilient non-responders (not differing from the non-stressed individuals; n=8) to traumatic foot-shock stress were compared for their blood levels of stress hormones as well as brain levels and activity of two opioid-degrading enzymes. β-endorphin is a substrate to insulin degrading enzyme, which also degrades insulin. Therefore, the effects of insulin application on behavioral and hormonal responses and on β-endorphin degradation were tested. Pre- and post-stress levels of serum corticosterone, and post-stress plasma β-endorphin concentration differentiated between the responders and the non-responders. In brain, responders showed enhanced degradation rates of β-endorphin, assessed by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), in hippocampal and amygdalar slices as compared to non-responders. Application of insulin to the amygdala, prior to exposure to traumatic stress, reduced post-stress anxiety and serum corticosterone levels only in the responders. In parallel, amygdalar β-endorphin degradation rate was also reduced by insulin. These results suggest that slowing down β-endorphin degradation rate may constitute an integral part of the normal stress-response, upon a failure of which an extreme anxiety develops. Modulation of opioid degradation may thus present a potential novel target for interference with extreme anxiety.

Topics: Aminopeptidases; Amygdala; Animals; beta-Endorphin; Corticosterone; Disease Models, Animal; Electroshock; Exploratory Behavior; Functional Laterality; Insulin; Male; Maze Learning; Rats; Rats, Sprague-Dawley; Stress, Psychological; Time Factors

To observe effects of electroacupuncture (EA) on the expression of kappa-opioid receptor in the dorsal horn of the spinal cord and contents of enkephalin(ENK) and beta-endorphin (beta-EP) in the periaqueductal gray (PAG) of midbrain in dysmenorrheal rats, so as to reveal its underlying mechanism in relieving dysmenorrhea.. A total of 80 female SD rats were randomized into saline control (control), model, Sanyinjiao (SP 6), Xuanzhong (GB 39), non-acupoint groups (16 rats/group). Dysmenorrhea model was established by subcutaneous injection of estradiol benzoate (0.5 mg/rat on the 1st day and 10th day, 0.2 mg/rat from the 2nd day to the 9th day). One hour after the last injection, oxytocin (2 U/rat) was given intraperitoneally, for rats of the control group, the same dose of saline was given (i. p.). On the 10th day, EA (2 Hz/100 Hz, 0.1-0.3 mA) was applied to "Sanyinjiao" (SP 6), "Xuanzhong" (GB 39) and non-acupoint (the mid-point between the Stomach Meridian and Gallbladder Meridian, and in parallel with GB 39) for 20 min, respectively. Latency and number of writhing response, and writhing score (according to Schmauss's and Yaksh's method) were recorded. The expression of kappa-opioid receptor (kappa-OR) in T13, L1 , L2, L6 and S1 segments of spinal cord was determined by immunohistochemistry, and the contents of ENK and beta-EP in the midbrain PAG were assayed by ELISA.. (1) Compared with the saline control group, the writhing latency of the model group was significantly shortened (P < 0.01), while the writhing times and writhing score of the model group were increased significantly (P < 0.01). Compared with the model group, the writhing latency of SP 6 group was significantly prolonged (P < 0.05), while the writhing scores and writhing times of the SP 6, GB 39 and the non-acupoint groups decreased significantly (P < 0.01). (2) In comparison with the control group, kappa-OR expression in the dorsal horn of L2 segment of spinal cord was upregulated significantly in the model group (P < 0.05). Compared to the model group, kappa-OR expression levels in the dorsal horns (DHs) of spinal T13, L1, L2, L6 and S1 segments in the SP 6 group were upregulated significantly (P < 0.01). ENK and beta-EP contents of PAG in the SP 6 and GB 39 groups were increased considerably (P < 0.01, P < 0.05). The effects of SP 6 were significantly superior to those of GB 39 in upregulating kappa-OR expression of spinal L1, L2 and L6 DHs and in upregulating beta-EP content of PAG; and superior to non-acupoint in upregulating kappa-OR expression of spinal T13, L1, L2, L6 and S1 DHs and in increasing both ENK and beta-EP contents of PAG (P < 0.01, PF < 0.05). No significant differences were found between the non-acupoint group and the model group in writhing latency, kappa-OR expression levels of spinal T13, L1, L2 and S1 DHs, and in ENK and beta-EP contents of PAG (P > 0.05).. EA of SP 6 can significantly alleviate pain reactions in dysmenorrhea rats, which is closely associated with its functions in upregulating spinal kappa-OR expression and ENK and beta-EP contents in PAG. EA of SP 6, GB 39 and non-acupoint has some different degrees of efficacies in relieving dysmenorrhea and in upregulating spinal K-OR expression.

Topics: Acupuncture Points; Animals; beta-Endorphin; Disease Models, Animal; Dysmenorrhea; Electroacupuncture; Enkephalins; Female; Humans; Mesencephalon; Pain Management; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Spine

Metformin is widely used in clinic for handling the diabetic disorders. However, action mechanisms of metformin remain obscure. It has recently been indicated that guanidinium derivatives are ligands to activate type-2 imidazoline receptors (I-2 receptors) that can improve diabetes through increment in skeletal muscle glucose uptake. Also, activation of I-2 receptors can increase the release of ß-endorphin in diabetic animals. Because metformin is a guanidinium derivative, we were interested in the effect of metformin on I-2 receptors. In the present study, the marked blood glucose-lowering action of metformin in streptozotocin-induced type-1 like diabetes rats was blocked by specific I-2 receptor antagonist, BU224, in a dose-dependent manner. Also, the increase of ß-endorphin release by metformin was blocked by BU224 in same manner. A specific competition between metformin and BU224 was observed in isolated adrenal medulla. Otherwise, amiloride at the dose sufficient to block I-2A receptor abolished the metformin-induced ß-endorphin release, but only the blood glucose-lowering action of metformin was markedly reduced. In addition, the blood glucose-lowering action of metformin in bilateral adrenalectomized rats was diminished by amiloride at higher doses. These results suggest that metformin might activate imidazoline I-2 receptors while I-2A receptors link the increase of ß-endorphin release and I-2B receptors couple to the other actions for lowering of blood glucose in type-1 like diabetic rats.

Topics: Animals; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Hypoglycemic Agents; Imidazoline Receptors; Male; Metformin; Rats; Rats, Wistar

Many recent researches have confirmed the effectiveness of antiepileptic drugs in preventing alcohol dependency, whereas our previous study showed that repeated treatment with topiramate, a new antiepileptic drug, was effective in increasing the plasma levels of beta-endorphin (an endogenous opioid peptide) in rats. It is well documented that in humans a genetic deficit of beta-endorphin is often associated with alcohol addiction as alcohol consumption elevates the level of this peptide. The aim of the present study is multifaceted: to investigate the effect of repeated treatment of levetiracetam (50 or 100mg/kg b.w., twice daily) on voluntary alcohol intake in alcohol preferring rats (Warsaw High Preferring; WHP) and to assess changes in plasma beta-endorphin levels while alcohol is available and when it is not available for an extended period of time. We observed a noticeable increase in the levels of beta-endorphin in rats with free access to alcohol whether in a prolonged levetiracetam-treated or vehicle-treated group. However, in the levetiracetam group, a voluntary intake of alcohol diminished in comparison with both the pretreatment period and in comparison with the vehicle-treated rats. A similar increase in the plasma beta-endorphin levels was observed in levetiracetam-treated rats that did not have access to ethanol. This finding lets us to believe that levetiracetam may be a promising medication in treatment of alcohol dependency as its application leads to the increase in the beta-endorphin concentration and ultimately results in reducing deficiency of this peptide.

Topics: Alcohol Drinking; Alcoholism; Animals; Anticonvulsants; beta-Endorphin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Ethanol; Female; Humans; Levetiracetam; Piracetam; Rats; Rats, Inbred Strains; Self Administration; Substance Withdrawal Syndrome

We have evaluated the possible underlying mechanisms of immobilization stress-induced analgesia (SIA) by behavioral cross-tolerance studies and molecular studies. In the behavioral studies, the cross-tolerance between single or repeated immobilization SIA and the antinociceptive effects of β-endorphin, morphine, 5-hydroxytryptamine (5-HT), or WIN55,212-2 were assessed. Both single and repeated (×7) immobilization stress significantly attenuated the β-endorphin and 5-hydroxytryptamine-induced antinociception in the 2nd phase of formalin response, respectively. However, these cross-tolerances disappeared in prolonged repetition of the stress (×14). Neither single nor repeated (×7 and ×14) immobilization stress affected the antinociceptive effect of morphine or WIN55,212-2 at all. We also found that immobilization stress activated hypothalamic proopiomelanocortin (POMC) gene and β-endorphin expression. Since, it has potent inhibitory activity on the noxious stimuli-induced POMC expression, immobilization stress seemed to dissipate the POMC gene expression process. Meanwhile, we did not find any changes in the opioid receptors' (mu-, delta- and kappa-receptor) and the cannabinoid receptors' (CB1 and CB2) expressions in the midbrain regions elicited by single or repeated stress. These results suggested that a single immobilization stress activates the descending pain modulatory system, which is mainly mediated through endorphinergic and serotonergic activation. Moreover, the tolerance of SIA induced by repeated stresses may be due to the prolonged activation of these systems induced by repeated immobilization.

Topics: Analgesics; Animals; Benzoxazines; beta-Endorphin; Disease Models, Animal; Inflammation; Infusions, Intraventricular; Male; Mice; Mice, Inbred ICR; Morphine; Morpholines; Naphthalenes; Pain; Receptors, Cannabinoid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Restraint, Physical; Serotonin; Stress, Physiological; Stress, Psychological

Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain. This study tests the hypothesis that regular aerobic exercise leads to sustained reversal of neuropathic pain by activating endogenous opioid-mediated pain modulatory systems.. After baseline measurements, the L5 and L6 spinal nerves of male Sprague-Dawley rats were tightly ligated. Animals were randomized to sedentary or 5-week treadmill exercise-trained groups. Thermal and tactile sensitivities were assessed 23 h after exercise, using paw withdrawal thresholds to von Frey filaments and withdrawal latencies to noxious heat. Opioid receptor antagonists were administered by subcutaneous, intrathecal, or intracerebroventricular injection. Opioid peptides were quantified using immunohistochemistry with densitometry.. Exercise training ameliorated thermal and tactile hypersensitivity in spinal nerve-ligated animals within 3 weeks. Sensory hypersensitivity returned 5 days after discontinuation of exercise training. The effects of exercise were reversed by using systemically or intracerebroventricularly administered opioid receptor antagonists and prevented by continuous infusion of naltrexone. Exercise increased β-endorphin and met-enkephalin content in the rostral ventromedial medulla and the mid-brain periaqueductal gray area.. Regular moderate aerobic exercise reversed signs of neuropathic pain and increased endogenous opioid content in brainstem regions important in pain modulation. Exercise effects were reversed by opioid receptor antagonists. These results suggest that exercise-induced reversal of neuropathic pain results from an up-regulation of endogenous opioids.

Topics: Animals; beta-Endorphin; Brain Stem; Disease Models, Animal; Enkephalin, Methionine; Male; Naltrexone; Narcotic Antagonists; Neuralgia; Pain Threshold; Physical Conditioning, Animal; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid

Endogenous β-endorphin (β-EP) in the central nervous system (CNS) is decreased upon opioid addiction. The current study examined whether exogenous β-EP, delivered using an adenoviral vector into the CNS could attenuate morphine withdrawal syndrome in rats.. The model of opioid-dependent rats was set up by receiving subcutaneous injection of morphine using an escalating regimen for 6days (5, 10, 20, 40, 50, 60mg/kg, three times/day). The adenovirus mediated β-EP gene was constructed based on our previous work. The ilea of opioid-dependent rats were isolated and treated with the supernatant of Ad-NEP. The basic and naloxone-induced (4μm/l) contractions of dependent ilea were recorded. The Ad-NEP was injected into the left lateral ventricle of the addition rats. The expression of the β-EP gene was verified by radioimmunoassay of the cerebrospinal fluid (CSF) and immunocytochemistry for β-EP. Withdrawal syndrome was evaluated after intraperitoneal injection of naloxone.. The contractions of dependent ilea were attenuated with supernatant containing β-EP expressed by Ad-NEP. Injection of the Ad-NEP resulted in significant increases in β-EP level in the CSF and β-EP-positive neurons. Rats receiving adenovirus carrying the β-EP gene had significantly less severe withdrawal symptoms upon naloxone challenge.. Exogenous β-EP mediated by adenovirus could attenuate withdrawal syndrome in morphine-dependent rats.

Topics: Acute Disease; Adenoviridae; Animals; beta-Endorphin; Disease Models, Animal; Genetic Therapy; Genetic Vectors; HEK293 Cells; Humans; Male; Morphine; Morphine Dependence; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

To explore the mechanism of acupuncture in preventing and treating stress-induced gastric mucosal injury from the view of brain-gut axis.. Forty male Wister rats were randomly divided into normal control, model 1, treatment, model 2 and prevention groups (n=8). Gastric mucosa injury model was established by intragastric perfusion of dehydrated alcohol (1.0 mL/rat). Rats of the treatment group were treated with acupuncture after modeling, while those of the prevention group treated first, followed by modeling. The time of modeling in model 1 group and model 2 group was simultaneous with that of the treatment group and prevention group respectively. Acupuncture was applied to "Zusanli"(ST 36), "Zhongwan" (CV 12) and "Neiguan" (PC 6) for 20 min, once daily for 5 days. Before sampling the tissues, 10% charcoal suspension was intragastric perfused 1 h for analyzing the rate of gastrointestinal propulsion(distance from the upper end of the charcoal powder to the cardia/total length of the cardia to the anus x 100%). Gastric mucosal ulcer index was measured by using Guth's method. The contents of beta-endorphin(beta-EP)in plasma and hypothalamus were determined by enzyme-linked immunosorbent assay.. Compared with the normal control group, the gastrointestinal propulsion rates were decreased considerably in the two model groups (P < 0.05), while the gastric mucosal ulcer indexes and the contents of beta-EP in both plasma and hypothalamus were increased significantly in the model groups (P < 0.05, P < 0.01). Compared with the corresponding model groups, the gastrointestinal propulsion rate was increased remarkably in the prevention group (P < 0.05), and the gastric mucosal ulcer indexes and the contents of plasma beta-EP level were decreased obviously in both treatment and prevention groups (P < 0.05, P < 0.01). The contents of hypothalamic beta-EP were increased further in the later two groups (P < 0.01).. Acupuncture of ST 36, CV 12 and PC 6 can promote the repair of gastric mucosal injury and improve gastrointestinal function, which may be related to its effects in reducing plasma beta-EP and upregulating hypothalamic beta-EP level. Acupuncture also has a better effect in preventing gastric mucosal injury.

Topics: Acupuncture Therapy; Animals; beta-Endorphin; Disease Models, Animal; Gastric Mucosa; Humans; Hypothalamus; Male; Rats; Rats, Wistar; Stomach Diseases; Stress, Physiological

To observe the effect of balance acupuncture on the thermal pain threshold and plasma beta-endorphin (beta-EP) and adrenocorticotrophic hormone (ACTH) levels in lumbar disc herniation rats so as to research its mechanisms underlying improvement of lumbar disc protrusion.. A total of 120 male rats were randomly divided into blank control (control) group, model group, sham-operation(sham)group, and acupuncture group (n=30) which were further divided into 7-days (d) and 14-d subgroups. Rats in the acupuncture group were treated with balance acupuncture of "Back Pain" point (the midpoint between two eyes) and "Hip Pain"point (the midpoint between the acromial process and the axillary furrow). Thermal pain threshold was detected by using radiant heat detector. Plasma beta-EP and ACTH levels were determined by radioimmunoassay.. Compared with the control group and pre-operation and sham group, the thermal pain reaction was increased significantly in the model group (P < 0.05). In comparison with the model group, the thermal pain reaction was decreased obviously from day 10 after acupuncture treatment in the acupuncture group (P < 0.05). Compared to the control group, plasma beta-EP contents on day 7 and 14 and ACTH level on day 14 in the model group were increased significantly (P < 0.05), while in comparison with the model group, plasma beta-EP contents on day 7 and 14 and ACTH level on day 14 in the acupuncture group were down-regulated markedly (P < 0.05). No significant difference were found between the control and sham groups in plasma beta-EP contents and ACTH levels on day 7 and 14 (P > 0.05).. Balance acupuncture treatment can lower plasma ACTH level in lumbar disc herniation rats, which may contribute to its effect in easing lumbar disc herniation pain in clinic practice.

Topics: Acupuncture Analgesia; Acupuncture Points; Acupuncture Therapy; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Disease Models, Animal; Humans; Intervertebral Disc Displacement; Male; Random Allocation; Rats; Rats, Sprague-Dawley

Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.

Topics: Animals; beta-Endorphin; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Endothelin-1; Endothelins; Humans; Mice; Mice, Nude; Narcotic Antagonists; Neoplasm Transplantation; Neoplasms; Nociceptors; Oligopeptides; Opioid Peptides; Pain; Peptide Fragments; Piperidines; Receptor, Endothelin B; Receptors, Opioid; Sensory Receptor Cells; Up-Regulation

Neuropathic pain is a debilitating consequence of nerve injuries and is frequently resistant to classical therapies. T lymphocytes mediate adaptive immune responses and have been suggested to generate neuropathic pain. In contrast, in this study we investigated T cells as a source of opioidergic analgesic β-endorphin for the control of augmented tactile sensitivity following neuropathy. We employed in vivo nociceptive (von Frey) testing, flow cytometry and immunofluorescence in wild-type and mice with severe combined immunodeficiency (SCID) subjected to a chronic constriction injury of the sciatic nerve. In wild-type mice, T lymphocytes constituted approximately 11% of all immune cells infiltrating the injury site, and they expressed β-endorphin and receptors for corticotropin-releasing factor (CRF), an agent releasing opioids from leukocytes. CRF applied at the nerve injury site fully reversed neuropathy-induced mechanical hypersensitivity in wild-type animals. In SCID mice, T cells expressing β-endorphin and CRF receptors were absent at the damaged nerve. Consequently, these animals had substantially reduced CRF-mediated antinociception. Importantly, the decreased antinociception was fully restored by transfer of wild-type mice-derived T lymphocytes in SCID mice. The re-established CRF antinociception could be reversed by co-injection of an antibody against β-endorphin or an opioid receptor antagonist with limited access to the central nervous system. We propose that, in response to CRF stimulation, T lymphocytes accumulating at the injured nerves utilize β-endorphin for activation of local neuronal opioid receptors to reduce neuropathy-induced mechanical hypersensitivity. Our findings reveal β-endorphin-containing T cells as a crucial component of beneficial adaptive immune responses associated with painful peripheral nerve injuries.

Topics: Analgesics; Animals; beta-Endorphin; Disease Models, Animal; Flow Cytometry; Fluorescent Antibody Technique; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Narcotic Antagonists; Neuralgia; Pain Measurement; Pain Threshold; Receptors, Corticotropin-Releasing Hormone; Sciatic Nerve; T-Lymphocytes

Protracted opiate withdrawal can extend for months of disrupted hormonal circadian rhythms. We examined rodent behaviors and these circadian disturbances in hormone and peptide levels as well as brain clock gene expression during 60 days of protracted withdrawal. Our behavioral tests included open field, elevated plus maze, and sucrose preference tests at 36 h, 10, 30, and 60 days after stopping chronic morphine. At these four assessment points, we collected samples every 4 h for 24 h to examine circadian rhythms in blood hormone and peptide levels and brain expression of rPER1, rPER2, and rPER3 clock genes. Decreased locomotor activity and elevated adrenocorticotropic hormone and melatonin levels persisted for 2 months after morphine withdrawal, but corticosterone was elevated only at 36 h and 10 days after withdrawal. Orexin levels were high at 36 h after withdrawal, but then reversed during protracted withdrawal to abnormally low levels. Beta-endorphin (β-EP) levels showed no differences from normal. However, circadian rhythms were blunted for all of these hormones. Corticosterone, adrenocorticotropic hormone, and orexin blunting persisted at least for 60 days. The blunted circadian rhythm of β-EP and melatonin recovered by day 60, but the peak phase of β-EP was delayed about 8 h. Blunted circadian rhythms and reduced expression of rPER1, rPER2, and rPER3 persisted at least for 60 days in the suprachiasmatic nucleus, prefrontal cortex, nucleus accumbens core, central nucleus of the amygdala, Hippocampus, and ventral tegmental area. Circadian rhythms of rPER1 in the nucleus accumbens shell and basolateral nucleus of the amygdala and of rPER2 in the central nucleus of the amygdala were reversed. Disrupted circadian rhythms of rPER1, rPER 2, and rPER3 expression in reward-related brain circuits and blunted circadian rhythms in peripheral hormones and peptides may play a role in protracted opiate withdrawal and contribute to relapse.

Topics: Adrenocorticotropic Hormone; Animals; Behavior, Animal; beta-Endorphin; Brain; Circadian Rhythm; Disease Models, Animal; Gene Expression Regulation; Intracellular Signaling Peptides and Proteins; Male; Maze Learning; Melatonin; Morphine; Neurobiology; Neuropeptides; Orexins; Period Circadian Proteins; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Time Factors

To investigate the effect of electroacupuncture (EA) of "Sanyinjiao" (SP 6) on the uterus in dysmenorrhea rats so as to study its underlying analgesic mechanism.. A total of 48 SD rats during diestrus were randomized into normal saline (control) group, model group and acupuncture group according to a random number table, with 16 rats in each group. Dysmenorrhea model was established by subcutaneous injection of Estradiol benzoate (0.5 mg/d on the 1st and 10th day, and 0.2 mg/d from day 2 to day 9, once daily for 10 days) and oxytocin (2 U/rat, once on day 10). Malondialdehyde (MDA) and beta-endorphin (beta-EP) contents in the uterus were detected by radioimmunoassay, and the heat shock protein 70 (HSP 70) immunoactivity of the uterus was detected by immunohistochemistry.. In comparison with the control group, MDA content in the uterus was increased significantly in the model group (P < 0.01), while the beta-EP level and the immunoactivity of HSP 70 immune-reaction (IR) positive products in the uterus decrease significantly (P < 0.01) and moderately, respectively in the model group. In comparison with the model group, uterine MDA content in the EA group was decreased significantly (P < 0.01), while uterine beta-EP level increased considerably (P < 0.01) and HSP 70 expression was upregulated to a certain degree.. EA of "Sanyinjiao" (SP 6) can reduce MDA content and upregulate beta-EP level of the uterus in rats with dysmenorrhea, which may contribute to its analgesic effect in relieving dysmenorrhea by clearing away oxygen free radicals and raising analgesic substance in the uterus.

Topics: Acupuncture Analgesia; Acupuncture Points; Animals; beta-Endorphin; Disease Models, Animal; Dysmenorrhea; Electroacupuncture; Female; Gene Expression; HSP70 Heat-Shock Proteins; Humans; Malondialdehyde; Random Allocation; Rats; Rats, Sprague-Dawley; Uterus

The timing of the measurement of biological samples (e.g. biomarkers) is not always standardized. Biomarkers are the focus of many recent studies and treatments. The purpose of this study was to determine the timing of the release of beta-endorphin (BE), a possible biomarker, after exposure to pain and/or handling stress in order to standardize measurements. Mouse plasma was collected for BE analysis following handling i.e. being picked up by the investigator, exposure to a painful (55 degrees C hot-plate), or exposure to a nonpainful stimulus (room temperature hot-plate). The groups exposed to either a painful or nonpainful stimulus released BE in response to the stimulus, but the duration of the response was longer in mice exposed to a painful stimulus than in mice exposed to a nonpainful stimulus. The BE in the mice exposed to a nonpainful stimulus peaked at 1 min and returned to baseline levels by 5 min while the BE response of the mice exposed to a painful stimulus peaked at 10 min and remained elevated for 25 min. The results of this study indicate that BE can be a biomarker for pain and handling stress, however, the timing of the measurement should differ.

Topics: Acute Disease; Animals; beta-Endorphin; Biomarkers; Disease Models, Animal; Male; Mice; Mice, Inbred DBA; Neurochemistry; Pain; Pain Measurement; Physical Stimulation; Radioimmunoassay; Reproducibility of Results; Time Factors; Up-Regulation

The endocrine response is an important component of the physiological response to blood loss. There is some variability in reported levels of certain hormones during hemorrhage such as the stress hormone adrenocorticotrophic hormone (ACTH). Therefore, the effect of two anesthetic agents, ketamine and saffan, on ACTH and beta-endorphin levels during hemorrhage was assessed in 12 minipigs. The animals were divided into two groups, group I saffan and group II ketamine (n=6). Pigs were subjected to a continuous fixed volume hemorrhage under one of the above anesthetics while spontaneously breathing. Blood pressure and heart rate responses were recorded together with beta-endorphin and ACTH levels both before and at 10, 20, 30, 40 min after the onset of bleeding. ACTH levels were higher in the ketamine-anesthetized pigs and rose significantly faster with falling blood pressure than ACTH measured in pigs under saffan anesthesia. In contrast, the hemorrhage induced beta-endorphin increase was not significantly different between the two anesthetic groups. These results indicate that choice of anesthetic agent is important when investigating the hormone response to hemorrhage and may account for the variable hormone levels in the published literature to date.

Topics: Adrenocorticotropic Hormone; Alfaxalone Alfadolone Mixture; Anesthetics; Animals; beta-Endorphin; Biomarkers; Blood Pressure; Disease Models, Animal; Heart Rate; Hemorrhage; Ketamine; Swine; Swine, Miniature; Time Factors; Up-Regulation

Opioids/opiates are commonly administered to alleviate pain, unload the heart, or decrease breathlessness in patients with advanced heart failure. As such, it is important to evaluate whether the myocardial opioidergic system is altered in cardiac disease. A hamster model of spontaneous hypertension was investigated before the development of hypertension (1 mo of age) and in the hypertensive state (10 mo of age) to evaluate the effect of prolonged hypertension on myocardial opioidergic activity. Plasma beta-endorphin was decreased before the development of hypertension and in the hypertensive state (P < 0.05). There was no change in cardiac beta-endorphin content at either time point. No differences were detected in cardiac or plasma dynorphin A, Met-enkephalin, or Leu-enkephalin, or in cardiac peptide expression of kappa- or delta-opioid receptors. mu-Opioid receptor was not detected in either model. To determine how hypertension affects myocardial opioid signaling, the ex vivo work-performing heart was used to assess the cardiac response to opioid administration in healthy hearts and those subjected to chronic hypertension. Agonists selective for the kappa- and delta-opioid receptors, but not mu-opioid receptors, induced a concentration-dependent decrease in cardiac function. The decrease in left ventricular systolic pressure on administration of the kappa-opioid receptor-selective agonist, U50488H, was attenuated in hearts from hamsters subjected to chronic, untreated hypertension (P < 0.05) compared with control. These results show that peripheral and myocardial opioid expression and signaling are altered in hypertension.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Benzamides; beta-Endorphin; Blood Pressure; Cricetinae; Cyclic AMP; Disease Models, Animal; Dynorphins; Enkephalin, Leucine; Enkephalin, Methionine; Hypertension; Hypertrophy, Left Ventricular; Myocardial Contraction; Myocardium; Piperazines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Systole; Ventricular Remodeling

Earlier studies suggest that opioid receptors in the ventral tegmental area, but not the nucleus accumbens (NAc), play a role in relapse to drug-seeking behavior. However, environmental stimuli that elicit relapse also release the endogenous opioid beta-endorphin in the NAc. Using a within-session extinction/reinstatement paradigm in rats that self-administer cocaine, we found that NAc infusions of the mu-opioid receptor (MOR) agonist DAMGO moderately reinstated responding on the cocaine-paired lever at low doses (1.0-3.0 ng/side), whereas the delta-opioid receptor (DOR) agonist DPDPE induced greater responding at higher doses (300-3000 ng/side) that also enhanced inactive lever responding. Using doses of either agonist that induced responding on only the cocaine-paired lever, we found that DAMGO-induced responding was blocked selectively by pretreatment with the MOR antagonist, CTAP, whereas DPDPE-induced responding was selectively blocked by the DOR antagonist, naltrindole. Cocaine-primed reinstatement was blocked by intra-NAc CTAP but not naltrindole, indicating a role for endogenous MOR-acting peptides in cocaine-induced reinstatement of cocaine-seeking behavior. In this regard, intra-NAc infusions of beta-endorphin (100-1000 ng/side) induced marked cocaine-seeking behavior, an effect blocked by intra-NAc pretreatment with the MOR but not DOR antagonist. Conversely, cocaine seeking elicited by the enkephalinase inhibitor thiorphan (1-10 microg/side) was blocked by naltrindole but not CTAP. MOR stimulation in more dorsal caudate-putamen sites was ineffective, whereas DPDPE infusions induced cocaine seeking. Together, these findings establish distinct roles for MOR and DOR in cocaine relapse and suggest that NAc MOR could be an important therapeutic target to neutralize the effects of endogenous beta-endorphin release on cocaine relapse.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; beta-Endorphin; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Male; Narcotic Antagonists; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Recurrence; Reward; Self Administration; Substance Withdrawal Syndrome

Experimental evidence suggests that ethanol alters the activity of the endogenous opioid peptide systems in a dose and brain-region dependent manner. These alterations may influence the processes of ethanol reward and reinforcement. Thus, it was the objective of this study to investigate the response of the 3 major opioid peptide systems (endorphins, enkephalins, and dynorphins) to acute ethanol administration, at the level of the midbrain including the ventral tegmental area (midbrain/VTA), a region important for drug, including ethanol reinforcement.. Using the in vivo microdialysis technique coupled with specific solid-phase radioimmunoassay for beta-endorphin, met-enkephalin, and dynorphin A(1-8,) changes in the extracellular concentration of theses peptides at the level of midbrain/VTA were determined at distinct time points following the administration of 0.0 (saline), 0.8, 1.2, 1.6, 2.0, and 2.4 g ethanol/kg B.Wt.. A biphasic effect of ethanol on beta-endorphin release was found, with low to medium (1.2, 1.6, and 2.0 g) but not high (2.4 g) doses of ethanol, inducing a significant increase in the dialysate content of beta-endorphin. A late increase in the dialysate content of dynorphin A(1-8) was observed in response to the 1.2 g ethanol dose. However, none of the ethanol doses tested significantly altered the content of met-enkephalin in the dialysate.. The present findings suggest that the ethanol-induced increase of beta-endorphin release at the level of midbrain/VTA may influence alcohol reinforcement.

Topics: Alcoholism; Animals; beta-Endorphin; Central Nervous System Depressants; Disease Models, Animal; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Methionine; Ethanol; Injections, Intraperitoneal; Male; Mesencephalon; Opioid Peptides; Peptide Fragments; Rats; Rats, Sprague-Dawley; Time Factors; Ventral Tegmental Area

In an attempt to clarify the role of endogenous opioid in peripheral I2-imidazoline receptors activation for improvement of insulin action, bilateral adrenalectomy was carried out in rats with insulin resistance induced by 4-week fructose-rich chow feeding. Single intravenous (i.v.) injection of agmatine (1mg/kg) for 30 min increased the plasma beta-endorphin-like immunoreactivity (BER) in a way parallel to the reduction of plasma glucose in sham-operated fructose chow-fed rats; this action of agmatine was totally abolished by BU224 at sufficient dosage (1mg/kg, i.v.) to block I2-imidazoline receptors. The plasma glucose lowering effect of agmatine was markedly reduced but not totally deleted by adrenalectomy in fructose chow-fed rats. A direct effect of agmatine on glucose homeostasis can thus be considered. The hyperinsulinemic-euglycemic clamp technique was performed to evaluate insulin sensitivity. The effect of agmatine on elevation of the average rate of glucose infusion at the glucose clamp steady state in sham-operated fructose chow-fed rats was lessen in adrenalectomized fructose chow-fed rats, but was completely abolished by BU224. The obtained results suggest that the improvement of insulin sensitivity by agmatine is produced by two mechanisms, stimulation of adrenal gland to enhance beta-endorphin secretion and a direct activation of peripheral I2-imidazoline receptor in tissues, for the amelioration of insulin action.

Topics: Adrenalectomy; Agmatine; Analysis of Variance; Animals; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fructose; Glucose Clamp Technique; Hypoglycemic Agents; Imidazoles; Imidazoline Receptors; Insulin; Insulin Resistance; Male; Rats; Rats, Wistar

Opioid analgesics are generally used to combat the pain associated with cancerous conditions. These agents not only inhibit respiratory function and cause constipation, but also induce other significant side effects such as addiction and tolerance, all of which further contribute to a reduced quality of life for cancer patients. Thus, in the present study, the effects of electro-acupuncture treatment (EA) on mechanical allodynia were examined in a cancer pain mouse model.. In order to produce a neuropathic cancer pain model, S-180 sarcoma cells were inoculated around the sciatic nerve of left legs of Balb/c mice. Magnetic Resonance Imaging (MRI) scanning confirmed the mass of S-180 cancer cells embedded around the sciatic nerve. Mechanical allodynia was most consistently induced in the mouse sarcoma cell line S-180 (2 x 10(6)sarcoma cells)-treated group compared to all the other groups studied. EA stimulation (2 Hz) was administered daily to ST36 (Zusanli) of S-180 bearing mice for 30 min for 9 days after S-180 inoculation.. EA treatment significantly prolonged paw withdrawal latency from 5 days after inoculation. It also shortened the cumulative lifting duration from 7 days after inoculation, compared to the tumor control. Also, the overexpression of pain peptide substance P in the dorsal horn of the spinal cord was significantly decreased in the EA-treated group compared to the tumor control on Day 9 post inoculation. Furthermore, EA treatment effectively increased the concentration of beta-endorphin in blood and brain samples of the mice to a greater extent than that of the tumor control as well as the normal group. The concentration of beta-endorphin for EA treatment group increased by 51.457% in the blood and 12.6% in the brain respectively, compared to the tumor control group.. The findings of this study suggest that a S-180 cancer pain model is useful as a consistent and short time animal model. It also indicated that EA treatment could be used as an alternative therapeutic method for cancer pain due to a consequent decrease in substance P and increase in beta-endorphin levels.

Topics: Acupuncture Analgesia; Animals; beta-Endorphin; Cell Line, Tumor; Disease Models, Animal; Electroacupuncture; Immunohistochemistry; Male; Mice; Neurotransmitter Agents; Pain Threshold; Sarcoma 180; Sciatic Nerve; Substance P

Cancer pain impairs the quality of life of cancer patients, but opioid analgesics can not only cause inhibition of respiratory function, and constipation, but also other significant side effects such as addiction and tolerance that further decrease quality of life. Thus, in the present study, the effects of electro-acupuncture treatment (EA) on mechanical allodynia were examined in cancer pain mouse model. In order to induce neuropathic cancer pain model, S-180 sarcoma cells were inoculated around the sciatic nerve of left legs of Balb/c mice. The mass of S-180 cancer cells embedded around sciatic nerve in a time course was confirmed by Magnetic Resonance Imaging (MRI) scanning. Mechanical allodynia was most consistently induced in mouse sarcoma cell line S-180 (2 x 10(6) sarcoma cells) treated group among all groups. EA stimulation (2Hz) was daily given to ST36 (Zusanli) of S-180 bearing mice for 30 min for 9 days after S-180 inoculation. EA treatment significantly prolonged paw withdrawal latency from 5 days after inoculation as well as shortened cumulative lifting duration from 7 days after inoculation compared with tumor control. In addition, the overexpressions of pain peptide substance P in dorsal horn of spinal cord were significantly decreased in EA treated group compared with tumor control on Day 9 after inoculation. Furthermore, EA treatment effectively increased the concentration of beta endorphin in blood and brain of mice more than tumor control as well as normal group. The concentration of beta-endorphin for EA treatment group increased by 51.457% in blood 12.6% in brain respectively, compared with tumor control group. These findings suggest that S-180 cancer pain model can be a consistent and short time animal model and also EA treatment can be an alternative therapeutic method for cancer pain via decreased substance P and increased beta endorphin.

Topics: Acupuncture Analgesia; Acupuncture Points; Animals; beta-Endorphin; Cell Line, Tumor; Disease Models, Animal; Electroacupuncture; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasms; Pain; Pain Management; Pain Threshold; Substance P

To observe the analgesic effect of heat-reinforcing needling manipulation for acute inflammatory arthritis and its underlying mechanism in experimental rheumatoid arthritis rabbits.. A total of 60 rabbits were randomized into control (n=6), model (n=6), needle-twirling (n=24) and heat-reinforcing (n=24) groups, and the later 2 groups were further divided into 0 h, 0.5 h, 1 h and 2 h subgroups,with 6 cases in each. Rheumatoid arthritis model was established by injecting mixed solution of egg-albumin (4 mg/ml) and equal volume of complete Freund's adjuvant (CFA) into the subcutaneous tissue (6 points around the shoulder, 0.2 ml/point). Fourteen days later,the injection was repeated once again,and another 6 days later, egg-albumin (0.4 ml, 20 mg/ml) solution was injected into the bilateral knee-joints. "Zusanli" (ST 36) and "Hegu" (LI 4) were punctured and stimulated by needle-twirling or by heat-reinforcing needling technique for 1 min, with the needle retained for 30 min. The pain threshold of the paw was detected with K+ import stimulation method. beta-EP and PGE2 contents of the joint tissue were assayed with radioimmunoassay.. Compared with model group, the pain threshold of needle-twirling group and heat-reinforcing group at each time-point increased significantly (P<0.01, P<0.05). Compared with needle-twirling group, the pain threshold of heat-reinforcing group at 0.5 h, 1 h and 2 h subgroups increased significantly (P<0.05, P<0.01). Both beta-EP and PGE2 contents of model group were significantly higher than those of control group (P<0.01, P<0.05). In comparison with model group, beta-EP contents of needle-twirling group and heat-reinforcing group at each time-point increased significantly (P<0.01, P<0.05), and PGE2 contents of needle-twirling group and heat-reinforcing group at each time-point decreased significantly (P<0.01, P<0.05). The beta-EP content of heat-reinforcing group was significantly higher than that of needle-twirling group at 2 h (P<0.05), while PGE2 content of the former group was significantly lower than that of needle-twirling group at 0 h (P<0.01).. Both needle-twirling and heat-reinforcing needling can effectively raise the pain threshold in acute arthritis rabbits, which my be closely associated with their effects in upregulating beta-EP content and lowering PGE2 level in the local joint tissue. The analgesic effect of heat-reinforcing needling manipulation is superior to that of needle-twirling.

Topics: Acupuncture Analgesia; Acupuncture Points; Animals; Arthritis; beta-Endorphin; Dinoprostone; Disease Models, Animal; Female; Humans; Joints; Male; Rabbits; Random Allocation

Experimental evidence indicates that the endogenous opioid system influences stress responses as well as reinforces effects of addictive drugs. Because stress is an important factor contributing to drug dependence and relapse, we have now studied ethanol preference in enkephalin- and beta-endorphin-deficient mice under baseline conditions and after stress exposure.. In the present study we used a two-bottle choice paradigm to study ethanol consumption and stress-induced ethanol preference. To examine alcohol withdrawal symptoms the forced drinking procedure was employed. We performed an association analysis in two case-control samples of alcohol addicts to determine whether these opioid peptides also contribute to ethanol dependence in humans.. Ethanol consumption was significantly reduced in the absence of beta-endorphins, particularly in female knockout animals. Stress exposure results in an increased ethanol consumption in wild-type mice but did not influence ethanol-drinking in beta-endorphin knockouts. Enkephalin-deficient mice showed no difference from wild-type mice in baseline ethanol preference but also showed no stress-induced elevation of ethanol consumption. Interestingly, we found a two-marker haplotype in the POMC gene that was associated with alcohol dependence in females in both cohorts.. Together these results indicate a contribution of beta-endorphin to ethanol consumption and dependence.

Topics: Adult; Alcohol Drinking; Alcoholism; Animals; beta-Endorphin; Body Weight; Choice Behavior; Disease Models, Animal; Enkephalins; Female; Food Preferences; Gene Frequency; Genotype; Humans; Linkage Disequilibrium; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Polymorphism, Single Nucleotide; Pro-Opiomelanocortin; Sex Characteristics; Stress, Psychological

Given that stressful experiences can change the reaction to a subsequent exposure to stress, we tested the in vitro effects of the stress mediator corticosterone and the opioid peptide beta-endorphin on the function of macrophages isolated from control rats and from rats exposed to electric tail shock stress (ES) or a stress-witnessing procedure (SW) 24 h earlier.. Peritoneal macrophages isolated from control and stressed rats of the Dark Agouti (DA) strain were treated in vitro with corticosterone or beta-endorphin and tested for adherence, phagocytosis and hydrogen peroxide release.. ES diminished adherence and SW decreased phagocytosis. The suppressive effect of corticosterone on phagocytosis was absent in rats exposed to ES and SW, while the suppressive effect of beta-endorphin on adherence was not observed in rats exposed to SW. ES and SW did not affect H(2)O(2) release, neither directly nor indirectly by changing macrophage response to corticosterone and beta-endorphin in this test.. In DA rats early macrophage activation steps, i.e. adherence and phagocytosis, were more sensitive to stress than their effector function, corresponding to H(2)O(2) production. We suggest that neuroendocrine mediators of stress that converge on macrophages might have changed specific macrophage receptors or postreceptor events and alter their response to artificial stressors, represented by corticosterone and beta-endorphin in vitro.

Topics: Acute Disease; Animals; beta-Endorphin; Cell Adhesion; Cell Separation; Cells, Cultured; Chemotaxis, Leukocyte; Corticosterone; Disease Models, Animal; Electroshock; Hydrogen Peroxide; Immune System; Immune Tolerance; Immunologic Factors; Immunosuppressive Agents; Macrophages, Peritoneal; Male; Neuroimmunomodulation; Neurosecretory Systems; Phagocytosis; Rats; Species Specificity; Stress, Psychological

Little is known about effects of naloxone, an opiate receptor antagonist, upon experimental autoimmune myocarditis (EAM) in mice. The aim of the present study was to test the effects of naloxone upon EAM in mice. Four-week-old C57BL/6 mice were injected with porcine cardiac myosin. Naloxone 1 mg/kg/day was given intraperitoneally daily on days 0 to 21 in experiment I (acute stage) and on days 21 to 42 in experiment II (chronic stage). For the analysis of endogenous opiate and neurohumoral system, plasma beta-endorphin and cytokines were measured. The cytotoxic activity of lymphocytes was determined by Cr-release assay. Naloxone reversed hypotension produced by massive myocardial injury in experiment I. In experiment I, the severity of cardiac pathology and inflammatory cytokines were decreased in the naloxone-treated group associated with higher beta-endorphin level compared with the untreated group. In addition, naloxone induced a shift from Th1 cytokine toward Th2 cytokine balance. Thus, cytotoxic activities of lymphocytes against EL-4 tumor cells were lower in the treated group than in the untreated group in experiment I, but not in experiment II. Naloxone is beneficial for heart failure caused by EAM in the acute stage, but not in the chronic stage, due to decreasing cytotoxic activities of lymphocytes and to its neurohumoral modulating effects.

Topics: Acute Disease; Animals; Autoimmune Diseases; beta-Endorphin; Cell Line, Tumor; Cytokines; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Disease Models, Animal; Erythrocytes; Mice; Mice, Inbred C57BL; Myocarditis; Myocardium; Naloxone; Narcotic Antagonists; Radioimmunoassay

Our previous studies have shown that repeated acamprosate administration to ethanol-naive Warsaw high preferring (WHP) rats resulted in increased plasma beta-endorphin levels and at least partially prevents increases in levels of this peptide after a single administration of ethanol compared with untreated control rats. The objective of the present study, which included 45 WHP rats, was to continue the past research and investigate the effect of 10-day acamprosate treatment (200 mg/kg p.o.) on alcohol intake using a free-choice procedure and on changes in plasma beta-endorphin levels while alcohol is available, and 10 days after alcohol withdrawal. Voluntary alcohol consumption increases plasma levels of beta-endorphin from 440+/-25 pg/ml to 711+/-57 pg/ml (p=0.0002). After a 10-day of alcohol withdrawal, the levels of this peptide were significantly reduced compared with levels in rats with free access to ethanol (711+/-57 pg/ml vs. 294+/-38 pg/ml, p=0.000001) and in control naive rats (440+/-25pg/ml vs. 294+/-38pg/ml, p=0.044). Chronic treatment with acamprosate increased plasma beta-endorphin levels both in WHP rats with free access to ethanol (440+/-25 pg/ml vs. 616+/-49 pg/ml, p=0.008) and in rats after ethanol withdrawal (440+/-25 pg/ml vs. 620+/-56 pg/ml, p=0.007). In the group with free access to ethanol, there was a significant reduction in mean ethanol intake, from 6.75+/-0.20 g/kg body weight/day to 4.68+/-0.25 g/kg/day. Our results indicate that chronic acamprosate treatment may have beneficial effects, as it increases the beta-endorphin concentration thereby compensating for beta-endorphin deficiency during ethanol withdrawal. As the endogenous opioid system has an important role in the development of craving for alcohol, restoring the alcohol-induced deficits in beta-endorphin levels may be an important factor to prevent craving and maintaining abstinence. We suppose that the anti-craving mechanism of acamprosate that has been reported to abolish excessive glutamate release during alcohol withdrawal may be accompanied by compensation for the beta-endorphin deficiency.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Animals; Behavior, Animal; beta-Endorphin; Disease Models, Animal; Ethanol; Female; Rats; Taurine; Time Factors

Lumbar puncture (LP) is an attractive route to deliver drugs to the nervous system because it is a safe bedside procedure. Its use for gene therapy has been complicated by poor vector performance and failure to target neurons. Here we report highly effective gene transfer to the primary sensory neurons of the dorsal root ganglia (DRGs) with self-complementary recombinant adeno-associated virus serotype 8 (sc-rAAV8) modeling an LP. Transgene expression was selective for these neurons outlining their cell bodies in the DRGs and their axons projecting into the spinal cord. Immunohistochemical studies demonstrated transduction of cells positive for the nociceptive neuron marker vanilloid receptor subtype 1, the small peptidergic neuron markers substance P and calcitonin gene-related peptide, and the nonpeptidergic neuron marker griffonia simplicifolia isolectin B4. We tested the efficacy of the approach in a rat model of chronic neuropathic pain. A single administration of sc-rAAV8 expressing the analgesic gene prepro-beta-endorphin (ppbetaEP) led to significant (P < 0.0001) reversal of mechanical allodynia for >/=3 months. The antiallodynic effect could be reversed by the mu-opioid antagonist naloxone 4 months after gene transfer (P < 0.001). Testing of an alternative nonopioid analgesic gene, IL-10, alone or in combination with ppbetaEP was equally effective (P < 0.0001). All aspects of the procedure, such as the use of an atraumatic injection technique, isotonic diluent, a low-infusion pressure, and a small injection volume, are consistent with clinical practice of intrathecal drug use. Therefore, gene transfer by LP may be suitable for developing gene therapy-based treatments for chronic pain.

Topics: Animals; beta-Endorphin; Chronic Disease; Dependovirus; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Immunohistochemistry; Kinetics; Male; Neurons, Afferent; Pain; Pain Management; Peripheral Nervous System Diseases; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Spinal Puncture

It is well known that alcohol consumption leads to an increase in the levels of beta-endorphin (an endogenous opioid), which can contribute to the reinforcing effect of alcohol. Our previous studies have shown that repeated treatment with naltrexone, a nonselective opioid antagonist, results in increased plasma beta-endorphin levels. Ample studies in animals and humans have shown that naltrexone diminishes ethanol consumption. The aim of the present study in alcohol-preferring rats (Warsaw High Preferring; WHP) was to investigate the effect of 10 days of naltrexone treatment (2 mg/kg i.p.) on voluntary alcohol intake and on changes in plasma beta-endorphin levels while alcohol was available and 10 days after imposed abstinence. It was observed that voluntary alcohol intake induces an increase in plasma beta-endorphin levels in WHP rats. After a 10-day period of alcohol withdrawal, the levels of this peptide were significantly reduced compared with the levels in rats with free access to ethanol and in control alcohol-naïve rats. In chronic naltrexone-treated rats with free access to alcohol, an increase in the levels of this peptide was also observed; however, voluntary alcohol intake was diminished. A similar increase in plasma beta-endorphin levels was observed in naltrexone-treated rats that did not have access to ethanol. As the endogenous opioid system has an important role in the development of a craving for alcohol, it is likely that chronic naltrexone treatment may have a beneficial effect leading to a compensatory increase in the beta-endorphin concentration and ameliorating its deficiency during ethanol withdrawal. Restoring the alcohol-induced deficiency of beta-endorphin may be an important factor in the prevention of craving and maintenance of abstinence. This finding supports the proposition that the endogenous opioid system plays an important role in developing a craving for alcohol.

Topics: Alcohol Drinking; Alcoholism; Analysis of Variance; Animals; Behavior, Animal; beta-Endorphin; Central Nervous System Depressants; Disease Models, Animal; Ethanol; Female; Naltrexone; Narcotic Antagonists; Rats; Time Factors

Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective mu-opioid receptor agonist [d-Ala(2), N-MePhe(4), Gly-ol(5)] enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5'-o-(3-[(35)S]thio) triphosphate ([(35)S]GTPgammaS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the beta-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous mu-opioid peptide beta-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous beta-endorphin to cause the dysfunction of mu-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.

Topics: Analysis of Variance; Animals; Behavior, Animal; beta-Endorphin; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Knockout; Morphine; Narcotics; Pain Measurement; Protein Binding; Reaction Time; Reward; Sciatica; Time Factors; Tyrosine 3-Monooxygenase

To explore the possible central and peripheral mechanisms of connexin 43 gene knockout in acupuncture analgesia.. Fifty-four wide type (WT) mice and 54 connexin 43 gene knockout (heterozygote, HT) mice were randomly divided into WT control group, WT model group, WT acupuncture group, HT control group, HT model group and HT acupuncture group (n = 18/group). Visceral pain model was established by intraperitoneal injection of 0.6% acetic acid (0. 1 mL/10 g). "Zhongwan" (CV 12) and bilateral "Zusanli" (ST 36) were punctured with filiform needles and stimulated for 30 min by manipulating the needle for 30 s every 5 min. The latency and the number of body-writhing response were observed and the contents of beta-endorphin (beta-EP) in hypothalamus and serum prostaglandin E2 (PGE2) were detected with radioimmunoassay (RIA).. There was no significant difference in the latency and the number of body-writhing response, and contents of hypothalamic beta-EP and serum PGE2 between HT and WT control groups (P > 0.05). Compared with the corresponding control groups, the latency of body-writhing in WT model and HT model groups shortened significantly and the number of body- writhing increased considerably in two model groups (P < 0.01). While in comparison with WT model group, the latency of body-writhing prolonged significantly and the number of body-writhing decreased apparently in WT acupuncture group (P < 0.01); but no marked differences were found between HT model and HT acupuncture groups in these two indexes (P > 0.05). Compared with the corresponding control groups, the contents of both beta-EP and PGE2 increased obviously in WT model and HT model groups (P < 0.05). In comparison with WT model group, beta-EP levels in WT acupuncture group increased further significantly (P < 0.05), and serum PGE2 in WT acupuncture group decreased obviously (P < 0.05); but no significant changes were found between HT model and HT acupuncture groups in beta-EP and PGE2 levels (P > 0.05).. Acupuncture has a marked antinociceptive effect in WT mice with visceral pain, which may be related to its effects in increasing hypothalamic beta-EP and decreasing serum PGE2; while in connexin 43 gene knockout mice, all the above-mentioned effects of acupuncture are eliminated, indicating an important role of connexin 43 in the analgesic effect of acupuncture.

Topics: Acetic Acid; Acupuncture Analgesia; Animals; beta-Endorphin; Connexin 43; Dinoprostone; Disease Models, Animal; Female; Male; Mice; Mice, Knockout; Pain Management; Radioimmunoassay; Random Allocation; Viscera

To observe the expression of beta-endorphin and micro-opioid receptor (MOR) during wound healing process in rat with deep partial-thickness scald.. Thirty-six Wistar rats were randomly divided into control( n = 6, without treatment) , and scald ( n = 30, with 5% TBSA deep-partial thickness scald) groups. Skin specimens from wound were harvested immediately after scald and on 3, 7, 14, 21 post-scald days( PSD) for the determination of 1-endorphin and MOR expression with immunofluorescent staining.. beta-endorphin and MOR were mainly distributed in nerve terminal at the border of dermis and epidermis , keratinocyte in some epidermis , in the fibroblast in dermis , with a weak expression The expression of beta-endorphin peaked in whole layer of skin on 3 PSD( 196 +/-16, P <0. 01) ,while that of MOR was concentrated in keratinocytes in the basal layer and the basement membrane. The expression of MOR was strengthened on 7 PSD with disarrangement of collagen , and it peaked on 14 PSD (306 +/- 23, P < 0.01) with epithelization in some wounds. There was still strong expression of beta-endorphin on 7 and 14 PSD. Complete epithelization was observed in scald group on 21 PSD, with nerve terminal approaching the boundary between the dermis and epidermis, and collagen began to arrange in good order. The expression of P-endorphin in scald group (31 +/-24)was similar to that in control group(30 +/- 18) on 21 PSD, but the expression of MOR (56 +/- 16) was still higher than that in control group (28 +/- 15 ).. The expression of MOR and P-endorphin exhibits chronobiological nature during the process of wound healing,

Topics: Animals; beta-Endorphin; Burns; Disease Models, Animal; Male; Random Allocation; Rats; Rats, Wistar; Receptors, Opioid, mu; Wound Healing

Both obesity and increased endorphin production are associated with an increase in blood pressure. We have previously demonstrated that the acute and chronic central nervous system (CNS) administration of beta-endorphin can increase or decrease blood pressure, respectively. Also high fat (HF) diet-induced obesity is associated with increased hypothalamic mu opioid receptors and increased blood pressure in response to ss-endorphins. In this study we investigated the effect of high fat diet-induced obesity on blood pressure, heart rate, and physical activity as well as determined the effect of mu opioids in unanesthetized rats. Male Wistar rats were implanted with a radiotelemetry transmitter to record cardiovascular dynamics and activity. They were fed either a HF diet (HF; 59% fat by caloric content, soy bean oil) or regular chow (control; 12% fat by caloric content). HF rats had higher body weights and their total caloric intake was greater than controls. The systolic blood pressures (SBP) were greater in the HF-obese rats. After 12-13 weeks the rats were infused chronically with a mu opioid agonist (D)-Ala(2), N-Me-Phe(4), Gly(5)-ol]-ENKEPHALIN (DAMGO) or a mu opioid antagonist ss-funaltrexamine (beta-FNA) via intracerebroventricular cannula. DAMGO increased the SBP and heart rate in controls, but not in HF obese rats. DAMGO did not affect physical activity; beta-FNA decreased SBP and increased HR in controls. We concluded that HF rats consumed more calories, gained more weight, and had higher SBP. However, the responsiveness to the mu-receptor agonist was not higher in the HF rats.

Topics: Animals; beta-Endorphin; Blood Pressure; Body Weight; Consciousness; Dietary Fats; Disease Models, Animal; Follow-Up Studies; Heart Rate; Male; Motor Activity; Neurotransmitter Agents; Obesity; Rats; Rats, Wistar; Receptors, Opioid, mu

Sleep-wake disturbances and stress hyper-responsiveness have been observed in human neonates, children and adolescents who were exposed to alcohol during the prenatal period. Using the laboratory rat as an animal model, we investigated whether fetal ethanol exposure during gestational days 10-21 affects the circadian function of the stress-axis regulatory beta-endorphin neurons in the hypothalamus. Fetal ethanol-exposed rats showed abnormality in the circadian expression of proopiomelanocortin (POMC) mRNA encoding the peptide beta-endorphin in the arcuate nucleus of the hypothalamus during the adult period. These rats also showed altered circadian expression of the clock governing Period genes rPer1, rPer2 and rPer3, in the arcuate nucleus, and rPer1 and rPer 2 mRNA levels in the suprachiasmatic nucleus. Laser captured microdissection analysis identified constitutive expression of rPer1, rPer2 and rPer3 genes in beta-endorphin-containing neurons. These data suggest for the first time that fetal exposure to ethanol significantly alters the clock mechanisms governing the circadian function of beta-endorphin neurons.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Animals, Newborn; beta-Endorphin; Cell Cycle Proteins; Central Nervous System Depressants; Chronobiology Disorders; Disease Models, Animal; Ethanol; Female; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Hypothalamus; Male; Neurons; Nuclear Proteins; Period Circadian Proteins; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sleep Wake Disorders; Stress, Physiological

Acute nicotine administration has been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis and stimulate secretion of adrenocorticotrophic hormone (ACTH), corticosterone/cortisol and beta-endorphin (beta-END) in both rodents and humans, raising the possibility that activation of the HPA axis by nicotine may mediate some of the effects of nicotine. Since stress can increase the risk of drug use and abuse, we hypothesized that repeated stress would increase the ability of nicotine to stimulate the secretion of HPA hormones. To test our hypothesis, mice were exposed to repeated stress (swimming in 15 degrees C water for 3 min/day for 5 days) and killed 15 min after injection of saline or nicotine (0.1 mg/kg, s.c.). Repeated exposure to stress increased the ability of nicotine to stimulate plasma ACTH (p<0.05) and beta-END (p<0.05), but not corticosterone secretion. In contrast, repeated exposure to stress increased the post-saline injection levels of corticosterone (p<0.05), but not ACTH and beta-END. The present results suggest that chronic stress leads to an enhanced sensitivity of some components of the HPA axis to a subsequent nicotine challenge.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Chronic Disease; Corticosterone; Disease Models, Animal; Hypothalamo-Hypophyseal System; Male; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Agonists; Pituitary-Adrenal System; Stress, Psychological; Tobacco Use Disorder

The immunomodulatory properties of melatonin (Mel) are generally recognized but the mechanisms of its action are not fully understood. In mammals, some of the immunomodulatory effects of Mel are mediated by opioids synthesized by immune cells under its influence. The present study was performed to examine whether Mel-induced opioids are involved in the immunomodulatory activity of Mel in chickens. Experimental peritonitis was evoked by a single ip injection of thioglycollate (TG), and half of the birds were pre-treated with Mel. Some of the Mel-treated birds were additionally pre-treated with naltrexone, an antagonist of opioid receptors. Control birds received an injection of saline, Mel or were untreated. At specific post-injection intervals chickens were sacrificed, the peritoneal cavity was flushed out and peritoneal leukocytes (PTLs) were counted. The activity of PTLs was measured in vitro by the level of reactive oxygen species (ROS). Splenocytes were isolated aseptically and mitogen-stimulated in vitro proliferation was assessed. In PTLs and splenocytes the expression of opioid (proopiomelanocortin and proenkephalin) genes was also examined. Mel exerted a bi-phasic effect on TG-induced peritonitis in chickens: initially it blocked the development of peritonitis, decreasing the number of PTLs and intracellular ROS level (anti-inflammatory action), and thereafter an increase in both PTL number and ROS level was observed (pro-inflammatory action). The pro-inflammatory effect occurred a few hours after the induction of expression of the proenkephalin gene in PTLs and both the proenkephalin and proopiomelanocortin genes in splenocytes. These effects were prevented by naltrexone, suggesting involvement of the opiatergic mechanism.

Topics: Adjuvants, Immunologic; Animals; beta-Endorphin; Cell Proliferation; Chickens; Disease Models, Animal; Enkephalins; Gene Expression; Macrophages, Peritoneal; Male; Melatonin; Naltrexone; Narcotic Antagonists; Opioid Peptides; Peritonitis; Pro-Opiomelanocortin; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spleen; Thioglycolates

To observe the multiple immunoregulating effects of beta-endorphin (beta-END) on synovium cells of collagen-induced arthritis (CIA) in rats and to determine whether the regulation involves the transcriptional factor-kappaB (NF-kappaB) signal pathway.. CIA was induced in female Wistar rats by immunization with native bovine type-II collagen emulsified with complete Freund's adjuvant. Synovial cells in the knees of the CIA rats were cultivated, and the effects of beta-END, beta-END receptor inhibitor (naloxone, Nal) in proliferation and apoptosis of the synovial cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, flow cytometry, and DNA integrity, respectively. The effects of beta-END and Nal on mRNA expression of several cytokines in the synovial cells, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, regulated upon activation normal T-cell expressed and secreted (RANTES), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2) and MMP-9 were estimated by quantitative reverse transcription-polymerase chain reaction. Effects of beta-END and Nal on NF-kappaB activity were analyzed using luciferase gene reporter assays. The effects of beta-END and Nal on p65NF-kappaB expression of the synovial cells were examined using Western blot.. 75% of the rats were demonstrated to have established the CIA model successfully. beta-END was shown to exert multiple effects on synovial cells of CIA rats including decreased proliferation, induced apoptosis, and downregulation of TNF-alpha, IL-1beta, IL-6, RANTES, iNOS, MMP-2 and MMP-9 mRNA expression. beta-END seemed to play an immunoregulating role by downregulating the activity and expression of NF-kappaB. It was found that the beta-END receptor blockage could counteract all the effects.. beta-END ameliorates synovial cell functions of CIA rats through binding with receptors and downregulating the NF-kappaB signal pathway. This suggests that beta-END, by blocking the activity and expression of NF-kappaB, is a potential anti-inflammatory and anti-rheumatic agent against CIA.

Topics: Analysis of Variance; Animals; Apoptosis; Arthritis; Arthritis, Experimental; beta-Endorphin; Cell Proliferation; Cells, Cultured; Chemokine CCL5; Collagen Type III; Cytokines; Disease Models, Animal; DNA Fragmentation; Dose-Response Relationship, Drug; Down-Regulation; Drug Interactions; Female; Flow Cytometry; Naloxone; NF-kappa B; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Synovial Membrane; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha

The aim of this study was to evaluate the beta-endorphin (beta-endorphin) plasma level in Warsaw Low Preferring (WLP) and Warsaw high-preferring (WHP) rats after repeated administration of acamprosate, one of most effective drug in the treatment of alcoholism. Treatment with acamprosate in dose 200mg/kg, p.o. for 10 days induced an increase in plasma beta-endorphin levels. A single injection of ethanol also results in the increase of beta-endorphin level. Moreover, it was found that single injection of ethanol to WHP rats resulted in lower increase of plasma beta-endorphin content in rats earlier treated with acamprosate. In WLP rats, repeated acamprosate treatment prevents the ethanol-induced increase in plasma beta-endorphin level. It may be concluded that acamprosate modulates the endogenous opioid system.

Topics: Acamprosate; Alcohol Deterrents; Alcohol-Induced Disorders, Nervous System; Alcoholism; Animals; beta-Endorphin; Brain; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Ethanol; Female; Genetic Predisposition to Disease; Opioid Peptides; Rats; Taurine; Treatment Outcome; Up-Regulation

Opioid peptides and glycyl-glutamine (Gly-Gln) have been implicated in the control of ethanol consumption. A recognized beta-endorphin cleavage product, Gly-Gln, inhibits voluntary alcohol consumption when microinjected into the nucleus accumbens (AcbSh) of P rats. To evaluate the site-specific efficacy of Gly-Gln on ethanol consumption following AcbSh application, ethanol preferring (P) rats were allowed to establish individual baseline ethanol/water consumption utilizing a voluntary self-administration paradigm. Subsequent to baseline ethanol consumption being established, bilateral guide cannulae were stereotaxically implanted +1 mm dorsal to the AcbSh for subsequent Gly-Gln (100 nmol/microl) or saline vehicle (1 microl) injections. Alcohol intake, body weight, and water intake were measured at 24 h post-injection intervals. Unilateral Gly-Gln injections reduced ethanol consumption 35.6% (P < 0.05) from pre-established baseline consumption (6.24 +/- 0.64 g/kg to 4.06 +/- 0.28 g/kg). Bilateral Gly-Gln injections further reduced consumption to 51.9% (6.4 +/- 1.0 g/kg to 3.08 +/- 0.65 g/kg at 24 h (P < 0.01) below established baseline values within 24 h without significant changes in body weight or water consumption. Also, the amino acid constituents of the dipeptide had no influence on ethanol consumption behavior; however, Gly-Gln efficacy was shown to be comparable to central beta-endorphin-(1-27) or intraperitoneal (i.p.) naltrexone-induced suppression of ethanol intake. These data indicate that the AcbSh exhibits a site-specific sensitivity to the suppressive actions of Gly-Gln or beta-endorphin-(1-27) injections that modulate voluntary ethanol consumption in P rats. These findings support the broader concept that select forebrain opioid-responsive neural sites may influence the development or expression of alcohol abuse syndromes in animal models or humans.

Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Animals; beta-Endorphin; Central Nervous System Depressants; Dipeptides; Disease Models, Animal; Ethanol; Genetic Predisposition to Disease; Narcotic Antagonists; Nucleus Accumbens; Rats; Rats, Mutant Strains; Receptors, Opioid

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Disease Models, Animal; Dogs; Electric Stimulation; Female; Humans; Male; Spinal Cord Injuries; Spinal Cord Neoplasms

To observe the effects and mechanisms of beta-endorphin (beta-END) preventing collagen induced arthritis (CIA) by neuroimmuno-regulating pathway.. Female wistar (Ws) rats were used in this study. CIA was induced by Native bovine type II collagen emulsified with complete Freund's adjuvant (CFA). Beta-END was administered i.p. to CIA rats every other day from the 14th day (secondary immunization) to the 35th day after primary immunization. Clinical assessments were performed by two independent, blinded examiners every other day. Pathological and radiological observations were taken on the 35th day after the primary immunization. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), regulated upon activation, normal T-cell expressed and secreted (RANTES), inducible NO syntheses (iNOS), matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA expression of synovium tissues of CIA rats was estimated by quantitative RT-PCR. The frequency of spleen Th1 and Th2 cells were assessed by fluorescence activated cell sorter (FACS) assay.. Clinical manifestation of rats with CIA were significantly abrogated or ameliorated by treatment with beta-END. Beta-END treatment in vivo could down-regulate mRNA expression of several pro-inflammatory cytokines, chemokines and MMPs in CIA synovial, and polarize Th1/Th2 balance to Th2.. Beta-END alleviates CIA through both depressing Th1 responses and down-regulating proinflammatory and other rheumatic factors, suggesting beta-END is a promising anti-inflammatory and anti-rheumatic agent in treating CIA.

Topics: Analysis of Variance; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; beta-Endorphin; Chemokine CCL5; Collagen; Cytokines; Disease Models, Animal; Down-Regulation; Female; Interleukin-1; Interleukin-6; Lymphocyte Count; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neuroimmunomodulation; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; RNA, Messenger; Severity of Illness Index; Single-Blind Method; Spleen; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha

To determine separately the effect of corticotropin-releasing hormone (CRH) on analgesia and on inflammation, rats were assigned to receive CRH 60 microg/kg, CRH 300 microg/kg, morphine 4 mg/kg, or normal saline intravenously 15 min before a burn injury. Two mesh chambers that allowed collection of fluid had been previously implanted subdermally in each rat. The skin overlying the right chamber was subject to thermal injury. The left chamber served as a control. We assessed systemic analgesia, and levels of beta-endorphin and corticosterone in plasma and in chamber fluid before, 1, 4 and 24 h after drug administration. The CRH groups exhibited longer tail flick latencies than the control group (P=0.0001) although the increase in latency was of smaller magnitude than in the morphine group. We did not observe a CRH dose response for analgesia. Plasma corticosterone levels were higher in the CRH 300 microg/kg group than in the normal saline group at 4 h (P=0.03). Levels of beta-endorphin in plasma as well as the levels of corticosterone and beta-endorphin in chambers were similar in the CRH 300 microg/kg group and in the normal saline group (all P values>0.1). Thus, systemically administered CRH produces analgesia in thermal injury independent of its effect on these two markers of local or systemic inflammation.

Topics: Analgesia; Animals; beta-Endorphin; Burns; Corticosterone; Corticotropin-Releasing Hormone; Diffusion Chambers, Culture; Disease Models, Animal; Dose-Response Relationship, Drug; Hot Temperature; Male; Pain Measurement; Rats; Rats, Wistar; Time Factors

Antagonistic properties of buprenorphine for epsilon- and micro -opioid receptors were characterized in beta-endorphin- and [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO)-induced antinociception, respectively, with the tail-flick test in male ICR mice. epsilon-Opioid receptor agonist beta-endorphin (0.1-1 micro g), micro -opioid receptor agonist DAMGO (0.5-20 ng), or buprenorphine (0.1-20 micro g) administered i.c.v. dose dependently produced antinociception. The antinociception induced by 10 micro g of buprenorphine given i.c.v. was completely blocked by the pretreatment with beta-funaltrexamine (beta-FNA) (0.3 micro g i.c.v.), indicating that the buprenophine-induced antinociception is mediated by the stimulation of the micro -opioid receptor. The antinociceptive effects induced by beta-endorphin (1 micro g i.c.v.) and DAMGO (16 ng i.c.v.) were dose dependently blocked by pretreatment with smaller doses of buprenorphine (0.001-1 micro g i.c.v.), but not by a higher dose of buprenorphine (10 micro g i.c.v.). beta-FNA at a dose (0.3 micro g i.c.v.) that strongly attenuated DAMGO-induced antinociception had no effect on the antinociception produced by beta-endorphin (1 micro g i.c.v.). However, pretreatment with buprenorphine (0.1-10 micro g) in mice pretreated with this same dose of beta-FNA was effective in blocking beta-endorphin-induced antinociception. beta-FNA was 226-fold more effective at antagonizing the antinociception induced by DAMGO (16 ng i.c.v.) than by beta-endorphin (1 micro g i.c.v.). The antinociception induced by delta-opioid receptor agonist [d-Ala2]deltorphin II (10 micro g i.c.v.) or kappa1-opioid receptor agonist trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamine methanesulfonate salt [(-)-U50,488H] (75 micro g i.c.v.) was not affected by pretreatment with buprenorphine (0.1-1.0 micro g i.c.v.). It is concluded that buprenorphine, at small doses, blocks epsilon-opioid receptor-mediated beta-endorphin-induced antinociception and micro -opioid receptor-mediated DAMGO-induced antinociception, and at high doses produces a micro -opioid receptor-mediated antinociception.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; beta-Endorphin; Buprenorphine; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

Opioids remain the most efficacious pharmacological agents for various clinical pain syndromes. Recently, various engineered cells capable of secreting opioidergic peptides have been applied to relieve pain in animal models. In vivo gene delivery by viruses encoding endogenous opioids has also been used with success. In this study, we attempted non-viral intrathecal in vivo gene delivery by electroporation to induce analgesia. Thirty Sprague-Dawley rats were used in this study, six in each of five groups. Rats were treated as follows: vehicle without electroporation (group A), vehicle with electroporation (group B), 100 microg of pCMV-hPOMC plasmid without electroporation (group C), or 100 microg of pCMV-hPOMC plasmid with electroporation (group D). Group E was treated with both pCMV-hPOMC plasmid and electroporation, and given naloxone (1mg/kg) 1h before the formalin test. The tail flick, paw withdrawal latency from radiant heat, and formalin test results for each groups were compared. Radioimmunoassay (RIA) and reverse transcription-polymerase chain reaction (RT-PCR) were used to determine the levels of expression of beta-endorphin in the spinal cord. beta-Endorphin expression was localized by immunohistochemistry. A significant decrease in the number of flinches in phase 2 of the formalin test was observed in the group treated with both plasmid and electroporation (group D), whereas the other measures of pain did not differ between groups. RIA and RT-PCR both showed increased expression of beta-endorphin in group D. The expression of beta-endorphin was highest in laminae I and II of the dorsal horn of the spinal cord. We conclude that electroporation successfully delivered intrathecally administered pCMV-hPOMC into the dorsal horn cells of the spinal cord, and induced analgesia in phase 2 of the formalin test in rats.

Topics: Analgesia; Animals; beta-Endorphin; Disease Models, Animal; DNA, Complementary; Drug Delivery Systems; Electroporation; Humans; Male; Pain; Pain Measurement; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Spinal Cord

Clients report more pain at some times of day than at others due, in part, to the temporal variation of the body's inhibitory pain response. The analgesic effectiveness of morphine varies with the time of day, perhaps due to the inhibiting or enhancing effects of the drug on plasma beta-endorphin (BE). This experiment was designed to examine the timed effects of morphine on the pain-induced BE response. Six groups of treatment mice (injected with morphine sulfate) and 6 groups of control mice (injected with saline) were exposed to an acute pain stimulus at 4-h intervals, and blood was collected. Plasma BE was analyzed using radioimmunoassay. Control mice showed a robust circadian BE-response rhythm with a peak at 0000 and a nadir at 1200, whereas the BE response of mice that received morphine was arrhythmic. Animals that received morphine tolerated the noxious stimulus longer, but the analgesia varied with time of day. These results indicate that morphine abolishes the rhythmic BE response to pain and does not inhibit pain equally at all times of day. Morphine doses should be titrated to maximize the endogenous pain control system while achieving analgesia with decreased dosages.

Topics: Acute Disease; Analgesics, Opioid; Animals; Behavior, Animal; beta-Endorphin; Chronobiology Disorders; Chronotherapy; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Monitoring; Humans; Male; Mice; Mice, Inbred DBA; Morphine; Pain; Pain Measurement; Pain Threshold; Radioimmunoassay; Reaction Time; Time Factors; Treatment Outcome

Involvement of both the serotonergic and the endogenous opioid systems in the onset of depressive behavior has been suggested. Previously we showed that serotonin (5-hydroxytryptamine) facilitates beta-endorphin release in the nucleus accumbens (NAcc). Herein, the microdialysis method was used to assess in vivo the effects of serotonin on beta-endorphin release in a rat model of depressive behavior (the Flinders sensitive line, FSL), before and after antidepressant treatment. The basal extracellular level of beta-endorphin in the NAcc of FSL rats did not differ significantly from that in control rats. However, serotonin-induced beta-endorphin release was impaired in FSL rats. Chronic treatment (18 days) with desipramine or paroxetine did not significantly affect the extracellular levels of beta-endorphin in the NAcc of either the FSL or control rats. However, the chronic antidepressant treatment did normalize the serotonin-induced release of beta-endorphin in FSL rats, as well as their behavioral manifestation of depressive behavior. Our results show that depressive behavior may relate to an impaired effect of serotonin on beta-endorphin release in the NAcc in a rat model of depression, and suggest a possible new mode of action of antidepressant drugs.

Topics: Animals; Antidepressive Agents, Tricyclic; beta-Endorphin; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Space; Male; Neural Pathways; Neurons; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin; Synaptic Transmission

Immunocyte-derived beta-endorphin can activate peripheral opioid receptors on sensory neurons to inhibit pain within inflamed tissue. This study examined mu-opioid receptors (MOR) on sensory nerves and beta-endorphin (END) in activated/memory CD4(+) cells (the predominant population homing to inflamed tissue). We found an upregulation of MOR in dorsal root ganglia, an increased axonal transport of MOR in the sciatic nerve and an accumulation of MOR in peripheral nerve terminals in Freund's adjuvant-induced hindpaw inflammation. A large number of CD4(+) cells containing beta-endorphin, but very few naive cells (CD45RC(+)), were observed in inflamed tissue, suggesting that this opioid is mainly present in activated/memory cells (CD4(+)/CD45RC(-)). Taken together, our results indicate an enhanced transport of both MOR and of the endogenous ligand beta-endorphin to injured tissue. This unique simultaneous upregulation of both receptors and ligands may serve to prevent excessive and/or chronic inflammatory pain.

Topics: Animals; Axonal Transport; beta-Endorphin; Blotting, Western; CD4-Positive T-Lymphocytes; Disease Models, Animal; Freund's Adjuvant; Ganglia, Spinal; Hindlimb; Immunologic Memory; Inflammation; Ligation; Male; Neurons, Afferent; Rats; Rats, Wistar; Receptors, Opioid, mu; Sciatic Nerve; Skin

This study evaluated the contribution of supraspinal opioid receptors to gastric mucosal protection in the rat. Intracerebroventricular (i.c.v.) and intracisternal (i.c.) injections of selective delta- [[D-Ala(2),D-Leu(5)]-enkephalin (DADLE), [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE), deltorphin II], selective mu- [[D-Ala(2),Phe(4),Gly(5)-ol]-enkephalin (DAGO)] opioid receptor agonists and beta-endorphin (ligand of both receptor types) produced a dose-dependent inhibition of acidified ethanol-induced gastric mucosal damage. The ED(50) values for beta-endorphin, DAGO, DADLE, deltorphin II, and DPDPE were 3.5, 6.8, 75, 120, and 1100 pmol/rat, respectively, following i.c.v. and 0.8, 9.0, 45, 0.25, and 7 pmol/rat following i.c. injection. The gastroprotective effect of DADLE, deltorphin II, and DPDPE, but not that of DAGO, was inhibited by naltrindole, the selective delta-receptor antagonist. Since the delta(2)-receptor agonist deltorphin II was more potent than the delta(1)-receptor agonist DPDPE, the dominant role of central delta(2)-receptors in gastroprotection might be raised. The site of action for delta-receptor agonists is likely to be the brain stem since the peptides were more potent following i.c. than following i.c.v. administration. The gastroprotective effect was reduced following acute bilateral cervical vagotomy. Moreover, both the nitric-oxide synthase inhibitor N(G)-nitro-L-arginine (3 mg/kg i.v.) and the prostaglandin synthesis inhibitor indomethacin (20 mg/kg p.o.) decreased the protective effect of opioid peptides. The results indicate that 1) activation of supraspinal delta- and mu-opioid receptors induces gastric mucosal protection, 2) integrity of vagal nerve is necessary for the gastroprotective action of opioids, and 3) mucosal nitric oxide and prostaglandins may be involved in the opioid-induced gastroprotection.

Topics: Animals; beta-Endorphin; Brain; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Hydrochloric Acid; Male; Narcotic Antagonists; Oligopeptides; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Stomach Ulcer; Vagotomy

The aim of the present study was to examine the role of opiate receptor activation in modulating the hemodynamic, neuroendocrine, and tissue (lung and spleen) cytokine responses to fixed pressure (40 mm Hg) hemorrhage. Chronically catheterized, conscious unrestrained non-heparinized male Sprague-Dawley rats were pretreated with either naltrexone (15 mg/kg intraperitoneally in 0.5 mL of saline) or saline (0.5 mL) 15 min prior to hemorrhage followed by fluid resuscitation with Ringer's lactate. Animals were sacrificed at completion of the 60-min resuscitation period. Blood loss required to achieve mean arterial blood pressure (MABP) of 40 mm Hg was higher in naltrexone-treated animals than in time-matched saline controls (4.4+/-0.2 versus 3.7+/-0.2 mL/100 g BW, P< 0.05). Hemorrhage increased plasma levels of corticosterone (30%) and ACTH (3-fold) within 15 min. Naltrexone prevented the hemorrhage-induced rise in corticosterone without affecting the rise in ACTH. Hemorrhage increased beta-endorphin levels (4-fold) and produced an immediate (5 min) and progressive increase in circulating epinephrine and norepinephrine levels reaching values that were 50- and 20-fold, respectively, higher than basal. Pre-treatment with naltrexone did not alter the time course or magnitude of the hemorrhage-induced increases in plasma beta-endorphin or catecholamines. Hemorrhage increased lung and spleen content of TNF (60%), IL-1alpha (300%), IL-6 (40%-60%), and IL-10 (80%) above values of time-matched sham control animals. Pre-treatment with naltrexone blunted the magnitude of the increases in tissue cytokine content in response to a given blood loss. These results indicate that endogenous opiates modulate the hemodynamic instability, neuroendocrine, and cytokine responses to hemorrhagic shock.

Topics: Adrenocorticotropic Hormone; Animals; Apoptosis; beta-Endorphin; Blood Pressure; Corticosterone; Cytokines; Disease Models, Animal; Hemodynamics; Interleukin-1; Interleukin-10; Interleukin-6; Lung; Male; Naltrexone; Narcotic Antagonists; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Hemorrhagic; Spleen; Time Factors; Tumor Necrosis Factor-alpha

LPS administration and hemorrhage are frequently used models for the in vivo study of the stress response. Both challenges stimulate cytokine production as well as activate opiate and neuro-endocrine pathways; which in turn modulate the inflammatory process. Differences in the magnitude and tissue specificity of the proinflammatory cytokine and neuro-hormonal responses to these stressors are not well established. We contrasted the tissue specificity and magnitude of the increase in circulating and tissue cytokine (TNF-alpha, IL-1alpha and IL-1beta) content in response to either fixed-pressure hemorrhage (approximately 40 mm Hg) followed by fluid resuscitation (HEM) or lipopolysaccharide (LPS; 100 microg/100 g BW) administration. LPS and HEM elevated circulating levels of TNF-alpha, while neither stress altered circulating IL-1-alpha and IL-beta. LPS-induced increases in TNF-alpha content were greater than those elicited by HEM in all tissues studied except for the lung, where both stressors produced similar increases. Tissue (lung, spleen and heart) content of IL-1alpha was increased by HEM but was not affected by LPS. Tissue (lung, spleen, and heart) content of IL-1beta was increased by LPS but was not affected by HEM. HEM produced greater increases than LPS in epinephrine (16- vs. 4-fold) and norepinephrine (4-fold vs. 60%) levels and similar elevations in beta-endorphin. LPS produced greater elevation in corticosterone levels (2-fold) than HEM (50%). These results suggest differential tissue cytokine modulation to HEM and LPS, both with respect to target tissue and cytokine type. The hormonal milieu to HEM is characterized by marked catecholaminergic and moderate glucocorticoid while that of LPS is characterized by marked glucocorticoid with moderate catecholaminergic influence.

Topics: Animals; beta-Endorphin; Blood Pressure; Catecholamines; Corticosterone; Disease Models, Animal; Epinephrine; Hemorrhage; Inflammation; Interleukin-1; Lipopolysaccharides; Male; Narcotics; Norepinephrine; Rats; Rats, Sprague-Dawley; Resuscitation; Stress, Physiological; Time Factors; Tumor Necrosis Factor-alpha

Opioid-containing immunocytes migrate to inflamed sites where they release beta-endorphin which activates peripheral opioid receptors and produces analgesia. The immigration of immunocytes to sites of inflammation is mediated by adhesion molecules. In this study, the expression of L-, P-, E-selectin and platelet-endothelial adhesion molecule-1 (PECAM-1) in relation to beta-endorphin expression was analyzed by immunohistochemistry in inflamed tissues. The proportion of immunocytes expressing L-selectin was increased in inflamed lymph nodes and subcutaneous paw tissue. P-selectin and PECAM-1 were constitutively expressed on endothelia of noninflamed lymph nodes and subcutaneous tissue and were upregulated in inflammation. beta-endorphin positive cells expressed L-selectin in lymph nodes and subcutaneous tissue. Upregulation of P-selectin and PECAM-1 and the co-localization of L-selectin and beta-endorphin in immunocytes suggest an important role of these adhesion molecules for the recruitment of immunocytes containing beta-endorphin to sites of painful inflammation.

Topics: Animals; beta-Endorphin; Cell Adhesion Molecules; Chemotaxis, Leukocyte; Disease Models, Animal; E-Selectin; Freund's Adjuvant; Hindlimb; Immunohistochemistry; Inflammation; L-Selectin; Lymph Nodes; Male; P-Selectin; Pain; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Wistar; Skin; Up-Regulation

To study the regulatory effect of Erbao granules (EBG) on central and peripheral brain-gut peptide in juvenile animal model of anorexia.. Juvenile rat model of anorexia was established by imitating the major cause of infantile anorexia and treated with EBG. The cholocystokinin-octapeptide (CCK-8) and beta-endorphin (beta-EP) concentration in hypothalamus, antrum pyloricum and peripheral blood were examined by radioimmunoassay.. CCK-8 concentration in hypothalamus and plasma in the model rats increased (P < 0.05), while blood beta-EP concentration decreased (P < 0.05). After EBG treatment, the CCK-8 concentration normalized and beta-EP increased significantly.. EBG could reduce the central and peripheral CCK-8 and increase beta-EP secretion significantly in the juvenile anorexia model.

Topics: Animals; Anorexia; beta-Endorphin; Disease Models, Animal; Drugs, Chinese Herbal; Female; Gastric Mucosa; Hypothalamus; Male; Rats; Rats, Sprague-Dawley; Sincalide

The effects of the extremely selective mu-opioid receptor agonist, [D-Arg2,Lys4]-dermorphin-(1-4)-amide (DALDA), the mu-opioid receptor agonist morphine, the mu/delta agonist D-Ala2, Leu5, Arg6-enkephalin (dalargin), the kappa-opioid receptor agonist spiradoline, and the sigma1-receptor antagonist DuP 734 on ventricular fibrillation threshold (VFT) was investigated in an experimental post-infarction cardiosclerosis model and an immobilization stress-induced model in rats. Both models produced a significant decrease in VFT. The postinfarction cardiosclerosis-induced decrease in VFT was significantly reversed by intravenous administration of dalargin (0.1 mg/kg), DALDA (0.1 mg/kg), or morphine HCl (1.5 mg/kg). Pretreatment with naloxone (0.2 mg/kg) completely eliminated the increase in cardiac electrical stability produced by DALDA. Both spiradoline (8 mg/kg, i.p.) and DuP 734 (1 mg/kg, i.p.) produced a significant increase in VFT in rats with post-infarction cardiosclerosis. This effect of spiradoline was blocked by nor-binaltorphimine. The immobilization stress-induced decrease in VFT was significantly reversed by administration of either DALDA, spiradoline or DuP 734. In conclusion, activation of either mu- or kappa1-opioid receptors or blockade of sigma1-receptors reversed the decrease in VFT in both cardiac compromised models. Since DALDA and dalargin essentially do not cross blood brain barriers, their effects on VFT may be mediated through peripheral mu-opioid receptors.

Topics: Animals; Anti-Arrhythmia Agents; beta-Endorphin; Disease Models, Animal; Dynorphins; Enkephalin, Leucine-2-Alanine; Heart; Immobilization; Ligands; Morphine; Myocardial Infarction; Myocardium; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Piperidines; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, delta; Stress, Physiological; Ventricular Fibrillation

To assess the role of beta-EP in the physiological and pathophysiological process of respiratory regulation in chronic hypoxic rats.. The chronic hypoxic rat model was established by intravenous injections of papain 6 times, once a week. The concentration of beta-endorphin in medulla, pons, hypothalamus, central gray and plasma of chronic hypoxic rats were measured by radioimmunoassay. All animals were pretreated with sodium pentobartital (35 mg/kg) before experiment. 102 rats were randomly divided into three groups. Group 1 (n = 36). The respiratory rate (RR) and tidal volume (VT) were measured after intravenous injection of naloxone (NLX, 2 mg/kg), beta-EP (40 micrograms/kg, 160 micrograms/kg) or normal saline, Group 2 (n = 48). By the intracerebroventricular administration of NLX and beta-EP to the models, RR, VT and PaCO2 were observed after microinjection 5, 15, 30, 45, 60 min. Group 3 (n = 18). The respiratory effects of beta-EP after directly into the nucleus tractus solitari of the anaesthetised rats were investigated.. The beta-EP contents in medulla, pons, hypothalamus, central gray and plasma of chronic hypoxic rats were significantly increased compared with control subjects (P < 0.01). It suggested that the pathophysiology of chronic hypoxic process infleuced the contents of beta-EP in the CNS and plasma in rats. Intracerebroventricular microinjection of beta-EP in normal rats, resulted in a significant decrease in RR (P < 0.05). No significant difference in RR and VT was observved after intravenous injection of naloxone (2 mg/kg) and beta-EP (40 micrograms/kg, 160 micrograms/kg) in treatment group compared with the control group (P > 0.05), Intracerebroventricular microinjection of NLX in chronic hypoxic rats, resulted in a marked increase in RR (P < 0.05) and central hypercapnic-sensitivity (t = 2.76, P < 0.05), Intracerebroventriculalr microinjection of beta-EP in chronic hypoxic models, resulted in severe respiratory depression after injection 15, 30, 45, 60 min (RR t = 3.41, 6.54, 6.97, 7.87, P < 0.01; VT t = 3.07, 7.27, 6.14, 6.08).. These results indicate the beta-endorphin may be involved in central respiratory control of chronic hypoxic rats.

Topics: Animals; beta-Endorphin; Chronic Disease; Disease Models, Animal; Hypoxia; Male; Naloxone; Narcotic Antagonists; Oxygen; Rats; Rats, Sprague-Dawley; Respiration

We sought to evaluate the antiinflammatory effects of synthetic human beta-endorphin (SHB) when injected into the canine knee joint. Sixteen healthy dogs, aged 1-2 yr, were selected. SHB was injected pre- and postinjury into each knee. The sample size was n = 32 after a randomized factorial arrangement; 2 x 4 with four cases per treatment being performed. Factors considered were: Factor A with two levels: A1 = Preinjury and A2 = Postinjury; Factor B (SHB dose) with four levels: B1 = Control, B2 = 250 micrograms, B3 = 500 micrograms, B4 = 1000 micrograms. The control group received 0.9% NaCl solution. Anesthesia was induced with intravenous thiopental, 14 mg/kg, and acepromazine, 0.5 mg/kg. Injury was produced with an intraarticular injection of 4 mL HCl 0.5 M, which was left in situ for 20 min. Inflammation was measured using the 610 nm absorbency of Evans blue extravasate in biopsy specimens. Histopathologic studies were performed on each knee. We found that beta-endorphin has a clear, dose-related, antiinflammatory effect, reducing the tissue extravasation of Evans blue and its absorbency, especially with large doses. This finding was consistent with the histopathologic observations. We conclude that SHB has an antiinflammatory effect. It is still not clear which mechanisms inhibit polymorphonuclear cell adhesion to vascular endothelium or cell and plasmatic protein extravasation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; beta-Endorphin; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Humans; Inflammation; Injections, Intra-Articular; Knee Injuries; Knee Joint

We investigated the effects of the opiate antagonist naloxone on the release of beta-endorphin and cortisol in rats subjected to sepsis. Sepsis was induced in weanling male Wistar albino rats (3-4 weeks old, 75-90 g) by cecal ligation and double perforation (CLP). Forty animals were randomly allocated to four groups. Group 1 was given naloxone hydrochloride 0.5 mg/kg subcutaneously after CLP and this treatment was repeated at 2-h intervals until the rats were killed. Group 2 rats underwent a sham operation. Group 3 (control group) rats had CLP. Group 4 consisted of nonoperated animals used to establish normal reference values. Eighteen hours after CLP or sham operation, the rats were killed by cervical dislocation and a blood sample was drawn via cardiac puncture to determine the beta-endorphin and cortisol levels. The beta-endorphin levels were significantly higher in the control group than in the sham-operated, naloxone-treated (NT), and nonoperated rats (P < 0.05). However, there were no significant differences in plasma beta-endorphin levels between sham-operated, NT and nonoperated rats (P > 0.05). Plasma cortisol levels were significantly higher in the control group compared with the other three groups and this difference was more significant in sham-operated and nonoperated rats (P < 0.01). However, no difference existed between sham-operated, NT, and nonoperated rats (P > 0.05). This study demonstrates that the endogenous opioid system may play a role in the activation of the pituitary-adrenal axis following sepsis, and shows that the increase in beta-endorphin and cortisol could be blocked by naloxone.

Topics: Animals; beta-Endorphin; Disease Models, Animal; Hydrocortisone; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Sepsis

Cerebrospinal fluid (CSF) obtained by acute percutaneous puncture of the cisternal membrane of the halothane anesthetized rat has low but measurable concentrations of beta-endorphin-like immunoreactivity (beta-EPir: 32.8 +/- 3.0 pmol/l). Chromatographic separation of beta-EPir showed that authentic beta-endorphin1-31 was the main component of beta-EPir in cisternal CSF. Subcutaneous injection of 5% formalin in the hind paws did not increase beta-EPir in cisternal CSF. Rats with tactile paw hyperalgesia evoked by unilateral ligation of the L5/6 nerve roots 2 weeks earlier had beta-EPir concentrations that did not differ from sham operated or unoperated control animals. In contrast, capsaicin injected in the hindpaws increased the mean beta-EPir concentration compared to saline injections (P = 0.006) 45 min after emerging from anesthesia following injection. These results show that acute activation of C fibers (by capsaicin) will evoke the release of beta-endorphin into the CSF, suggesting activation of the beta-endorphin terminal systems in the brain/midbrain. The failure of formalin injections to release beta-EPir to CSF may be due to specificity of the afferent stimulus evoking beta-EPir release, a lower stimulus intensity, and/or the duration of the stimulus generated by formalin. The normal concentrations of beta-EPir found in the hyperalgesic state following nerve injury suggest that the supraspinal beta-endorphin system does not display tonic changes under such conditions.

Topics: Animals; beta-Endorphin; Chromatography, High Pressure Liquid; Disease Models, Animal; Hyperalgesia; Male; Rats; Rats, Sprague-Dawley

The objective of the present studies was to investigate the effect of voluntary ethanol consumption for 21 days on the brain beta-endorphin system of C57BL/6 (alcohol-preferring) and DBA/2 (alcohol-avoiding) strains of mice. As expected, C57BL/6 mice consumed a significantly higher quantity of the 10% ethanol solution than the DBA/2 mice. Under basal conditions the content of beta-endorphin like peptides differed only in the nucleus accumbens, higher levels being found in the DBA/2 mice. Voluntary ethanol consumption induced an increase in the hypothalamic content of mRNA coding for proopiomelanocortin, associated with a significant increase in the tissue content of beta-endorphin-like peptides in the arcuate nucleus and septum of the C57BL/6 mice, but did not alter the activity of the brain beta-endorphin system of the DBA/2 mice. Since voluntary ethanol consumption was not associated with nutritional deficits and stress, the ethanol-induced enhanced activity of the brain beta-endorphin system of the C57BL/6 mice must be a direct effect of ethanol and may be important in controlling the voluntary ethanol consumption by this strain of mice.

Topics: Alcohol Drinking; Analysis of Variance; Animals; beta-Endorphin; Body Weight; Brain; Choice Behavior; Disease Models, Animal; Ethanol; Male; Mice; Mice, Inbred C57BL; Pro-Opiomelanocortin; Radioimmunoassay; RNA, Messenger

The purpose of this study was to determine the effects of naloxone on systemic hemodynamics and reflex function in dogs with congestive heart failure induced by rapid pacing.. We have shown previously that naloxone, an opiate receptor antagonist, improves cardiac output, aortic blood pressure, systolic performance and the baroreflex function in conscious dogs with chronic right-sided congestive heart failure. However, whether endogenous opioids also play a role n mediating the reduction of myocardial and baroreflex function in animals with left heart failure remains controversial.. We administered naloxone (1 mg/kg body weight) and normal saline solution to 15 dogs with pacing-induced congestive heart failure (225 beats/min for 8 weeks) and 11 control dogs. In addition to systemic hemodynamic measurements, the slope of pressure-area relation obtained from echocardiography with intravenous bolus injection of phenylephrine was taken as a load-independent index of myocardial contractility. Baroreflex function was estimated by the slope of the regression line relating systolic aortic pressure and RR interval.. Plasma beta-endorphin levels were elevated in dogs with congestive heart failure. Naloxone administration increased heart rate, mean aortic pressure, first derivative of left ventricular pressure, cardiac output and myocardial contractility in pacing-induced congestive heart failure. These changes correlated significantly with basal plasma beta-endorphin levels and were accompanied by increases in plasma beta-endorphin and catecholamines after naloxone administration. However, unlike the hemodynamic and cardiac effects of naloxone, baroreflex function did not change after naloxone in dogs with congestive heart failure.. The increase in basal plasma beta-endorphin suggests that the endogenous opiate system is activated in left-sided congestive heart failure. Because naloxone improves the systemic hemodynamics and myocardial contractile function under this condition, the endogenous opioids appear to play an important role in mediating the myocardial depression that occurs in heart failure. However, the endogenous opiate system has no apparent effect on the regulation of baroreflex control in heart failure induced by rapid pacing.

Topics: Animals; Baroreflex; beta-Endorphin; Disease Models, Animal; Dogs; Epinephrine; Heart Failure; Hemodynamics; Myocardial Contraction; Naloxone; Narcotic Antagonists; Norepinephrine; Ventricular Function, Left

A single intrastriatal injection of a slow release formulation of a metabolically-stable MPF analogue was given to rats with lesioned right nigrostriatal pathways. After 6 weeks the turning behaviour of the rats in response to D-amphetamine began to decline, and after 12 weeks the reduction was marked and consistent. The implication of our results in the use of intracerebral grafts in parkinsonian patients is discussed.

Topics: Amino Acid Sequence; Animals; beta-Endorphin; Delayed-Action Preparations; Disease Models, Animal; Male; Molecular Sequence Data; Parkinson Disease; Peptide Fragments; Rats; Rats, Wistar

The potential effect of intracerebroventricular (icv) alpha N-acetyl human beta-endorphin-(1-31) on morphine dependence was examined in mice and rats. Animals were rendered tolerant-dependent by subcutaneous (sc) implantation of an oily suspension (10 ml/Kg mouse and 3 ml/Kg rat) containing 0.1 g/ml of morphine. After 72 h of chronic morphine, 1 mg/Kg sc naloxone precipitated in both species a withdrawal syndrome that was moderate in animals pretreated with the acetylated derivative of beta-endorphin. Doses of 28 fmols/rat or 80 fmols/mouse alpha N-acetyl human beta-endorphin-(1-31) reduced the number of animals presenting the jumping behaviour, as well as the number of jumps recorded. Moreover, less than half of the rats presented the other withdrawal signs evaluated: squeak on touch, diarrhoea, chattering, chewing, ptosis and body shakes. This activity could be observed when alpha N-acetyl human beta-endorphin was injected 1 h to 24 h before naloxone; longer intervals resulted in a significant loss of this activity. The alpha 2 agonist clonidine given icv at pmol-nmol doses decreased the incidence of morphine withdrawal syndrome. Combinations of these two substances generally did not produce any further enhancement of the effects of clonidine and alpha N-acetyl beta-endorphin when used alone. Icv injections of the antagonist of alpha 2-adrenoceptors yohimbine prevented both clonidine and alpha N-acetyl beta-endorphin-(1-31) from reducing the jumping behaviour displayed by morphine-abstinent mice. It is suggested that alpha N-acetyl beta-endorphin produces this alleviation of the morphine withdrawal syndrome by improving the efficiency of alpha 2-mediated agonist effects after acting on a neural substrate that is distinct from the mu opioid receptor binding site.

Topics: Animals; beta-Endorphin; Clonidine; Disease Models, Animal; Male; Mice; Morphine; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Yohimbine

Prenatal stress affects fetal androgen milieu in the critical period of androgen-dependent brain differentiation, and induces permanent defects in reproductive functions of the offspring. We investigated the response of the fetal hypothalamo-pituitary-adrenal axis and the function of the placenta during an acute maternal stress, in order to clarify the mechanism of central endocrine regulation in the fetus with an inappropriate androgen level under stress. Pregnant rats at day 20-21 of gestation were subjected to forced immobilization stress. The plasma concentration of corticosterone (B) and ACTH, and tissue content of CRF and beta-EP like immunoreactivities (CRF-LI, beta-EP-LI) in the maternal and fetal hypothalamus and the placenta were measured by RIA. 3H-B was administered intravenously to pregnant rats and radioactivity was measured in blood and the hypothalamus. 1. In mothers, plasma B and ACTH increased at 20 and 60 minutes of stress. Hypothalamic CRF-LI decreased and beta-EP tended to decrease during stress. 2. In fetuses, plasma B and ACTH increased significantly during maternal stress. 3. Fetal hypothalamic CRF-LI and beta-EP-LI decreased significantly in males and females under maternal stress. 4. beta-EP-LI in the placenta decreased significantly after 120 minutes of stress, and beta-EP-LI was localized in trophoblast. No CRF-stained cell was detected in the placenta. 5. 3H-B given to mothers passed through the placenta, and the maximum radioactivity in fetal blood and the hypothalamus was found at 20 minutes after the injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Corticosterone; Disease Models, Animal; Female; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Placenta; Pregnancy; Pregnancy Complications; Rats; Rats, Inbred Strains; Stress, Physiological

Brain and blood iron deficiency (ID) can be nutritionally induced. Significant behavioral and brain-biochemical changes are observed in rats rendered iron deficient, including complete reversal of the circadian cycles of motor activity, changes in thermoregulation and stereotyped behavior, and an increased pain threshold. The increase in pain threshold is affected by diurnal factors and peripheral treatment with beta-endorphin has a significant analgesic effect, implicating selective changes in the blood-brain barrier. These effects along with modifications in responses to dopaminergic drugs, interactions of ID with neuroleptic drugs, and modifications in behavior as a result of selective brain lesions, lead to two conclusions: this animal model is appropriate for human anemia and the best explanation for the variety of behavioral and brain biochemical changes in ID rats is that the principal effect of brain ID is a selective decrease in the functional level of the dopaminergic D2 system.

Topics: Amphetamine; Anemia, Hypochromic; Animals; Antipsychotic Agents; Apomorphine; beta-Endorphin; Body Temperature Regulation; Brain; Disease Models, Animal; Dopamine; Iron; Iron Deficiencies; Learning; Motor Activity; Pain; Rats; Receptors, Dopamine; Sensory Thresholds

This study evaluated the effects of naloxone hydrochloride in the treatment of Escherichia coli-induced shock in baboons. The baboons were studied for 12 hours and monitored for survival times. All baboons were intravenously infused for two hours with E coli and treated as follows: group 1, E coli (control); group 2, E coli plus naloxone hydrochloride, 0.5 mg/kg bolus plus 0.5 mg/kg/h for 9.5 hours; and group 3, E coli plus naloxone hydrochloride, 2.0 mg/kg bolus plus 2.0 mg/kg/h for 3.8 hours. Naloxone was administered after arterial pressure had reached the nadir (more than two hours following initiation of E coli infusion). Mean arterial pressure was supported by the lower dose of naloxone; however, sustained leukopenia and neutropenia were not reversed by its infusion. Naloxone prevented the increase in plasma beta-endorphin level and blunted the increase in plasma cortisol level. Despite these effects, naloxone did not prevent multiple-organ disease and did not decrease mortality.

Topics: Animals; beta-Endorphin; Blood Pressure; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli Infections; Female; Heart Rate; Hydrocortisone; Injections, Intravenous; Male; Monitoring, Physiologic; Naloxone; Papio; Sepsis; Shock, Septic; Time Factors

Naltrexone, an opioid antagonist, had an inhibitory effect on the growth of murine S20Y neuroblastoma in BALB/c nude mice. Daily injections of 0.1 mg naltrexone/kg, which invoked a receptor blockade for 6-8 hours/day, resulted in 31-92% delay in latency time prior to tumor expression and a 27-49% increase in mean survival time; the magnitude of antitumor response was governed by tumor burden. Inoculation of neuroblastoma (10(6)-2.5 X 10(4) cells) resulted in measurable tumors in 10-13 days and mean survival times of 30-34 days. Immunoreactive beta-endorphin was detected in tumor tissue (39.7 pg/mg protein). Receptor binding assays revealed specific saturable binding of ligands related to delta- and kappa-binding sites, but not for the mu-binding site. These results demonstrate that opioid antagonist modulation of neuro-oncogenesis is not dependent on the integrity of T-cell-mediated immunity and suggest the feasibility of utilizing the nude mouse model in exploring the role of endogenous opioids in human cancers.

Topics: Animals; beta-Endorphin; Disease Models, Animal; Endorphins; Graft Survival; Immunity, Cellular; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Naltrexone; Neoplasm Transplantation; Neuroblastoma; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; T-Lymphocytes; Time Factors

Chronic arthritic pain was induced by intradermally inoculating rats at the tail-base with Mycobacterium butyricum, which results in swelling, inflammation, and hyperalgesia of the joints. These symptoms peak at 3 weeks after inoculation and disappear by 10 weeks. The following changes were seen at 3 weeks. Immunoreactive dynorphin (ir-Dyn) and ir-alpha-neo-endorphin (alpha-NE) manifested comparable patterns of change. Their levels were increased in the anterior, but not neurointermediate, pituitary. The thalamus showed a rise in ir-Dyn and ir-alpha-NE, but no alterations were seen in other brain regions. In each case, cervical, thoracic, and lumbosacral sections of the spinal cord showed a rise in ir-Dyn and ir-alpha-NE: This was most pronounced in the lumbosacral region, where the magnitude of these shifts correlated with the intensity of arthritic symptoms. In addition, a moderate elevation in ir-methionine-enkephalin (ME) was seen in lumbosacral spinal cord. In brain, ir was not changed. The level of ir-beta-endorphin (beta-EP) was elevated both in the plasma and the anterior, but not the neurointermediate, pituitary. In addition, the content of messenger RNA encoding the beta-EP precursor, proopiomelanocortin (POMC), was enhanced in the anterior lobe. Thus, there was a selective activation of synthesis of beta-EP in, and its secretion from, the anterior lobe. In no brain tissue did levels of ir-beta-EP change. At 10 weeks postinoculation, the above changes were no longer apparent, indicating their reversibility.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arthritis; Arthritis, Experimental; beta-Endorphin; Brain; Brain Chemistry; Chronic Disease; Diprenorphine; Disease Models, Animal; Dynorphins; Endorphins; Hypothalamus; Male; Mesencephalon; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Spinal Cord; Thalamus

The endogenous opiate beta-endorphin is released concomitantly with adrenocorticotropin from the pituitary during stress. In the present study we investigated the possible involvement of opiate receptors in the cardiovascular depression associated with hypovolemic shock in the nonhuman primate. Changes in circulating levels in beta-endorphin were monitored during hemorrhagic shock in 18 female baboons. Plasma levels of beta-endorphin increased significantly during hemorrhagic shock and were significantly correlated with a decrease in cardiac output (P less than 0.05). Single bolus administration of the opiate receptor antagonist naloxone (2 or 5 mg/kg) produced a transient but significant improvement in cardiac output (P less than 0.05) and mean arterial pressure (P less than 0.05). Hemodynamic improvement was maintained with a constant infusion of naloxone. Opiate receptor blockade with the longer acting antagonist naltrexone (2 or 5 mg/kg) significantly increased mean arterial pressure (MAP; P less than 0.05), and CO (P less than 0.05), and decreased heart rate. Our results suggest that the baboon is an excellent model for the study of hemorrhagic shock and provide further evidence for endogenous opiate involvement in the cardiovascular pathophysiology of hemorrhagic shock.

Topics: Animals; beta-Endorphin; Disease Models, Animal; Dose-Response Relationship, Drug; Endorphins; Female; Hemodynamics; Naloxone; Naltrexone; Narcotic Antagonists; Papio; Shock, Hemorrhagic; Time Factors

We measured basal plasma concentrations of the immunoreactive (IR) proopiomelanocortin (POMC)-derived peptides ACTH, beta-lipotropin (beta LPH), beta-endorphin (beta END), and alpha MSH in 160 normal dogs, 32 dogs with Addison's disease, 42 dogs with adrenocortical tumors causing Cushing's syndrome, and 169 dogs with pituitary-dependent Cushing's disease. In normal dogs, plasma IR-POMC peptide levels were similar to those in man, except that IR-alpha MSH, a pars intermedia POMC product, was readily detected. In Addisonian dogs, plasma cortisol was decreased, and the IR-POMC peptides were increased, except for IR-alpha MSH, which was normal. In 7 Addisonian dogs given dexamethasone, elevated plasma IR-ACTH, beta LPH, and beta END levels fell dramatically. In dogs with Cushing's syndrome due to adrenal tumors, plasma IR-ACTH, beta LPH, and beta END were decreased, and cortisol was increased, but IR-alpha MSH was normal. Dogs with Cushing's disease due to pars distalis tumors had elevated plasma IR-ACTH, beta LPH, beta END, and cortisol, but normal IR-alpha MSH; their plasma cortisol was suppressed by dexamethasone. There appeared to be 2 types of pars intermedia tumors causing Cushing's disease: 1 dexamethasone nonsuppressible and with disproportionately high plasma IR-alpha MSH levels, the other relatively dexamethasone suppressible and with normal to slightly elevated IR-alpha MSH levels. These 2 pars intermedia tumor types may arise from 2 distinct normal canine pars intermedia cell types. Canine Cushing's disease may provide a useful model for variants of the disorder in man.

Topics: Addison Disease; Adenoma; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Animals; beta-Endorphin; beta-Lipotropin; Cushing Syndrome; Dexamethasone; Disease Models, Animal; Dogs; Endorphins; Female; Hydrocortisone; Male; Melanocyte-Stimulating Hormones; Pituitary Hormones, Anterior; Pituitary Neoplasms

Endogenous opiate peptides have been implicated in the cardiovascular depression of hemorrhagic shock. Beta-endorphin immunoreactivity was measured during hemorrhagic shock and the effects of beta-endorphin suppression during shock on cardiac hemodynamics and myocardial blood flow were studied. Fourteen dogs (group 1) were pretreated with 30 milligrams per kilogram of methylprednisolone (MP) prior to shock. Ten dogs (group 2) received saline solution and were the control group. All dogs were bled to a mean arterial blood pressure of 35 millimeters of mercury for two hours, then resuscitated with blood and lactated Ringer's solution. Beta-endorphin concentrations increased 600 per cent during shock in the control group. Dogs pretreated with MP had lower beta-endorphin concentrations (p less than 0.05) during shock than did dogs in the control group. The rate of left ventricular pressure rise (dp/dt) was significantly improved during shock (p less than 0.04) and after resuscitation (p less than 0.006) in dogs with suppressed beta-endorphin immunoreactivity. Blood flow from the coronary artery was higher during shock and after resuscitation (p less than 0.001) in the dogs in group 1. Our data indicate significant correlation between improved ventricular performance and decreased beta-endorphin levels in shock and after resuscitation.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Blood Pressure; Coronary Circulation; Disease Models, Animal; Dogs; Endorphins; Evaluation Studies as Topic; Female; Hematocrit; Isotonic Solutions; Lactates; Male; Methylprednisolone; Myocardial Contraction; Ringer's Lactate; Shock, Hemorrhagic; Stroke Volume

Young and mature, genetically obese and non-obese, spontaneously hypertensive rats (SHR) were injected with saline (controls) or naloxone for 12 weeks. Naloxone stilled the hyperphagia to a normal intake in the obese SHR (Obese/SHR) so that young Obese/SHR did not develop their usual massive obesity and mature Obese/SHR that had become massively obese were reduced to leanness. The naloxone-treated young, obese and non-obese SHR (controls) exhibited marked reduction of the weight of their pituitary and adrenal glands, whereas the pituitary and adrenal glands of naloxone-treated mature, obese and non-obese/SHR were greatly increased in weight. The elevated systolic blood pressure of the obese and non-obese rats was reduced after chronic treatment with naloxone. Naloxone treatment caused reduction of blood ACTH, corticosterone, and beta endorphin levels but elevated growth hormone levels. The characteristic hyperinsulinemia, hyperlipidemia, hyperglycemia, elevated BUN levels, and the Cushingoid spectrum of degenerative changes found in Obese/SHR did not appear in naloxone-treated rats.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Blood Pressure; Body Weight; Corticosterone; Cushing Syndrome; Disease Models, Animal; Endorphins; Female; Growth Hormone; Male; Naloxone; Obesity; Organ Size; Pituitary Gland; Rats; Rats, Inbred SHR; Rats, Inbred Strains

Male and female, young (2 months old) and mature (10 months old), obese and nonobese, spontaneously hypertensive rats (SHR) were treated with dexamethasone, 5 micrograms/rat and 10 micrograms/rat, respectively, subcutaneously (SC) 2 times daily for 5 months. Steroid treatment stilled the voracious appetite of the obese SHR, and the massively obese, mature animals were reduced to almost normal size. The young, steroid-treated, obese SHR did not develop their genetically programmed corpulency. The untreated, young and mature, obese SHR ate voraciously, became massively obese, and developed their characteristic Cushing's disease-like spectrum of degenerative changes, eg, hypertension, hyperlipidemia, hyperglycemia, muscle wasting, kidney stones, thin skin, and accelerated aging. The blood pressure of the steroid-treated animals was lowered concomitant with reduced levels of circulating ACTH, beta endorphin, insulin, triglycerides, and cholesterol. Dexamethasone caused hyperlipidemia, hyperglycemia, and increased BUN levels in young obese and nonobese SHR only. The mature obese SHR had giant-sized thymus glands that were further enlarged with steroid treatment; dexamethasone was thymolytic in young, obese and nonobese SHR. Dexamethasone caused severe reduction of pituitary and adrenal gland size, simulating the condition of hypophysectomy. These findings demonstrate that dexamethasone suppression of the pituitary-adrenal axis palliates and prevents the spontaneous development of Cushingoid degenerative changes in these genetically obese and hypertensive rats.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Blood Glucose; Blood Urea Nitrogen; Cushing Syndrome; Dexamethasone; Disease Models, Animal; Endorphins; Female; Hypertension; Insulin; Lipids; Male; Obesity; Organ Size; Pituitary Gland; Rats; Rats, Inbred Strains

Topics: Animals; beta-Endorphin; Brain Chemistry; Disease Models, Animal; Dopamine; Endorphins; Enkephalin, Leucine; Female; Fetal Alcohol Spectrum Disorders; Neurotransmitter Agents; Norepinephrine; Pregnancy; Rats; Rats, Inbred Strains; Serotonin

Beta-Endorphin (0.3 or 0.6 nanomoles) was infused into the A10-ventral tegmental area (VTA) of male Wistar rats previously treated for 6 days with either morphine sulfate or lactose via subcutaneously implanted silastic pellets. Beta-Endorphin microinfusions occurred at 24 and 96 hours after pellets were removed. Profound changes in locomotor response to beta-endorphin were found, with morphine-pretreated rats showing a spontaneous switch from hyporesponsiveness to hyperresponsiveness over 72 hours, compared to lactose-pretreated controls. These findings may reflect on current biochemical theories regarding the "switch" process in bipolar affective disease. The data can be viewed within a heuristic model of receptor changes which may underlie the transition from depression to mania.

Topics: Affective Disorders, Psychotic; Animals; beta-Endorphin; Bipolar Disorder; Dextroamphetamine; Disease Models, Animal; Endorphins; Humans; Limbic System; Male; Morphine; Motor Activity; Naloxone; Neural Pathways; Rats; Rats, Inbred Strains; Receptors, Dopamine; Substance Withdrawal Syndrome; Tegmentum Mesencephali