dynorphins and Chronic-Disease

Chronic pain is one of the most ubiquitous diseases in the world, but treatment is difficult with conventional methods, due to undesirable side effects of treatments and unknown mechanisms of pathological pain states. The endogenous peptide, dynorphin A has long been established as a target for the treatment of pain. Interestingly, this unique peptide has both inhibitory (opioid in nature) and excitatory activities (nonopioid) in the CNS. Both of these effects have been found to play a role in pain and much work has been done to develop therapeutics to enhance the inhibitory effects. Here we will review the dynorphin A compounds that have been designed for the modulation of pain and will discuss where the field stands today.

Topics: Analgesics, Non-Narcotic; Chronic Disease; Dynorphins; Humans; Neuralgia; Neurotransmitter Agents; Receptors, Bradykinin; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa; Structure-Activity Relationship

Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both.

Topics: Animals; Brain; Chronic Disease; Comorbidity; Depressive Disorder; Disease Models, Animal; Dynorphins; Fear; Humans; Narcotic Antagonists; Receptors, Opioid, kappa; Stress, Psychological

Initial hypotheses regarding the role of the kappa opioid system in drug addiction suggested that kappa receptor stimulation had anti-addictive effects. However, recent research suggests that kappa receptor antagonists may reverse motivational aspects of dependence. In the present review, we revisit the studies that measured the effects of kappa receptor ligands on the reinforcing and rewarding effects of drugs and postulate underlying neurobiological mechanisms for these effects to elaborate a more complex view of the role of kappa receptor ligands in drug addiction.. The review of studies indicates that kappa receptor stimulation generally antagonizes the acute reinforcing/rewarding effects of drugs whereas kappa receptor blockade has no consistent effect. However, in a drug dependent-like state, kappa receptor blockade was effective in reducing increased drug intake. In animal models of reinstatement, kappa receptor stimulation can induce reinstatement via a stress-like mechanism. Results in conditioned place preference/aversion and intracranial self-stimulation indicate that kappa receptor agonists produce, respectively, aversive-like and dysphoric-like effects. Additionally, preclinical and postmortem studies show that administration or self-administration of cocaine, ethanol, and heroin activate the kappa opioid system.. kappa receptor agonists antagonize the reinforcing/rewarding effects of drugs possibly through punishing/aversive-like effects and reinstate drug seeking through stress-like effects. Evidence suggests that abused drugs activate the kappa opioid system, which may play a key role in motivational aspects of dependence. Kappa opioid systems may have an important role in driving compulsive drug intake.

Topics: Analgesics, Opioid; Animals; Chronic Disease; Drug Tolerance; Dynorphins; Humans; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reinforcement, Psychology; Reward; Self Administration; Substance-Related Disorders

In lumbar cerebrospinal fluid (CSF) obtained from patients with chronic tension-type headache (CTH), the concentrations of beta-endorphin, met-enkephalin, dynorphin, cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), and somatostatin were measured before and after 8 weeks of treatment with sulpiride or paroxetine. We previously reported higher than normal met-enkephalin concentrations in CTH. The present study reveals normal basal concentrations of CCK, CGRP and somatostatin and slightly decreased dynorphin in the same patients. Treatment with sulpiride or paroxetine did not change the concentration of any of the neuropeptides measured. These data suggest central changes in opioid systems but not in other peptide systems (CCK, CGRP, somatostatin) involved in nociceptive processing at the level of the spinal cord dorsal horn/nucleus caudalis of the trigeminal nerve in CTH. Such central changes might be pathophysiologically important or merely secondary to other more important occurrences. The lack of changes in neuropeptide concentrations during drug treatment makes planning of studies involving CSF analysis easier, but also limits the probability of obtaining information on specific neuropeptide systems through CSF analysis.

Topics: Adult; Aged; Basal Metabolism; Calcitonin Gene-Related Peptide; Cholecystokinin; Chronic Disease; Dopamine D2 Receptor Antagonists; Dynorphins; Female; Humans; Male; Middle Aged; Neuropeptides; Paroxetine; Somatostatin; Sulpiride; Tension-Type Headache

Accumulating evidence indicates that kappa-opioid receptors (KORs) and their endogenous ligand, dynorphin (DYN), can play important roles in regulating the effects of stress. Here, we examined the role of KOR systems in the molecular and behavioral effects of acute (1-day) and chronic (10-day) social defeat stress (SDS) in mice. We found that acute SDS increased DYN mRNA levels within the nucleus accumbens, a key element of brain dopamine (DA) systems. In contrast, chronic SDS produced long-lasting decreases in DYN mRNA levels. We then examined whether disruption of KOR function would affect development of SDS-induced depressive-like behaviors, as measured in the intracranial self-stimulation and social interaction tests. Ablation of KORs from DA transporter-expressing neurons delayed the development of SDS-induced anhedonia in the intracranial self-stimulation test, suggesting increased stress resilience. However, administration of the long-lasting KOR antagonist JDTic (30 mg/kg, intraperitoneally) before the SDS regimen did not affect anhedonia, suggesting that disruption of KOR function outside DA systems can oppose stress resilience. Social avoidance behavior measured after the 10-day SDS regimen was not altered by ablation of KORs in DA transporter-expressing neurons or by JDTic administration before testing. Our findings indicate that KORs expressed in DA systems regulate the effects of acute, but not chronic, social stress.

Topics: Acute Disease; Anhedonia; Animals; Chronic Disease; Dominance-Subordination; Dopamine Plasma Membrane Transport Proteins; Dynorphins; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Nucleus Accumbens; Psychological Tests; Receptors, Opioid, kappa; Resilience, Psychological; RNA, Messenger; Self Stimulation; Social Behavior; Stress, Psychological; Time Factors

The chronic use of nicotine, the main psychoactive ingredient of tobacco smoking, alters diverse physiological processes and consequently generates physical dependence. To understand the impact of chronic nicotine on neuropeptides, which are potential molecules associated with dependence, we conducted qualitative and quantitative neuropeptidomics on the rat dorsal striatum, an important brain region implicated in the preoccupation/craving phase of drug dependence. We used extensive LC-FT-MS/MS analyses for neuropeptide identification and LC-FT-MS in conjunction with stable isotope addition for relative quantification. The treatment with chronic nicotine for 3 months led to moderate changes in the levels of endogenous dorsal striatum peptides. Five enkephalin opioid peptides were up-regulated, although no change was observed for dynorphin peptides. Specially, nicotine altered levels of nine non-opioid peptides derived from precursors, including somatostatin and cerebellin, which potentially modulate neurotransmitter release and energy metabolism. This broad but selective impact on the multiple peptidergic systems suggests that apart from the opioid peptides, several other peptidergic systems are involved in the preoccupation/craving phase of drug dependence. Our finding permits future evaluation of the neurochemical circuits modulated by chronic nicotine exposure and provides a number of novel molecules that could serve as potential therapeutic targets for treating drug dependence.

Topics: Administration, Oral; Amino Acid Sequence; Animals; Chromatography, Liquid; Chronic Disease; Corpus Striatum; Dynorphins; Enkephalins; Gene Expression Regulation; Isotope Labeling; Male; Molecular Sequence Data; Nerve Tissue Proteins; Neuropeptides; Nicotine; Protein Precursors; Proteome; Rats; Rats, Long-Evans; Somatostatin; Tandem Mass Spectrometry; Tobacco Use Disorder

Although morphine and other mu-opioid agonists are the main analgesics for severe pain, these compounds have potential for abuse and/or addiction. This has complicated the use of mu-agonists in the treatment of chronic pain. However, clinical studies show that when mu-agonist analgesics are appropriately used to control pain, actual abuse or addiction does not usually occur, although some risk factors that increase vulnerability need to be considered, including genetic variation. We review recent findings on molecular adaptations in sustained pain models, and propose how these adaptations (including sustained release of the endogenous mu-agonist beta-endorphin) can result in decreased abuse potential of mu-agonists in chronic pain states. We also review data on particular gene polymorphisms (e.g. in the mu-receptor gene) that could also influence the relative abuse potential of mu-agonists in clinical pain populations.

Topics: Analgesics, Opioid; Chronic Disease; Down-Regulation; Dynorphins; Endorphins; Extracellular Signal-Regulated MAP Kinases; Humans; Neuralgia; Opioid-Related Disorders; Pain; Protein Kinase C; Receptors, Dopamine; Receptors, Opioid, mu; Reward; Up-Regulation; Ventral Tegmental Area

Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-gamma agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Catalepsy; CD11b Antigen; Chromatography, High Pressure Liquid; Chronic Disease; Disease Models, Animal; Dopamine; Drug Interactions; Dynorphins; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Globus Pallidus; Locomotion; Male; Mice; Mice, Inbred C57BL; Motor Activity; MPTP Poisoning; PPAR gamma; Psychomotor Performance; RNA, Messenger; Rosiglitazone; Smell; Tandem Mass Spectrometry; Thiazolidinediones; Tyrosine 3-Monooxygenase

The Fischer 344 (F344) rat strain differs from the Lewis strain in the response to neuropathic pain. Recently, we found that F344 rats totally recover from mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve 28 days after surgery whereas Lewis rats are initiating their recovery at this time point. Thus, the use of this neuropathic pain model in these different rat strains constitutes a good strategy to identify possible target genes involved in the development of neuropathic pain. Since differences between Lewis and F344 rats in their response to pain stimuli in acute pain models have been related to differences in the endogenous opioid and noradrenergic systems, we aimed to determine the levels of expression of key genes of both systems in the spinal cord and dorsal root ganglia (DRG) of both strains 28 days after CCI surgery. Real time RT-PCR revealed minimal changes in gene expression in the spinal cord after CCI despite the strain considered, but marked changes in DRG were observed. A significant upregulation of prodynorphin gene expression occurred only in injured DRG of F344 rats, the most resistant strain to neuropathic pain. In addition, we found a significant downregulation of tyrosine hydroxylase and proenkephalin gene expression levels in both strains whereas delta-opioid receptor was found to be significantly downregulated only in injured DRG of Lewis rats although the same trend was observed in F344 rats. The data strongly suggest that dynorphins could be involved in strain differences concerning CCI resistance.

Topics: Animals; Chronic Disease; Denervation; Disease Models, Animal; Down-Regulation; Dynorphins; Enkephalins; Ganglia, Spinal; Gene Expression Regulation; Hyperalgesia; Ligation; Male; Neurons, Afferent; Norepinephrine; Peripheral Nerve Injuries; Peripheral Nerves; Peripheral Nervous System Diseases; Protein Precursors; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptors, Opioid, delta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Species Specificity; Spinal Cord; Tyrosine 3-Monooxygenase

Clinically, it has been reported that chronic pain induces depression, anxiety, and reduced quality of life. The endogenous opioid system has been implicated in nociception, anxiety, and stress. The present study was undertaken to investigate whether chronic pain could induce anxiogenic effects and changes in the opioidergic function in the amygdala in mice. We found that either injection of complete Freund's adjuvant (CFA) or neuropathic pain induced by sciatic nerve ligation produced a significant anxiogenic effect at 4 weeks after the injection or surgery. Under these conditions, the selective mu-opioid receptor agonist [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO)- and the selective delta-opioid receptor agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)-stimulated [35S]GTPgammaS binding in membranes of the amygdala was significantly suppressed by CFA injection or nerve ligation. CFA injection was associated with a significant increase in the kappa-opioid receptor agonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride (ICI199,441)-stimulated [35S]GTPgammaS binding in membranes of the amygdala. The intracerebroventricular administration and microinjection of a selective mu-opioid receptor antagonist, a selective delta-opioid receptor antagonist, and the endogenous kappa-opioid receptor ligand dynorphin A caused a significant anxiogenic effect in mice. We also found that thermal hyperalgesia induced by sciatic nerve ligation was reversed at 8 weeks after surgery. In the light-dark test, the time spent in the lit compartment was not changed at 8 weeks after surgery. Collectively, the present data constitute the first evidence that chronic pain has an anxiogenic effect in mice. This phenomenon may be associated with changes in opioidergic function in the amygdala.

Topics: Amygdala; Analgesics, Opioid; Analysis of Variance; Animals; Anxiety; Behavior, Animal; Benzamides; Chronic Disease; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Freund's Adjuvant; Guanosine 5'-O-(3-Thiotriphosphate); Injections, Intraventricular; Male; Maze Learning; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pain Measurement; Piperazines; Protein Binding; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reaction Time; Sciatica; Somatostatin; Sulfur Isotopes; Time Factors; Tranquilizing Agents

The aging process is associated with various morphological and biochemical changes in the nervous system that may affect the processing of noxious inputs. This study showed greater hyperalgesia and up-regulation of spinal dynorphin (DYN) expression in aging than in young adult rats during CFA-induced peripheral inflammation. These data indicate that nociception is regulated differently in aging individuals, a fact that should be considered when selecting treatment strategies for aging populations with persistent pain.

Topics: Aging; Animals; Chronic Disease; Disease Models, Animal; Dynorphins; Freund's Adjuvant; Functional Laterality; Hyperalgesia; Immunohistochemistry; Inflammation; Male; Peripheral Nervous System Diseases; Physical Stimulation; Posterior Horn Cells; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

In vivo electroporation has been successfully used for the introduction of DNA, RNA, oligonucleotides, and proteins into cells for experimental and therapeutic purposes. The authors evaluated the efficacy of electroporation-mediated c-Fos antibody therapy for neuropathic pain in vitro and in vivo.. First, the authors studied the inhibitory effects of intrathecal c-Fos antibody electroporation on the activating protein (AP-1) promoter activity in cultured spinal neuronal cells transfected with p-AP-Luc plasmid and activated with 100 microm glutamate. The inhibitory effect of c-Fos antibody electroporation in the regulation of AP-1 promoter activity was assessed according to the relative luciferase activity. Second, rats with chronic constrictive injury underwent electroporation treatment for neuropathic pain using c-Fos antibody. Thermal nociceptive thresholds were measured before chronic constrictive injury and then on even-numbered days, up to and including day 14, to assess and compare the therapeutic effects of intrathecal electroporation. The time course was assessed by Western blot analysis and by immunohistochemical analysis. Pronociceptive gene expression was measured by assessing prodynorphin mRNA and dynorphin peptides on days 2 and 10 after intrathecal c-Fos electroporation.. Cotransfection of c-Fos antibody significantly decreased glutamate-induced AP-1 activity. Intrathecal electrotransfer of c-Fos antibody attenuated spinal dynorphin levels, as manifested by significantly elevated pain thresholds in the chronic constrictive injury-affected limbs.. This study shows that transfer of antibody into rat spinal cords by intrathecal electroporation is a useful method to study the function of endogenous factors of spinal-related disorders.

Topics: Animals; Antibodies; Cells, Cultured; Chronic Disease; Dose-Response Relationship, Drug; Dynorphins; Electroporation; Gene Expression Regulation; Genes, fos; Hyperalgesia; Injections, Spinal; Male; Neurons; Protein Precursors; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Spinal Cord

Some antiepileptic drugs have been shown to be clinically effective in the treatment of neuropathic pain. This study determined whether the new antiepileptic drug tiagabine, a GABA uptake inhibitor, is efficacious in mice in a broad range of nociceptive tests (hot-plate, formalin, and dynorphin-induced chronic allodynia) and compared tiagabine's potency with two other antiepileptic drugs, gabapentin and lamotrigine. Intraperitoneally administered tiagabine, but not lamotrigine, gabapentin, or i.t. tiagabine, produced dose-dependent antinoception in the hot-plate test. A 5-min pretreatment with tiagabine (2-29 nmol i.t.) dose-dependently inhibited both the acute and late phase formalin behaviors; pretreatment with lamotrigine (4-265 nmol i.t.) inhibited only the late phase. In the formalin assay the GABA(A) antagonist bicuculline reversed the acute phase antinociception, whereas the GABA(B) antagonist saclofen reversed both the acute and late phase tiagabine-induced antinociception. Tiagabine administered i.p. but not i.t. dose-dependently reduced dynorphin-induced chronic allodynia for 120 min. Gabapentin and lamotrigine produced antinociception administered either i.t. or i.p. in a dose-dependent manner. Thus, we have shown that gabapentin and lamotrigine produced antinociception in two mouse models of pain, whereas tiagabine produced antinociception in all three mouse models of pain.

Topics: Acetates; Acute Disease; Adrenergic alpha-Agonists; Amines; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Anticonvulsants; Chronic Disease; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Dynorphins; Formaldehyde; GABA Antagonists; Gabapentin; gamma-Aminobutyric Acid; Hot Temperature; Injections, Intraperitoneal; Injections, Spinal; Lamotrigine; Male; Mice; Mice, Inbred ICR; Nipecotic Acids; Pain; Pain Measurement; Reaction Time; Tiagabine; Triazines

The influence of chronic arthritic pain on two endogenous opioid peptides, dynorphin B and [Met5]enkephalin-Arg6-Phe7, and multiple opioid receptors in discrete brain, lumbar spinal cord and pituitary pools was investigated. Using radioimmunoassay and receptor binding assay, we examined the changes in regional opioid peptide levels and opioid receptor activity due to chronic inflammation in adjuvant arthritic rats. At 4 weeks post-inoculation, increased levels of immunoreactive dynorphin B and [Met5]enkephalin-Arg6-Phe7 were measured in tissues of arthritic rats compared with controls. No significant changes in mu-, delta- or kappa-opioid receptors were seen after chronic inflammation. Taken together, these results indicate that in chronic arthritis, opioid receptor changes do not follow the peptide alterations of pro-dynorphin and pro-enkephalin systems. Thus, dynamic modification and modulation of nociceptive information takes place during chronic inflammation. This supports the key role of the central nervous system in chronic inflammatory pain conditions.

Topics: Animals; Brain; Chronic Disease; Disease Models, Animal; Dynorphins; Endorphins; Enkephalin, Methionine; Female; Inflammation; Opioid Peptides; Pain; Pain Measurement; Rats; Rats, Inbred Lew; Receptors, Opioid; Spinal Cord

Whereas tissue injury increases spinal dynorphin expression, the functional relevance of this upregulation to persistent pain is unknown. Here, mice lacking the prodynorphin gene were studied for sensitivity to non-noxious and noxious stimuli, before and after induction of experimental neuropathic pain. Prodynorphin knock-out (KO) mice had normal responses to acute non-noxious stimuli and a mild increased sensitivity to some noxious stimuli. After spinal nerve ligation (SNL), both wild-type (WT) and KO mice demonstrated decreased thresholds to innocuous mechanical and to noxious thermal stimuli, indicating that dynorphin is not required for initiation of neuropathic pain. However, whereas neuropathic pain was sustained in WT mice, KO mice showed a return to baselines by post-SNL day 10. In WT mice, SNL upregulated lumbar dynorphin content on day 10, but not day 2, after injury. Intrathecal dynorphin antiserum reversed neuropathic pain in WT mice at post-SNL day 10 (when dynorphin was upregulated) but not on post-SNL day 2; intrathecal MK-801 reversed SNL-pain at both times. Opioid (mu, delta, and kappa) receptor density and G-protein activation were not different between WT and KO mice and were unchanged by SNL injury. The observations suggest (1) an early, dynorphin-independent phase of neuropathic pain and a later dynorphin-dependent stage, (2) that upregulated spinal dynorphin is pronociceptive and required for the maintenance of persistent neuropathic pain, and (3) that processes required for the initiation and the maintenance of the neuropathic pain state are distinct. Identification of mechanisms that maintain neuropathic pain appears important for strategies to treat neuropathic pain.

Topics: Animals; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Hyperesthesia; Immune Sera; Injections, Spinal; Ligation; Lumbosacral Region; Male; Mice; Mice, Knockout; Neuralgia; Pain Measurement; Pain Threshold; Physical Stimulation; Reaction Time; Receptors, Opioid; Spinal Cord; Spinal Nerves

To establish a reliable animal model of chronic arthritic inflammatory pain, to find the optimal parameters and appropriate intervals of repeated 100 Hz transcutaneous electrical nerve stimulation (TENS) for the treatment of the chronic arthritic pain, and to explore the possible central neurochemical mechanisms.. (1) Injection of water-in-oil type complete Freund's adjuvant into the tibio-tarsal joint of the rat produced a reliable, reproducible monoarthritic model. (2) The interval between 2 sessions of stimulations and the intensity of stimulation were important factors determining the therapeutic effects of repeated 100 Hz TENS on both acute and stable period of monoarthritis. (a) For acute period of monoarthritis, the optimal frequency is twice a week, while in the stable period, once a week seems better. (b) The effects of TENS in three intensities: the weaker stimulation was found to produce better results. (3) In the period from 2 to 9 weeks, the levels of spinal release of SP-ir in the TENS group were lower than the control group. This may constitute one of the possible neuro-chemical mechanisms underlying the therapeutic effects of multiple TENS treatment. (4) In both acute and stable period of adjuvant-induced monoarthritis, intrathecal microinjection of Nor-BNI produced dose-dependent increase of arthritic flexion pain scores (i.e. hyperalgesia), suggesting that spinal dynorphin/kappa system plays a role in suppressing arthritic pain.

Topics: Animals; Arthralgia; Arthritis, Experimental; Chronic Disease; Dynorphins; Naltrexone; Pain Threshold; Rats; Substance P; Transcutaneous Electric Nerve Stimulation

The effects of N-methyl-D-aspartate(NMDA) receptor antagonist, Mk-801, on the expression of spinal dynorphin (DYN) mRNA and the hyperalgesia induced by peripheral inflammation were studied by Northern analysis and behavioral test. Following an unilateral injection of complete Freund's adjuvant (CFA) into the rat hindpaw, there appeared a significant hyperalgesia of inflamed hindpaw and up-regulation of ipsilateral spinal DYN mRNA; while the pre-emptive and continuous intrathecal administration of Mk-801 (10 microg/microl per h) could significantly suppress both the hyperalgesia and the up-regulation of spinal DYN mRNA induced by peripheral inflammation. The results suggest that NMDA receptor activation may contribute to the development and maintenance of the thermal hyperalgesia that is associated with the up-regulation of DYN expression in spinal dorsal horn.

Topics: Animals; Binding, Competitive; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Dynorphins; Freund's Adjuvant; Hindlimb; Hyperalgesia; Inflammation; Infusion Pumps, Implantable; Injections, Spinal; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Spinal Cord; Up-Regulation

We have used a partial sciatic nerve ligation model to examine the time course for changes in the expression of mRNA for three peptides related to pain transmission at spinal sites (dynorphin, enkephalin and substance P), during the development of allodynia. Enhanced expression of mRNA for dynorphin and substance P was observed in the dorsal horn on the same side as the partial nerve ligation. Increased expression of dynorphin mRNA was biphasic. The initial increases in expression of dynorphin mRNA occurred at 3 h, and a secondary peak was observed 1-3 days after surgery. The secondary increases coincided roughly with increased substance P mRNA expression. However, both dynorphin and substance P mRNA returned to control values after 1 week despite continuing allodynia. No significant changes in expression of mRNA for enkephalin were observed. The elevation of substance P mRNA in intrinsic spinal cord neurons may be secondary to changes in immediate early genes c-fos and jun-B, whereas the expression of dynorphin and enkephalin mRNA is differently regulated. The results also suggest that changes in the expression of the three neuropeptides are not critically involved in the development and maintenance of chronic pain or allodynia.

Topics: Animals; Behavior, Animal; Chronic Disease; Disease Models, Animal; Dynorphins; Enkephalins; Gene Expression; Male; Neuropeptides; Pain; Rats; Rats, Sprague-Dawley; RNA, Messenger; Spinal Cord; Substance P; Time Factors

The aim of our study was to evaluate the effects of endogenous opioids on the secretion of atrial natriuretic factor (ANF) in moderate chronic heart failure (HF).. We evaluated the effects of i.v. volume load (NaCl 0.9% at 0.25 ml/Kg/min for 60 minutes) on heart rate (HR), on mean arterial pressure (MAP) and on the plasma levels of beta-endorphin (beta-end), met-enkephalin (Met-enk), dynorphin (Dyn), atrial natriuretic factor (ANF) and noradrenaline (NA) in 10 patients (age 58 +/- 9) with HF in NYHA class II (group I) and in 8 healthy control subjects (age 54 +/- 10) group II). The volume load was repeated after at least three days during infusion of naloxone (2 micrograms/Kg/min), evaluating the above mentioned hemodynamic and hormonal parameters.. The acute volume expansion caused an increase in ANF concentration (from 51.7 +/- 19.7 to 67.4 +/- 36.9 pg/ml; p < 0.05) and in beta-end (from 11.9 +/- 5.3 to 16.6 +/- 7.5 fmol/ml; p < 0.05), In group I. In group II an isolated increase in ANF was observed (from 14.1 +/- 7.8 to 21.9 +/- 7.9 pg/ml; p < 0.02). No significant changes were detected for HR, MAP, Dyn, Met-enk and NA. In group I the percent increase of ANF is less than in group II (30 vs 55%; p < 0.05). The volume load infused during naloxone infusion caused a significant increase in HR (from 73 +/- 6 to 78 +/- 9 bpm; p < 0.05) and in NA (from 311 +/- 123 to 415 +/- 142 pg/ml; p < 0.05) In group I. In group II, an increase in ANF was detected (from 13.8 +/- 6.0 to 23.6 +/- 5.0 pg/ml; p < 0.01).. Our data suggest that in moderate HF beta-end stimulates the secretion of ANF and inhibits the activity of the sympatho-adrenergic system during acute volume expansion.

Topics: Adult; Aged; Analysis of Variance; Atrial Natriuretic Factor; beta-Endorphin; Chronic Disease; Data Interpretation, Statistical; Dynorphins; Enkephalin, Methionine; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Norepinephrine; Plasma Volume; Receptors, Adrenergic; Sodium Chloride; Sympathetic Nervous System

Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.

Topics: Animals; Chronic Disease; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Injections, Spinal; Male; Naloxone; Narcotic Antagonists; Pain; Peptide Fragments; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sensory Thresholds

We investigated the effects of collagen II-induced arthritis on two cerebrospinal fluid (CSF) enzymes converting dynorphin A and substance P (SP), namely dynorphin-converting enzyme (DCE) and substance P endopeptidase (SPE). The products generated by these enzymes are the bioactive fragments Leu-enkephalin-Arg6 and substance P, respectively. The strain used (DA rats) is very sensitive towards induction of arthritis. The collagen arthritis is a chronic autoimmune arthritis induced by native rat collagen type II (CII). Following intradermal injection of CII into the tailbase. CSF was sampled on day 21 (acute arthritis) and day 38 (chronic arthritis). Control rats were untreated because the strain used developed an acute and self-limited arthritis (adjuvant arthritis) when administered vehicle (i.e. incomplete Freund's adjuvant). The DCE activity was significantly lowered in the acute phase of arthritis (P less than 0.05) when analysed with two-factor analysis of variance (ANOVA). The enzyme converting SP (SPE) also showed a significant decrease in the acute phase of arthritis (P less than 0.05). These results demonstrate that both DCE and SPE are affected in the acute phase of arthritis. A functional role of these enzymes in processing pain-related neuropeptides is therefore implicated.

Topics: Acute Disease; Amino Acid Sequence; Analysis of Variance; Animals; Arthritis, Experimental; Chromatography, High Pressure Liquid; Chronic Disease; Collagen; Cysteine Endopeptidases; Dynorphins; Hemoglobins; Metalloendopeptidases; Molecular Sequence Data; Rats; Rats, Wistar; Regression Analysis; Substance P; Time Factors

Thirteen patients with pain from various causes were treated by electroacupuncture for 30 min. Cerebrospinal fluid (CSF) was obtained before and after treatment. Opioid-like substances in the CSF were fractionated by high pressure liquid chromatography and assayed by competitive receptor binding using a mu-specific radioligand, [D-ala2, MePhe4, gly-ol5]-enkephalin (DAGO). Opioid activity, associated with a fraction, eluted at 18-20% acetonitrile, consistently showed an increase in level after acupuncture. Two other fractions eluted at larger concentrations of acetonitrile also increased significantly after acupuncture; however the increase was not consistently observed in every patient. Measurements of beta-endorphin and dynorphin by radioimmunoassay indicated that 80 and 60% of the patients, respectively, had a higher level of these peptides after acupuncture. The nature of the opioid activity, eluted at 18-20% acetonitrile is unknown; however a small amount of it could be found in various parts of the brain of rat.

Topics: beta-Endorphin; Chromatography, High Pressure Liquid; Chronic Disease; Dynorphins; Electroacupuncture; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Humans; Pain; Pain Management; Radioimmunoassay

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

Inoculation of rats at the tail-base with Mycobacterium led to arthritic swelling and inflammation of all four limbs. Immunoreactive (ir)-dynorphin (DYN) increased in anterior but not neurointermediate pituitary. In the brain, only thalamus showed a rise and, in spinal cord, a large elevation was seen. Ir-vasopressin (VP) was not affected in these tissues but increased in midbrain. These effects might reflect a role of DYN in the control of chronic pain. In addition, they support a differential modulation of DYN as compared to VP extrinsic to the hypothalamic-neurohypophyseal axis.

Topics: Animals; Central Nervous System; Chronic Disease; Dynorphins; Mesencephalon; Pain; Pituitary Gland, Anterior; Rats; Spinal Cord; Thalamus; Vasopressins

Inoculation of rats with Mycobacterium butyricum produced an arthritis of the limbs which revealed an enhanced sensitivity to noxious mechanical pressure (hyperalgesia). Arthritic rats displayed a pronounced rise in immunoreactive dynorphin in lumbo-sacral spinal cord which correlated both with the intensity and time-course of this hyperalgesia. MR-2266, a relatively preferential antagonist at the chi-opioid receptor (at which dynorphin is considered to act) potentiated this hyperalgesia. In contrast, MR 2267 (its inactive stereo-isomer) was ineffective. Further, naloxone (a weak chi-antagonist), and ICI 154,129 (a preferential delta-antagonist) were, in each case, inactive. The data demonstrate a pronounced response of spinal dynorphin to chronic arthritic pain in the rat. In addition, they raise the possibility of a function of spinal DYN, via a chi-receptor, in the modulation of chronic arthritic pain.

Topics: Animals; Arthritis; Chronic Disease; Conditioning, Classical; Dynorphins; Enkephalin, Methionine; Mycobacterium Infections; Naloxone; Nociceptors; Pain; Radioimmunoassay; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Spinal Cord