beta-endorphin and Opioid-Related-Disorders

Psychiatric pharmacogenetics involves the use of genetic tests that can predict the effectiveness of treatments for individual patients with mental illness such as drug dependence. This review aims to cover these developments in the pharmacotherapy of alcohol and opiates, two addictive drugs for which we have the majority of our FDA approved pharmacotherapies.. We conducted a literature review using Medline searching terms related to these two drugs and their pharmacotherapies crossed with related genetic studies.. Alcohol's physiological and subjective effects are associated with enhanced beta-endorphin release. Naltrexone increases baseline beta-endorphin release blocking further release by alcohol. Naltrexone's action as an alcohol pharmacotherapy is facilitated by a putative functional single nucleotide polymorphism (SNP) in the opioid mu receptor gene (Al18G) which alters receptor function. Patients with this SNP have significantly lower relapse rates to alcoholism when treated with naltrexone. Caucasians with various forms of the CYP2D6 enzyme results in a 'poor metabolizer' phenotype and appear to be protected from developing opioid dependence. Others with a "ultra-rapid metabolizer" phenotype do poorly on methadone maintenance and have frequent withdrawal symptoms. These patients can do well using buprenorphine because it is not significantly metabolized by CYP2D6.. Pharmacogenetics has great potential for improving treatment outcome as we identify gene variants that affect pharmacodynamic and pharmacokinetic factors. These mutations guide pharmacotherapeutic agent choice for optimum treatment of alcohol and opiate abuse and subsequent relapse.

Topics: Alcoholism; beta-Endorphin; Buprenorphine; Cytochrome P-450 CYP2D6; Humans; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Polymorphism, Single Nucleotide; Predictive Value of Tests; Receptors, Opioid, mu

The majority of medicines developed for narcotic and stimulant dependence were agonists or antagonists of neurotransmitters and their receptors. Recently it has been shown that the nervous system, the endocrine system and the immune system are regulated by mutual interaction. The nervous system and the endocrine system are influenced by an immunomodulator, and the immune system is regulated by a neurotransmitter. In this report, medicines for morphine and cocaine dependence are first surveyed and then medicines for drug dependence through the activation of the immune system are introduced including our results which show the effect of macrophage activator such as LPS on morphine and cocaine dependence. The LPS purified from Pantoea agglomerans showed a relief effect on physical dependence of morphine and psychic dependence of cocaine, while it induced endogenous opioid, beta-endorphin. The induction of beta-endorphin was recognized to be in synchrony with the time course and dose response of the relief of dependence. These data suggest the participation of endogenous opioid such as beta-endorphin induced by LPS after the activation of macrophage leading to the relief of morphine and cocaine dependence.

Topics: Adjuvants, Immunologic; beta-Endorphin; Cocaine; Humans; Lipopolysaccharides; Macrophage Activation; Morphine Dependence; Opioid-Related Disorders

Topics: Affective Disorders, Psychotic; Animals; Anxiety; beta-Endorphin; Catatonia; Dyskinesia, Drug-Induced; Electroconvulsive Therapy; Endorphins; Humans; Mental Disorders; Narcotic Antagonists; Opioid-Related Disorders; Pain; Rats; Receptors, Opioid; Renal Dialysis; Schizophrenia; Stress, Psychological

Topics: Amino Acid Sequence; Animals; beta-Endorphin; Central Nervous System; Endorphins; Enkephalins; Humans; Lithium; Narcotics; Neurotransmitter Agents; Opioid-Related Disorders; Phylogeny; Pituitary Gland; Receptors, Opioid; Sodium; Solubility

The effect of clonidine on plasma beta-endorphin, cortisol and growth hormone was studied in nine opiate-addicted subjects and seven control subjects aged 15 to 37 years. Clonidine, 0.15 mg, was administered orally in the morning, 18 to 24 h after the last administration of opioid drugs. Basal morning beta-endorphin levels were lower in the addicted than in the control subjects (3.76 +/- 0.8 vs. 7.42 +/- 1.2 pmol/l). Following the clonidine, there was an increase to normal values in the addicted subjects, but in the control subjects there was no change. Basal morning levels of cortisol were higher in the addicted subjects than in the controls (21.0 +/- 3.6 micrograms/dl vs. 13.0 +/- 1.2 microgram/dl, mean +/- SE). In control subjects clonidine induced a decrease of 50% in plasma cortisol, whereas in addicted subjects the decrease was not significant. It is hypothesized that in addicted subjects there is impaired activity of endogenous opioid peptides, leading to alteration in beta-endorphin and cortisol secretion.

Topics: Adolescent; Adult; beta-Endorphin; Clinical Trials as Topic; Clonidine; Endorphins; Female; Growth Hormone; Heroin Dependence; Humans; Hydrocortisone; Male; Opioid-Related Disorders; Substance Withdrawal Syndrome

The study aimed to examine the genetic contribution to buprenorphine (BUP) treatment in individuals with opioid use disorder (OUD), with a specific focus on BDNF and OPRM1 genes. A total of 113 controls and 111 OUD patients receiving sublingual BUP/naloxone were enrolled. OPRM1 A118G and BDNF Val66Met polymorphisms were investigated by PCR-FRLP. Plasma BDNF and beta-endorphin levels were assessed by ELISA kits in both groups. Blood BUP levels were measured by LC-MS/MS and normalized with daily BUP dose (BUP/D). OPRM1 A118G and BDNF Val66Met polymorphisms didn't have an effect on plasma beta-endorphin and BDNF levels in OUD patients, respectively. Interestingly, OUD patients had significantly higher plasma BDNF and lower beta-endorphin levels compared to the controls (p < 0.001). A negative and significant correlation between plasma BUP/D and BDNF levels was found. Age onset of first use was associated with OPRM1 A118G polymorphism. The findings indicated that sublingual BUP/naloxone may increase plasma BDNF levels, but may decrease beta-endorphin levels in individuals with OUD. Plasma BDNF level seemed to be decreased in a BUP/D concentration-dependent manner.

Topics: beta-Endorphin; Brain-Derived Neurotrophic Factor; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Chromatography, Liquid; Humans; Opioid-Related Disorders; Receptors, Opioid, mu; Tandem Mass Spectrometry

The regulation of blood glucose level in intracerebroventricular (i.c.v.) administration with opioid alone or opioid withdrawal model was studied in ICR mice. In the first group, we found that i.c.v. administered morphine or beta-endorphin alone causes an elevation of blood glucose level. Blood glucose level induced by i.c.v. morphine or beta-endorphin began to increase within 30min and reached maximal level at 1h, decreasing to the basal level after 2h. In another group, we observed that intraperitoneal (i.p.) injection with naloxone (10mg/kg) post-treated 3h after either a single i.c.v. injection with morphine or beta-endorphin did not affect the increased blood glucose level in either group. In the next study, we observed that multiple (1 time/day for 3 days) i.c.v. injection with morphine alone significantly increased the blood glucose level. However, i.p. injection with naloxone post-treated 3h after the last i.c.v. injection with morphine caused a decrease of blood glucose level. We found that multiple (1 time/day for 3 days) i.c.v. injections with beta-endorphin did not affect the blood glucose level. Furthermore, i.p. injection with naloxone did not affect the blood glucose level in the mice injected with multiply beta-endorphin. Our results suggest that both morphine and beta-endorphin administered i.c.v. acutely increases the blood glucose level. However, blood glucose levels in the groups of multiply administered morphine alone, beta-endorphin alone, and naloxone-treated withdrawal model in multiply injected morphine and beta-endorphin appear to be differentially regulated.

Topics: Animals; beta-Endorphin; Blood Glucose; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Substance Withdrawal Syndrome

The effect exerted by two beta-endorphin fragments (DTgammaE and DEgammaE) was investigated on the acute opioid dependence induced by mu, kappa and delta receptor agonists in vitro. After a 4-min in vitro exposure to morphine (less selective mu agonist), DAGO (highly selective mu agonist), U50-488H (highly selective kappa agonist) and beta-endorphin (selective mu-delta agonist), a strong contracture of guinea pig isolated ileum was observed after the addition of naloxone. This effect was also observed when rabbit isolated jejunum was pretreated with deltorphin (highly selective delta agonist). DTgammaE or DEgammaE injection treatment before or after morphine, DAGO, U50-488H, beta-endorphin or deltorphin were able to both prevent and reverse the naloxone-induced contracture after exposure to the opioid agonists in a concentration-dependent fashion. Our results indicate that both DTgammaE or DEgammaE are able to reduce significantly opioid dependence in vitro, suggesting an important functional interaction between beta-endorphin fragments and opioid dependence induced by mu, kappa and delta receptors.

Topics: Analgesics, Opioid; Animals; Antidepressive Agents; beta-Endorphin; Dose-Response Relationship, Drug; Endorphins; Guinea Pigs; Ileum; Male; Morphine; Muscle Contraction; Opioid-Related Disorders; Peptide Fragments; Substance Withdrawal Syndrome

Cytokines are known to influence neuronal functions. The purpose of this study was to investigate the putative role of the cytokine interleukin-6 (IL-6) in the pathways involved in opioid-mediated responses, by using IL-6-deficient mice. We reported that with a thermal stimulus IL-6-knock-out (IL-6KO) mice presented nociceptive thresholds similar to those measured in their controls. However, they showed a reduced analgesic response both to the restraint stress and to the administration of low doses of morphine. Hypothalamic levels of the opioid peptide beta-endorphin were significantly higher in IL-6KO mice than they were in their controls. The development of tolerance to the analgesic effect of morphine was more rapid in IL-6-deficient mice than in wild-type controls. Binding experiments showed that the number of opioid receptors in the midbrain, but not in the hypothalamus, decreased in IL-6KO mice. Autoradiographic binding analysis revealed that the density of mu receptors diminished while the delta-opioid receptors did not. These results suggest that IL-6 is necessary for a correct development of neuronal mechanisms involved in the response to both endogenous and exogenous opiates.

Topics: Analgesics, Opioid; Animals; beta-Endorphin; Brain Chemistry; Drug Tolerance; Hypothalamus; Interleukin-6; Mice; Mice, Knockout; Morphine; Nociceptors; Opioid-Related Disorders; Pain Threshold; Receptors, Opioid, mu; Restraint, Physical; Stress, Physiological

Topics: Animals; Aorta, Thoracic; Cocaine; Cyclic AMP; Electric Stimulation; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Male; Mice; Muscle, Smooth; Opioid-Related Disorders; Rats; Receptors, Dopamine; Receptors, Opioid; Receptors, Serotonin; Substance-Related Disorders

Plasma beta-endorphin-like radioimmunoreactivity (BEND) was measured in opiate addicts and controls with an antisera which cross reacted with lipotropin but not with other endogenous opiate peptides. 43 stable male methadone maintained patients had mean BEND of 18 +/- 11 pg/ml. No relationship was found between BEND, and time of day, dose or time since last methadone. Controls had 22 +/- 8pg/ml. 9 hospitalized freshly detoxified male opiate addicts, 7-23 days after last opioid, had BEND of 32 +/- 11 pg/ml. These same took 7 days of 50 mg oral naltrexone (NTX) daily, and repeat BEND was 41 +/- 13 pg/ml, rising in all instances compared to baseline. Ex-addicts after detoxification had high BEND which rose further during a short course of NTX. Methadone maintained patients had normal BEND. These data are consistent with previous animal and human reports of high plasma BEND level with NTX or detoxification.

Topics: Adult; beta-Endorphin; Endorphins; Humans; Male; Methadone; Middle Aged; Naltrexone; Opioid-Related Disorders; Time Factors

The early symptoms of brain dysfunction in infants born to heroin-addicted mothers were studied during the first month of life by a multimethod approach. Neurological examination and polygraphic EEG studies of sleep patterns were performed; concomitantly plasma levels of beta-endorphin and met-enkephalin were measured. Whenever possible, these parameters were correlated with each other and with the severity of the withdrawal syndrome. While the neurological examination of addicted newborns was almost negative, altered sleep cycles with a decrease in active sleep and an increase in quiet sleep were noted together with a marked increase in the plasma concentration of the endogenous opioid peptides. Furthermore, instead of reverting to the adult values (as for normal babies), the peptides remained at high levels up to the 40th day of life.

Topics: beta-Endorphin; Brain; Electroencephalography; Endorphins; Enkephalin, Methionine; Female; Humans; Infant, Newborn; Morphine Dependence; Opioid-Related Disorders; Pregnancy; Sleep

1 Morphine and related synthetic surrogates as well as beta-endorphin and methionine enkephalin caused a contractile response of the longitudinal musculature of the terminal colon of Long Evans rats.2 The muscular contraction caused by the narcotic analgesics exhibited stereospecificity, with levorphanol being about 50 times more potent than dextrorphan and (-)-methadone 4 times more potent than (+)-methadone. In addition, the rank order in potency of a homologous series of N-alkyl substituted norketobemidones demonstrated that the activity of these compounds in eliciting contractile responses corresponded to that for analgesic efficacy in the rat and also correlated to the ability of these derivatives to inhibit the muscular twitch evoked by electrical stimulation of the guinea-pig ileum.3 Naloxone blocked the contractile response of the opiates following competitive kinetics; the naloxone pA(2) values for morphine, etorphine, levorphanol and methadone were very close, in spite of the marked differences in potency of these agents.4 The contractile effect of morphine on the rat colon was abolished by incubation of the tissues with tetrodotoxin 2.0 x 10(-7) M or by decreasing the external Ca(2+) level 100 fold. Increasing the external Ca(2+) concentration caused an apparent non-competitive antagonism of the response to morphine.5 Pretreatment of the tissues with hexamethonium 8.3 x 10(-5) M caused a modest antagonism of the morphine effect while atropine 5.8 x 10(-7) M did not significantly modify the morphine contractile effect. In contrast, methysergide 10(-5) M caused a 10 fold increase in the morphine EC(50).6 Colons from rats rendered tolerant-dependent on morphine were markedly less sensitive to the contractile effects of morphine than those from placebo-treated controls. Tolerance to morphine was also accompanied by an increased sensitivity to the contractile effects of 5-hydroxytryptamine (5-HT).7 A marked increase in the spontaneous muscular activity of segments of the terminal colon of rats chronically treated with morphine was found to occur upon removal of the residual morphine in the tissues by repetitive washings. The spontaneous activity was arrested by applications of morphine, suggesting that physical dependence can be demonstrated in vitro in this particular preparation.8 It is concluded that the opiate-induced contractile response is mediated via stereospecific, naloxone-sensitive, opiate receptors and that the muscular response involves

Topics: Animals; beta-Endorphin; Calcium; Colon; Dose-Response Relationship, Drug; Drug Tolerance; Endorphins; Enkephalin, Methionine; Enkephalins; Hexamethonium Compounds; Histamine Release; Humans; In Vitro Techniques; Male; Morphine; Muscle Contraction; Naloxone; Narcotics; Opioid-Related Disorders; Rats; Rats, Inbred Strains; Tetrodotoxin

Topics: Alcoholism; Animals; beta-Endorphin; Brain; Corpus Striatum; Endorphins; Enkephalins; Heroin Dependence; Humans; Morphine Dependence; Opioid-Related Disorders; Pituitary Gland; Rats; Receptors, Opioid