beta-endorphin and Heroin-Dependence

In 1963, Professor Vincent P. Dole at the Rockefeller University formed a small team to develop a pharmacotherapy for the management of heroin addiction. They hypothesized that heroin addiction is a disease of the brain with behavioral manifestations, and not merely a personality disorder or criminal behavior and began to address the specific question of whether a long-acting opioid agonist could be used in the long-term maintenance treatment of heroin addiction. Over the next 35 years, many studies documented the safety, efficacy and effectiveness of methadone pharmacotherapy for heroin addiction, but Federal regulations and stigmatization of heroin addiction prevented implementation of treatment. Finally, in 1999, NIH published a report unequivocally supporting methadone maintenance pharmacotherapy for heroin addiction. Two other effective opioid agonist treatments have been developed: the even longer acting opioid agonist l-alpha-acetylmethadol (LAAM) has been approved for pharmacotherapy for heroin addiction, and still under study is the opioid partial agonist-antagonist buprenorphine-naloxone combination. A variety of studies, both laboratory based and clinical, have revealed the mechanisms of action of long-acting opioid agonists in treatment, including prevention of disruption of molecular, cellular and physiologic events and, in fact, allowing normalization of those functions disrupted by chronic heroin use. Recent molecular biological studies have revealed single nucleotide polymorphisms of the human mu opioid receptor gene; the mu opioid receptor is the site of action of heroin, the major opiate drug of abuse, analgesic agents such as morphine, and the major treatment agents for heroin addiction. These findings support the early hypotheses of our laboratory that addiction may be due to a combination of genetic, drug-induced and environmental (including behavioral) factors and also, that atypical stress responsivity may contribute to the acquisition and persistence of, as well as relapse to, use of addictive drugs.

Topics: Adrenocorticotropic Hormone; beta-Endorphin; Corticotropin-Releasing Hormone; Heroin Dependence; Humans; Hypothalamo-Hypophyseal System; Methadone; Methadyl Acetate; Pituitary-Adrenal System; Pro-Opiomelanocortin

To explore the clinical effect and mechanism of electroacupuncture at Jiaji (EX-B 2) on drug craving of heroin addicts.. One hundred and twenty cases of heroin addicts were randomly divided into 4 groups, 30 cases in each. In acupuncture group 1, the Jiaji (EX-B 2) points of T5-T7 and Shenshu (BL 23) were selected with electroacupuncture; in acupuncture group 2, Neiguan (PC 6), Shenmen (HT 7) and Zusanli (ST 36) etc. were selected with electroacupuncture; in simulation group, Zusanli (ST 36) and Sanyinjiao (SP 6) were selected with analog electrical stimulation, and in blank group no any therapy was applied. The changes of drug craving were evaluated by Visual Analogue Scale (VAS) and the changes of beta-EP and Dyn-A in plasma before and after treatment were tested by radioimmunoassay.. The relapse rate of 77.3% (17/22) in acupuncture group 1 was lower than those of 88.5% (23/26) in acupuncture group 2, 90.5% (19/21) in simulation group and 95.7% (22/23) in blank group (all P < 0.05). At the 8th and 10th week of treatment, the VAS scores in acupuncture group 1 and 2 were much lower than those in blank group and simulation group (all P < 0.01); in which, it was lower in acupuncture group 1 than that in acupuncture group 2 (P < 0.05), and lower in simulation group than that in blank group. After 10 weeks of treatment, compared with the status before treatment, beta-EP and Dyn-A in plasma were increased in acupuncture group 1 and 2 (P < 0.05, P < 0.01), Dyn-A was decreased in both simulation and blank groups (both P < 0. 01) which was less obvious than those in both acupuncture groups (both P < 0.01) and superior in acupuncture group 1 than that in group 2 (P < 0.05).. Electroacupuncture at Jiaji (EX-B 2) can suppress the drug craving and reduce the relapse rate, and the mechanism may be related with the content of beta-EP, especially the increase of Dyn-A in plasma.

Topics: Acupuncture Points; Adolescent; Adult; beta-Endorphin; Dynorphins; Electroacupuncture; Female; Heroin Dependence; Humans; Male; Middle Aged; Treatment Outcome; Young Adult

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

Childhood trauma is of importance for the manifestation of substance-related disorders and maintenance of hypothalamic-pituitary-adrenal (HPA)-axis disorders. Since stress plays a crucial role in opioid compliance and craving, we investigated the immediate effects of diacetylmorphine application on the HPA axis. In particular, adrenocorticotropic hormone (ACTH) and cortisol secretion, as well as satiety regulating proopiomelanocortin peptides α-melanocyte-stimulating hormone (MSH) and β-endorphin (END) in a cohort of opioid-dependent patients in diamorphine maintenance treatment concerning the clinical severity of their childhood trauma.. We compared the serum levels of ACTH, cortisol, MSH, and END in 15 opioid-dependent patients. All participants received treatment with diamorphine and were observed at 5 timepoints before and after injection. We split the cohort into 2 subgroups concerning childhood trauma measured by the Childhood Trauma Questionnaire.. Splitting in 2 subgroups for mild (5) and severe trauma (10), we found that while both groups show a significant reduction of ACTH and cortisol levels over time, slopes display different progressions over time for cortisol (F[1.6] = 9.38, p = 0.02), while remaining identical for ACTH (F[1.6] = 1.69, p = 0.24). Also, levels of both MSH and END were significantly lower in severely traumatized patients.. For the first time, we present a detailed representation of stress- and addiction-related proteins for the first 5 h after diamorphine application, demonstrating the interrelationship between stress hormones and childhood trauma as well as its potential effects on the progression of addictions such as opioid dependence.

Topics: Adrenocorticotropic Hormone; Adult; Adverse Childhood Experiences; beta-Endorphin; Child; Cohort Studies; Female; Heroin; Heroin Dependence; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Pituitary-Adrenal System; Stress, Psychological; Surveys and Questionnaires; Wounds and Injuries

Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7-10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility.. Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects.. Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels.. These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability.

Topics: Adrenocorticotropic Hormone; Adult; Animals; beta-Endorphin; Case-Control Studies; Chronobiology Disorders; CLOCK Proteins; Drug Users; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Heroin Dependence; Humans; Hydrocortisone; Hypothalamus; Interleukin-2; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Nuclear Proteins; Period Circadian Proteins; Rats; RNA; Substance Withdrawal Syndrome; Time Factors; Trans-Activators; Transcription Factors; Tumor Necrosis Factor-alpha

Heroin use and withdrawal cause abnormality in the endocrine system. However, the time course of neuroendocrine alterations in heroin addicts during pharmacologically unassisted withdrawal is still unclear.. To investigate alterations in cortisol, adrenocorticotrophic hormone (ACTH), beta-endorphin (beta-EP), leptin, and neuropeptide Y (NPY) during the first month of abstinence in heroin addicts.. Twelve heroin addicts and eight matched healthy control subjects were recruited for this study. The neuroendocrine alterations and self-reported heroin craving, anxiety, and depression in heroin addicts were assessed at different time points (days 3, 10, and 30) of first month of abstinence from heroin use.. Self-reported heroin craving, anxiety, and depression in heroin addicts decreased gradually during the first month of abstinence. The cortisol levels increased from abstinence day 3 to 30, while ACTH and beta-EP levels decreased over this period in heroin addicts. The leptin and NPY levels were significantly decreased on days 3 and 10 but had normalized on day 30 of abstinence. A positive correlation between cortisol level and heroin craving, anxiety, and depression was observed, while a negative correlation was observed between beta-EP level and craving and anxiety and between leptin and depression and NPY and anxiety.. Abnormal alterations in the neuroendocrine system, including levels of cortisol, ACTH and beta-EP persist throughout the first month of abstinence. These results suggest that neuroendocrine system dysfunctions in heroin abusers is independent of the acute and protracted withdrawal syndromes, and may thus contribute to relapse to heroin use.

Topics: Adrenocorticotropic Hormone; Adult; Analysis of Variance; Anxiety; beta-Endorphin; Case-Control Studies; Depression; Heroin; Heroin Dependence; Humans; Hydrocortisone; Leptin; Male; Neuropeptide Y; Neurosecretory Systems; Patient Selection; Psychiatric Status Rating Scales; Radioimmunoassay; Substance Withdrawal Syndrome; Time Factors

Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population. Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds beta-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor. Furthermore, beta-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.

Topics: Base Sequence; beta-Endorphin; DNA Primers; Genotype; Heroin Dependence; Humans; Mutagenesis, Site-Directed; Polymorphism, Genetic; Receptors, Opioid, mu

Noradrenergic receptor sensitivity of 16 healthy male siblings of heroin addicts and of 8 age and sex-matched controls was examined by administering a clonidine stimulation test and by measuring the resulting growth hormone (GH) (alpha-2-adrenoceptors) and beta-endorphin (beta-endorphin) (alpha-1-adrenoceptors) responses. Siblings were divided into two groups: A = siblings of heroin addicts with personality disorders and high aggressivity and B = siblings of heroin addicts without mental disorders. The GH and beta-endorphin responses to clonidine were blunted in group A subjects compared with controls and normal in group B.

Topics: Adult; Aggression; Antisocial Personality Disorder; beta-Endorphin; Clonidine; Growth Hormone; Heroin Dependence; Humans; Male; Norepinephrine; Personality Assessment; Personality Disorders; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Risk Factors

Growth hormone (GH) and beta-endorphin (beta-EP) responses to clonidine stimulation were examined in 18 male heroin addicts, 9 with and 9 without previous histories of attention deficit disorder with hyperactivity (ADD-H) and conduct disorder (CD). Ten psychophysically healthy volunteers were used as controls. ADD-H/CD addicts had blunted GH and beta-EP responses as compared to controls while those of non-ADD-H/CD addicts were normal. This suggests that postsynaptic adrenoceptor sensitivity is decreased and, possibly, that presynaptic noradrenaline secretion is increased in ADD-H/CD patients with heroin addiction.

Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; beta-Endorphin; Clonidine; Growth Hormone; Heroin Dependence; Humans; Male; MMPI; Norepinephrine; Receptors, Adrenergic, alpha-2; Reference Values; Synapses

The results are reported of experimental research into the hypophyseal endorphins in 42 drug addicts killed by heroin overdose. All samples were found to contain endorphins in widely varied amounts: 21-239 ng/g, mean 81.8 +/- 45.8 ng/g.

Topics: Adolescent; Adult; beta-Endorphin; Drug Overdose; Female; Heroin; Heroin Dependence; Humans; Male; Pituitary Gland

This paper discusses the role of endogenous opioids in response to hyperthermia and the alterations observed in drug or alcohol addicts. Endorphins, rather than enkephalins are involved in adaptation to heat in the central nervous system. The pituitary secretion of beta endorphin together with ACTH in response to thermal stress provided the opportunity to measure the opioid reactivity to hyperthermia in health and toxicomania, as an index of opioid function, in adaptation to heat. The review of the data in the literature shows absent responses of beta endorphin and its related hormone ACTH to the thermal stress of sauna in heroin, cocaine or alcohol addicts. A common explanation for this phenomenon is that the long-term stimulation of hypothalamic opioid neurotransmission that is produced directly or indirectly by heroin, alcohol or cocaine, disrupts the opioid response to thermal stress, and thus the adaptation to heat.

Topics: Adrenocorticotropic Hormone; Alcoholism; beta-Endorphin; Cocaine; Fever; Healthy Worker Effect; Heroin Dependence; Hot Temperature; Humans; Male; Stress, Physiological; Substance-Related Disorders

Performance in a vigilance task and the associated neuroendocrine changes during the performance in the task were examined in healthy subjects and in three groups of male heroin-addicts both before undergoing rehabilitation programmes and at various intervals from withdrawal (5 days, 1 to 2 mon, and 3 to 48 mon, respectively). Plasma levels of ACTH, beta-endorphin (EP) and prolactin (PRL) were measured every 10 min before and during performance. In drug addicts, simple reaction times never showed any significant difference as compared to control values. Despite similar baseline levels, ACTH exhibited a markedly depressed response to psychological testing in drug-addicts as compared to controls. Whereas a three-fold increase in ACTH was observed in 'normal' subjects during the performance (from 17 to 54 ng/l), mean values from drug-addicts remained unchanged. EP levels showed a wide scatter of individual values and inconsistent time courses over performance testing: after short-term abstinence, EP showed a three-fold increase over baseline control values but, contrary to what seen in 'normal' subjects, no changes over time were recorded. After long-term abstinence, basal EP was close to control values, but its increase during the testing period was still blunted. PRL levels decreased over the testing period both in controls and in heroin addicts. Thus, despite the lack of obvious signs of neurotoxicity, drug abusers show neuroendocrine changes consistent with a long-lasting selective impairment of the hypothalamic modulation of pituitary secretion.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; Heroin Dependence; Humans; Male; Neurosecretory Systems; Prolactin; Psychomotor Performance; Stress, Psychological; Time Factors

The aim of this study was to evaluate beta-endorphin, ACTH, and cortisol plasma levels during metyrapone administration in man after chronic opioid receptor stimulation. Metyrapone (750 mg every 4 hr for 6 doses) was administered to ten male heroin addicts, who had been on a maintenance therapy with methadone for at least 6 months and to ten healthy sex- and age-matched volunteers. Before metyrapone administration the basal levels of cortisol and ACTH were significantly decreased in addicts as compared to normal controls, while plasma beta-endorphin was not different. The response of beta-endorphin and ACTH to metyrapone administration was significantly blunted in addicts (p less than 0.01). These results suggest that the chronic stimulation of opiate receptors can impair the function of the anterior pituitary gland.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; Heroin Dependence; Humans; Hydrocortisone; Male; Methadone; Metyrapone; Receptors, Opioid; Reference Values; Substance-Related Disorders

To evaluate the responses of circulating beta-endorphin, met-enkephalin and ACTH to sauna-induced hyperthermia, 8 male heroin addicts recently admitted to a therapeutic community and 8 age-matched normal subjects were examined. Compared with control subjects, heroin addicts showed 1. A decrease of the basal levels of beta-endorphin; 2. Absence of the normal increase of beta-endorphin and ACTH after sauna; 3. A lower increase in systolic blood pressure. It is concluded that an impairment of the adaptive response to stress may be present in heroin addicts, even after a relatively short drug-free period (14 days).

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; beta-Endorphin; Body Temperature Regulation; Enkephalin, Methionine; Fever; Hemodynamics; Heroin Dependence; Humans; Male; Steam Bath

Endogenous opioid systems may be altered as a consequence of addiction, but evidence to support this idea is meager so far. We obtained 136 cerebrospinal fluid (CSF) samples from 72 opioid addicts during four distinct states: methadone maintenance, detoxification from methadone, opioid antagonist treatment, and drug-free status. CSF endorphins were measured in 86 patients samples using a radioreceptor assay (RRA), and beta-endorphin levels were measured in 85 patient samples using a radioimmuno assay (RIA). During detoxification, both RRA fraction I and beta-endorphin showed a generally similar pattern of changes. Both were lowest when measured 40-50 hr after the last opioid dose, and both showed an apparent rebound to higher than methadone maintenance values at 60-70 hr following the last dose. During methadone maintenance and drug-free states, the addicts' levels of fraction I RRA endorphins in the CSF were higher than levels found in a normal control group. Fraction II endorphins were also elevated in the addicts who were drug free. In contrast, CSF beta-endorphin during both methadone maintenance and drug-free states was lower in the addicts as compared to the normal, drug-naive group. Except for the pattern found during detoxification, there were no consistent changes in endorphin levels across different states of addiction.

Topics: Adult; beta-Endorphin; Heroin Dependence; Humans; Male; Methadone; Naltrexone; Radioimmunoassay; Radioligand Assay; Receptors, Opioid; Substance Withdrawal Syndrome

Topics: Adolescent; Adult; beta-Endorphin; Female; Heroin Dependence; Humans; Male; Pain; Sensory Thresholds; Substance Withdrawal Syndrome

Evidence is accumulating that hormonal systems present in the pituitary and the brain play a critical role in behavioral homeostase. The hormones and their fragments, called neuropeptides, produced by these systems modulate neurotransmitter activity and thereby control brain functions. Disturbances in this hormonal control may result in psychopathology, including addiction. Vasopressin and related peptides decrease under certain conditions addictive behavior of experimental animals and humans and brain reward. The pituitary and brain opioid peptides are candidates to play an essential role in reward processes and may be common factors in addiction to various psychoactive drugs, including heroin and alcohol, and to habits. Other pituitary hormones, like ACTH, gamma 2-MSH and prolactin have also been implicated in brain reward and drug addiction. It is postulated that disturbances in the hormonal and neuropeptide systems may lead to a state in which addiction behavior can easily be elicited and that the hormonal climate in the body may be of relevance for the individual susceptibility to addictive drugs. It is proposed to analyse the relation between hormonal systems and addictive behavior.

Topics: Adrenocorticotropic Hormone; Alcoholism; Animals; Arginine Vasopressin; beta-Endorphin; Brain; Endorphins; Haplorhini; Heroin Dependence; Humans; Melanocyte-Stimulating Hormones; Naltrexone; Neurotransmitter Agents; Peptides; Pituitary Gland; Rats; Reinforcement, Psychology; Reward; Substance-Related Disorders

Because opioid antagonists acutely produce rises in serum beta endorphin, we studied beta endorphin levels in 21 former opiate addicts chronically taking naltrexone. The mean AM (19.5 pg/ml) beta endorphin level was higher than the AM mean for 39 normals under 40 years old (12.1 pg/ml) (t = 3.2, p less than 0.001); the mean PM level for the naltrexone treated patients was 13.6 pg/ml. Four patients had beta endorphin levels more than 2 S.D. above the mean for the normals (greater than 26.4 pg/ml), and six others had relatively elevated PM levels. Thus, 47% (10/21) had abnormal patterns of beta endorphin levels. We had previously reported abnormally high cortisol levels in these patients, and AM cortisol correlated with AM beta endorphin levels (r = 0.7, p less than 0.001). We concluded that sustained beta endorphin elevations may occur during chronic naltrexone treatment.

Topics: Adolescent; Adult; beta-Endorphin; Circadian Rhythm; Endorphins; Heroin Dependence; Humans; Hydrocortisone; Naltrexone; Substance Withdrawal Syndrome

Plasma levels of beta-endorphin and beta-lipotropin in 18 heroin addicts were found to be similar to those in pregnant control subjects at all stages of gestation. In contrast, amniotic fluid levels of beta-endorphin were significantly lower in heroin abusers than in controls in both the first and second trimesters. Amniotic fluid levels of beta-lipotropin were reduced only in the second trimester. At term, when the patients were almost drug free, the amniotic fluid levels of both peptides were in the control range. These data support the existence of a specific control mechanism for amniotic fluid levels of beta-endorphin and beta-lipotropin, independent of the maternal pituitary, and show that exogenous opiates interfere with it negatively.

Topics: Amniotic Fluid; beta-Endorphin; beta-Lipotropin; Endorphins; Female; Gestational Age; Heroin Dependence; Humans; Pregnancy; Pregnancy Complications

The effects of iv stimulation with clonidine on plasma levels of beta-lipotropin (beta-LPH), beta-endorphin (beta-EP), cortisol, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) were tested in a group of 10 healthy volunteers and in 8 heroin abusers. Hormones were measured either by direct radioimmunoassay (RIA) (GH, cortisol) or after plasma extraction and Sephadex G-75 column chromatography (beta-LPH and beta-EP) or by immunoradiometric assay (IRMA) (ACTH). Plasma levels of GH increased in a similar fashion in the two groups. In the controls, clonidine induced release of beta-LPH and beta-EP after 30 min (from 8.9 +/- 1.0 to 19.1 +/- 4.6 fmol/ml, P less than 0.01 and from 8.1 +/- 0.6 to 17.9 +/- 4.6, P less than 0.01) and of ACTH after 60 min (from 12.1 +/- 1.8 to 18.1 +/- 1.8, P less than 0.05) while in addicts beta-EP but not beta-LPH showed a significant increase (from 8.5 +/- 0.7 to 19.8 +/- 4.2, P less than 0.05), 90 min after the injection. In heroin addicts, plasma cortisol levels decreased continuously after clonidine stimulation while in controls they showed a biphasic pattern, decreasing until the 60th min (from 135.2 +/- 30.4 ng/ml to 74.0 +/- 13.3, P less than 0.05) and regaining basal levels 1 h later (122.0 +/- 24.8, P less than 0.05 vs 60th min value). These data demonstrate the existence in human beings of noradrenergic control of proopiomelanocortin (POMC)-related peptides and indicate that chronic opiate abuse greatly interferes with this control. Clonidine-induced release of plasma beta-EP may be of importance with regard to its therapeutic effects in detoxification.

Topics: Adolescent; Adrenergic alpha-Agonists; Adrenocorticotropic Hormone; Adult; beta-Endorphin; beta-Lipotropin; Clonidine; Endorphins; Female; Growth Hormone; Heroin Dependence; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Pro-Opiomelanocortin

Neuroendocrine effects of intravenous injections of clonidine, 0.15 mg, were investigated in 13 heroin addicts and 14 normal control subjects. The study was designed to determine whether continuous opiate administration leads to the development of hypersensitive alpha 2-adrenergic receptors. The peak increments in levels of plasma growth hormone (GH) and beta-endorphin induced by clonidine did not differ between heroin addicts and normal control subjects. At no time interval could the clonidine-induced rise in GH levels in addicts be differentiated from that induced by placebo. Clonidine failed to alter plasma prolactin, gonadotropin, or thyrotropin levels in either heroin addicts or controls. Since clonidine's neuroendocrine effects are reportedly due to the activation of postsynaptic alpha 2-adrenoceptors, it appears that (1) continuous opiate use does not lead to the development of hypersensitive alpha 2-adrenergic receptors involved in neuroendocrine mechanisms and (2) brain norepinephrine does not play a role in the regulation of tonic prolactin, gonadotropin, and thyrotropin secretion in man.

Topics: Adolescent; Adult; beta-Endorphin; Clonidine; Endorphins; Female; Follicle Stimulating Hormone; Growth Hormone; Heroin Dependence; Humans; Luteinizing Hormone; Male; Pituitary Hormones, Anterior; Prolactin; Receptors, Adrenergic; Thyrotropin

The circadian rhythm of plasma proopiocortin-related peptides was studied in 15 heroin addicts and in 6 sex- and age-matched controls. ACTH, beta-lipotrophin, (beta-LPH), beta-endorphin (beta-EP) and cortisol were measured by RIA either directly (cortisol), or after plasma extraction (ACTH) and Sephadex G-75 gel chromatography (beta-LPH and beta-EP) every 4 h from 8 a.m. to 8 p.m. and again at 8 a.m. the next morning. The means of the two 8 a.m. measurements of beta-LPH (2.67 +/- 0.34 fmol/ml, mean +/- SE), ACTH (2.74 +/- 0.71) and cortisol (218 +/- 31 pmol/ml) levels in heroin addicts were significantly lower than those in controls (6.28 +/- 0.61, 10.1 +/- 0.74 and 364 +/- 27, respectively, P less than 0.01) while beta-EP concentrations in heroin addicts (5.1 +/- 0.6) were similar to those of healthy volunteers (6.44 +/- 0.56). In controls, all three peptides and cortisol show a circadian rhythm of secretion, the lowest values being in the evening and the highest ones in the morning. Heroin addicts partially lack this phenomenon showing constant levels of the three proopiocortin-related peptides throughout the day, with a slight but significant decrease of plasma cortisol. In the 7 subjects who took heroin throughout the study, no systematic changes were observed in the three proopiocortin-related peptides, while it seems that this group of addicts shows a cortisol decrease in the evening to a lesser extent than subjects receiving methadone maintenance only.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; beta-Endorphin; beta-Lipotropin; Chromatography, Gel; Circadian Rhythm; Endorphins; Female; Heroin Dependence; Humans; Hydrocortisone; Male; Morphine; Radioimmunoassay

Seven patients with heroin addiction were hospitalized and immediately withdrawn from opiates. Abstinence symptomatology was evaluated quantitatively by use of the Himmelsbach Score. Maximal intensity of withdrawal symptomatology was reached within 2 days. beta-Endorphin immunoreactivity in plasma was measured by use of a very sensitive radioimmunoassay with a low cross-reactivity (28%) against beta-LPH. A statistically significant increase of mean plasma beta-endorphin-like immunoreactivity during withdrawal could be demonstrated.

Topics: Adult; beta-Endorphin; Endorphins; Female; Heroin Dependence; Humans; Male; Substance Withdrawal Syndrome

The influence of different neuropeptides related to pro-opiomelanocortin were tested on acquisition of heroin self-administration in rats. The animals were allowed to self-administer heroin intravenously on a continuous reinforcement schedule during 6 h daily sessions on 5 consecutive days. Treatment was performed subcutaneously 1 h before each daily session. It was found that the opioid peptides alpha-, gamma- and beta-endorphin hardly influenced acquisition of heroin self-administration, while the non-opioid fragments of alpha- and gamma- endorphin modulated this behavioral response. In fact, beta-endorphin (beta E) 2-9 tended to facilitate the rate of acquisition, while the gamma-type endorphins, des-Tyr1-gamma-endorphin (beta E 2-17) and des-enkephalin-gamma-endorphin (beta E 6-17), decreased heroin intake. Concerning the ACTH/MSH related peptides, a decreasing effect of heroin intake was found following treatment with (D-Phe7)-ACTH 4-10, with a high dose of the ACTH 4-9 analog Org 2766 and with gamma 2-MSH, while ACTH 1-24, ACTH 4-10 and a low dose of Org 2766 did not significantly influence self-injecting behavior. It is concluded that pro-opiomelanocortin serves as a precursor molecule for peptide fragments, which modulate the acquisition of heroin self-administration in rats.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Endorphins; Heroin Dependence; Humans; Male; Melanocyte-Stimulating Hormones; Nerve Tissue Proteins; Pituitary Hormones, Anterior; Pro-Opiomelanocortin; Protein Precursors; Rats; Rats, Inbred Strains; Self Administration

Previous studies have shown alterations of neuroendocrine function in humans receiving any narcotic on short-term basis or short-acting narcotics on a chronic basis. In this study of 16 well-stabilized patients, it was demonstrated that normalization of hypothalamic-pituitary-adrenal axis function, as reflected by normal levels and normal circadian rhythm of levels of beta-endorphin, ACTH and cortisol, is achieved during long-term steady state methadone maintenance treatment of former heroin addicts.

Topics: Adrenocorticotropic Hormone; beta-Endorphin; Circadian Rhythm; Endorphins; Heroin Dependence; Humans; Hydrocortisone; Methadone; Reference Values

Topics: Adrenocorticotropic Hormone; Analgesics; Animals; Avoidance Learning; Behavior, Animal; beta-Endorphin; Body Temperature; Endorphins; Grooming; Guinea Pigs; Heroin Dependence; Humans; In Vitro Techniques; Male; Melanocyte-Stimulating Hormones; Naloxone; Rats; Substance Withdrawal Syndrome

A combination of radioimmunoassays and chromatography under acid-dissociating conditions has been used to obtain profiles of ACTH and LPH-related peptides in human plasma and cerebrospinal fluid. The spectra of peptides observed in these two fluids differ markedly. ACTH, beta-LPH, gamma-LPH and beta-endorphin are observed in the plasma of normal subjects and patients with increased pituitary ACTH secretion, whereas cerebrospinal fluid contains ACTH, beta-LPH, gamma-LPH and beta-endorphin, a 31 000-molecular-weight putative precursor having ACTH, LPH and gamma-MSH immunoreactivities, as well as pro-gamma-MSH(1-77) and smaller immunoreactive gamma-MSH fragments, alpha-MSH was not observed in blood or cerebrospinal fluid but this pars intermedia peptide and corticotropin-like intermediate lobe peptide (CLIP) were both found in tumour tissues obtained from patients with the ectopic ACTH syndrome. In vitro studies of human pituitary tumour tissues confirmed concomitant secretion of ACTH, beta-LPH, gamma-LPH, beta-endorphin and pro-gamma-MSH, which could be stimulated by a preparation of crude stalk median eminence and synthetic arginine vasopressin, from the rat, and could be suppressed by hydrocortisone. Clinical studies in which electroacupuncture was used to alleviate the symptoms of heroin withdrawal or recurrent pain revealed that concentrations of met-enkephalin and beta-endorphin, respectively, may rise in cerebrospinal fluid in association with relief of symptoms.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; beta-Lipotropin; Corticotropin-Like Intermediate Lobe Peptide; Endorphins; Heroin Dependence; Humans; Melanocyte-Stimulating Hormones; Peptide Fragments; Pituitary Gland; Pituitary Hormones; Radioimmunoassay; Reference Values; Substance Withdrawal Syndrome

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