Effect of experimenter-delivered and self-administered cocaine on extracellular beta-endorphin levels in the nucleus accumbens

Beta-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of beta-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular beta-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on beta-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 microm) and was blocked by coadministration of SCH-23390 (10 microm). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular beta-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in beta-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the beta-endorphin neurons within the arcuate nucleus-nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.     

Endogenous opiates and behavior: 2014

This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants).This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants).     

Endogenous opioids and ventilatory responses to hypercapnia in normal humans

Though administration of opioid peptides depresses ventilation and ventilatory responsiveness, the role of endogenous opioid peptides in modulating ventilatory responsiveness is not clear. We studied the interaction of endogenous opioids and ventilatory responses in 12 adult male volunteers by relating hypercapnic responsiveness to plasma levels of immunoactive beta-endorphin and by administering the opiate antagonist naloxone. Ventilatory responsiveness to hypercapnia was not altered by pretreatment with naloxone, and this by itself suggests that endogenous opioids have no role in modulating this response. However, there was an inverse relationship between basal levels of immunoactive beta-endorphin in plasma and ventilatory responsiveness to CO2. Furthermore, plasma beta-endorphin levels rose after short-term hypercapnia but only when subjects had been pretreated with naloxone. We conclude that measurement of plasma endorphin levels suggests relationships between endogenous opioid peptides and ventilatory responses to CO2 that are not apparent in studies limited to assessing the effect of naloxone.     

Lymphocyte-mediated regulation of beta-endorphin in the myenteric plexus

Lymphocytes are antinociceptive and can modulate visceral pain perception in mice. Previously, we have shown that adoptive transfer of CD4+ T cells to severe combined immune-deficient (SCID) mice normalized immunodeficiency-related visceral hyperalgesia. Pain attenuation was associated with an increase in beta-endorphin release by T cells and an upregulation of beta-endorphin in the enteric nervous system. In this study, we investigated the relationship between T cells and opioid expression in the myenteric plexus. We examined opioid peptide and receptor expression in the myenteric plexus in the presence and absence of mucosal T cells. We found a positive association between T cells and beta-endorphin expression; this was accompanied by a downregulation of the micro-opioid receptor (MOR). In vitro, T helper (Th) type 1 and type 2 cytokine stimulation of CD4+ T cells or isolation of T cells from in vivo Th-polarized mice did not increase T cell release of beta-endorphin or the induction of beta-endorphin expression in the myenteric plexus. However, exogenous beta-endorphin did upregulate beta-endorphin expression, and both cycloheximide and naloxone methiodide inhibited peptide upregulation. Therefore, our results suggest that nonpolarized CD4+ T cells release beta-endorphin, which, through an interaction with MOR, stimulates an upregulation of beta-endorphin expression in the myenteric plexus. Thus, we propose that the mechanism underlying lymphocyte modulation of visceral pain involves T cell modulation of opioid expression in the enteric nervous system.     

Endogenous opiates and behavior: 2007

This paper is the thirtieth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2007 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses.     

Butorphanol tartrate induces feeding in rats

Peripheral administration of butorphanol tartrate markedly enhanced feeding from 0800 to 1400 hours when compared with vehicle controls. Butorphanol tartrate feeding was not antagonized by doses of naloxone as high as 10 mg/kg. These data support the concept that the kappa or sigma opiate receptors are involved in feeding behavior.It is well recognized that the endogenous opiates play a role in the central regulation of appetite (1, 2, 3, 4). Numerous studies have shown that The endogenous opioid peptides and morphine can initiate feeding under various conditions (5–12) whereas the opiate antagonist, naloxine can reduce food consumption (13–20). Recently, the endogenous opiod peptide, dynorphin, has been reported to enhance food intake (12–25).Much evidence has been accumulated indicating that a number of opiate receptors are present in the brain, each one having a high affinity for a specific endogenous opioid peptide (26, 27). Both the cyclazocine related compounds (28) and the feeding enhancer, dynorphin (29–32), have been reported to be specific kappa receptor agonists. In the present study, we report on the effect of the morphinan congener, butorphanol tartrate (33), on ingestive behaviour.     

Increased level of immunoreactive opioid peptides in the brain and adrenals of rats as affected by adaptation to physical loading

The effect of long-term (7 weeks) swimming training on the content of beta-endorphin, met- and leu-enkephalins in various brain regions and adrenal glands has been studied in Wistar rats. It has been shown that the adaptation to exercise induced an increase in the content of opioid peptides in most of the brain regions and in adrenal glands. This increase in the level of opioid peptides seems to play an important role in the increase of the resistance to stress.     

Participation of endogenous opioid peptides in the pathogenesis of motion sickness

Investigations were performed with 19 healthy male volunteers to specify a possible role of endogenous opioid peptides in the pathogenesis of motion sickness. For this purpose the test subjects were administered naloxone, a specific antagonist of opiates and opioids, before rotation and during rotation in a BU-4 armchair at a rate of 30 rpm. In addition, the content of beta-endorphin in blood plasma was measured. It was discovered that naloxone exerts both prophylactic and therapeutic effects as regards the simulated motion sickness. In this respect it was more efficacious than the reference drug scopolamine. After rotation there was a significant increase in the beta-endorphin content in the blood plasma of the test subjects. It is assumed that endogenous opioid peptides (in particular beta-endorphin) may be directly involved in the genesis of vestibulo-vegetative disorders in motion sickness.     

The role of endogenous opioids and their receptors in the immune system.

Opioid peptides appear to be dynamic signaling molecules that are produced within the immune system and are active regulators of an immune response. Furthermore, the receptors for these peptides occurring on immunocyte membranes share characteristics with neuronal opioid receptors, including molecular size, immunogenicity, and the use of specific intracellular signaling pathways. Recent studies of the interaction of opioids with cytokines have indicated that opioid peptides are intimately involved within the immune system. Specifically, opioids, including 2-n-pentyloxy-2-phenyl-4-methyl-morpholine, naloxone, and beta-endorphin, have been shown to interact with IL-2 receptors (134) and regulate production of IL-1 and IL-2 (48-50, 135). Conversely, IL-1 has been shown to up-regulate opioid peptide binding in brain tissue (136). Furthermore, the induction of IL-1 by opioids has also been identified in the invertebrate Mytilus, indicating the evolutionary conservation of this relationship (137). These results seem to typify the intricate association between the immune and neuroendocrine systems through opioid pathways. It is predicted that future endeavors will use this relationship to diagnose and treat specific diseases that have at their basis neuroendocrine and immunologic imbalances.     

Opioid propeptide mRNA content and receptor density in the brains of AA and ANA rats

Recent evidence has indicated an association between the rewarding effects of ethanol intake and endogenous opioid activity. The present studies examine the presence of differences in opioid peptide mRNA content and mu and kappa opioid receptor densities, between ethanol naive AA and ANA rats bred selectively for their high and low alcohol consumption, respectively. In situ hybridization was used to compare the content of proopiomelanocortin, proenkephalin and prodynorphin mRNA in distinct brain regions known to be involved in the reinforcing properties of addictive drugs, between rats from each line. Results indicated that AA rats had a significantly greater content of proopiomelanocortin mRNA in the arcuate nucleus of the hypothalamus, of proenkephalin mRNA in the prefrontal cortex and of prodynorphin mRNA in the mediodorsal nucleus of the thalamus (p < or = .05). Receptor autoradiography was performed using 3H-labeled ligands specific for mu and kappa opioid receptors. AA rats were found to have a greater density of mu opioid receptors in the shell region of the nucleus accumbens and prefrontal cortex, but a lower density of kappa opioid receptors in the ventromedial hypothalamus, compared to ANA rats. The present data demonstrate the presence of inherited differences in the activity of distinct components of the endogenous opioid system in some brain regions associated with the processes of reward and reinforcement; and as such, may play a role in determining differences in ethanol drinking between AA and ANA rats.     

Neuroendocrine control of thymic hormonal production. II. Stimulatory effects of endogenous opioids on thymulin production by cultured human and murine thymic epithelial cells

Data have now accumulated to strongly demonstrate that several neuropeptides, including endogenous opioids, can have immunomodulatory functions. Most of the studies have so far focused on the direct action of these substances on lymphocytes. We decided to investigate whether thymic epithelial cells (TEC) - the major component of the thymic microenvironment - could also be modulated by endogenous opioids. Primary cultures of human and murine TEC were subjected to several opioids (alpha-beta- or gamma-endorphins, as well as met- or leuenkephalins) applied in concentrations ranging from 10(-6) to 10(-9) M. On the following days we measured the levels of thymulin (a chemically-defined thymic hormone known to stimulate some steps of T-cell differentiation) in the culture supernatants, as well as the numbers of thymulin containing cells, evaluated by immunofluorescence with an anti-thymulin monoclonal antibody. After treatment of TEC cultures with beta-endorphin or leu-enkephalin a significant increase in the levels of thymulin in the culture media was observed, paralleled by a rise in the percentage of thymulin containing cells. In addition, this stimulatory effect was dose-dependent. Preincubation of the opioids with the specific antibodies abrogated the opioid-induced stimulatory effect on TEC. Moreover, naloxone, an opioid receptor antagonist, blocked the effect of beta-endorphin on thymulin production, suggesting that the effect of this neuropeptide on epithelial cells was mediated by an opioid receptor. Importantly, no effect on thymulin production was observed with the other opioids used, whatever the dose. These results suggest that, at least in vitro, beta-endorphin and leu-enkephalin stimulate the hormonal function of the thymic epithelium. These findings lead to the general concept that the modulatory role of endogenous opioids on the immune system is not restricted to lymphocytes but can also take place at the level of cells belonging to T-cell differentiating microenvironments.     

Endogenous opiates and behavior: 2010

This paper is the thirty-third consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2010 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17).     

Endogenous opiates and behavior: 2010

This paper is the thirty-third consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2010 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17).     

Endogenous opiates and behavior: 2012

This paper is the thirty-fifth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2012 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).     

Endogenous opiates and behavior: 2004

This paper is the 27th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over 30 years of research. It summarizes papers published during 2004 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses.     

Endogenous opiates and behavior: 2011

This paper is the thirty-fourth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2011 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular–biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17).     

Investigation on cerebrospinal fluid opioids and neurotransmitters related to spinal cord stimulation

The purpose of this study was to assess the biochemical mechanisms underlying spinal cord stimulation (SCS). Seventeen patients with chronic pain were investigated by measuring cerebrospinal fluid concentrations of endogenous opioids and biogenic amines before and during dorsal column stimulation. Basal cerebrospinal fluid beta-endorphin levels were below the normal range. No significant change of norepinephrine, epinephrine, dopamine, beta-endorphin, beta-lipotropin, or adrenocorticotropic hormone levels were found after SCS. A 50% increase of cerebrospinal beta-endorphin and beta-lipotropin levels occurred in 6 out of 16 patients, namely those where SCS gave the major pain relief. These data confirm the derangement of the endogenous opioid system in chronic pain conditions and suggest that the beta-endorphin response to SCS could have clinical value in predicting the success of treatment.     

Endogenous opiates and behavior: 2003

This paper is the 26th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2003 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular–biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).     

Differences in basal and ethanol-induced levels of opioid peptides in Wistar rats from five different suppliers

One major cause for discrepancies in results from animal experimental studies is the use of different animal strains and suppliers. We have previously reported that Wistar rats from five different suppliers display profound differences in ethanol intake and behavior. One of the neurobiological processes that could be underlying these differences is the endogenous opioid system, which has been implicated in the rewarding and reinforcing effects of alcohol. We therefore hypothesized that the differences between the supplier groups would also be evident in the endogenous opioid system. Radioimmunoassay was used to determine the levels of the opioid peptides Met-enkephalin-Arg⁶Phe⁷ and dynorphin B in several brain areas of ethanol-drinking and ethanol naïve Wistar rats from five different suppliers. In the ethanol naïve animals, differences between the supplier groups were found in the pituitary gland, hypothalamus, frontal cortex, dorsal striatum and hippocampus. In the ethanol-drinking rats, differences were found in the same structures, with the addition of medial prefrontal cortex and substantia nigra. Correlations between ethanol intake and peptide levels were also found in several of the areas examined. The structures in which differences were found have all been implicated in the transition from drug use to addiction and these differences may lead to different propensities and vulnerability to this transition. Because the endogenous opioids have been suggested to be involved in a number of neurobiological disorders the results do not only have implications for research on alcohol or drug addiction, but many other fields as well.