Endogenous Opioid Peptide Systems Research Articles

Low-frequency electroacupuncture exerts antinociceptive effects through activation of POMC neural circuit induced endorphinergic input to the periaqueductal gray from the arcuate nucleus.

It has been widely recognized that electroacupuncture (EA) inducing the release of β-endorphin represents a crucial mechanism of EA analgesia. The arcuate nucleus (ARC) in the hypothalamus is a vital component of the endogenous opioid peptide system. Serving as an integration center, the periaqueductal gray (PAG) receives neural fiber projections from the frontal cortex, insular cortex, and ARC. However, the specific mechanisms how EA facilitates the release of β-endorphin within the ARC, eliciting analgesic effects are yet to be elucidated. In this study, we conducted in vivo and in vitro experiments by transcriptomics, microdialysis, photogenetics, chemical genetics, and calcium imaging, combined with transgenic animals. Firstly, we detected 2Hz EA at the Zusanli (ST36) increased the level of β-endorphin and transcriptional level of proopiomelanocortin (POMC). Our transcriptomics profiling demonstrated that 2Hz EA at the ST36 modulates the expression of c-Fos and Jun B in ARC brain nuclear cluster, and the transcriptional regulation of 2Hz EA mainly occur in POMC neurons by Immunofluorescence staining verification. Meaning while, 2Hz EA specifically activated the cAMP-PKA-CREB signaling pathway in ARC which mediating the c-Fos and Jun B transcription, and 2Hz EA analgesia is dependent on the activation of cAMP-PKA-CREB signaling pathway in ARC. In order to investigate how the β-endorphin produced in ARC transfer to integration center PAG, transneuronal tracing technology was used to observe the 2Hz EA promoted the neural projection from ARC to PAG compared to 100Hz EA and sham mice. Inhibited PAGGABA neurons, the transfer of β-endorphin from the ARC nucleus to the PAG nucleus through the ARCPOMC-PAGGABA neural circuit. Furthermore, by manipulating the excitability of POMC neurons from ARCPOMC to PAGGABA using inhibitory chemogenetics and optogenetics, we found that this inhibition significantly reduced transfer of β-endorphin from the ARC nucleus to the PAG nucleus and the effectiveness of 2Hz EA analgesia in neurological POMC cyclization recombination enzyme (Cre) mice and C57BL/6J mice, which indicates that the transfer of β-endorphin depends on the activation of POMC neurons prefect from ARCPOMC to PAGGABA. These findings contribute to our understanding of the neural circuitry underlying the EA pain-relieving effects and maybe provide valuable insights for optimizing EA stimulation parameters in clinical pain treatment using the in vivo dynamic visual investigating the central analgesic mechanism.

Mechanisms of acupuncture-electroacupuncture on inflammatory pain.

Acupuncture, as a traditional treatment, has been extensively used in China for thousands of years. According to the World Health Organization (WHO), acupuncture is recommended for the treatment of 77 diseases. And sixteen of these diseases are related to inflammatory pain. As a combination of traditional acupuncture and modern electrotherapy, electroacupuncture (EA) has satisfactory analgesic effects on various acute and chronic pain. Because of its good analgesic effects and no side effects, acupuncture has been widely accepted all over the world. Despite the increase in the number of studies, the mechanisms via which acupuncture exerts its analgesic effects have not been conclusively established. A literature review of related research is of great significance to elaborate on its mechanisms and to inform on further research directions. We elucidated on its mechanisms of action on inflammatory pain from two levels: peripheral and central. It includes the mechanisms of acupuncture in the periphery (immune cells and neurons, purinergic pathway, nociceptive ion channel, cannabinoid receptor and endogenous opioid peptide system) and central nervous system (TPRV1, glutamate and its receptors, glial cells, GABAergic interneurons and signaling molecules ). In this review, we collected relevant recent studies to systematically explain the mechanisms of acupuncture in treating inflammatory pain, with a view to providing direction for future applications of acupuncture in inflammatory pain and promoting clinical development.

Challenges and new opportunities for detecting endogenous opioid peptides in reward

The endogenous opioid peptide system, comprised of enkephalins, endorphins, dynorphins, and nociceptin, is a highly complex neurobiological system. Opioid peptides are derived from four precursor molecules and undergo several processing events yielding over 20 unique opioid peptides. This diversity together with low in vivo concentration and complex processing and release dynamics has challenged research into each peptide's unique function. Despite the subsequent challenges in detecting and quantifying opioid peptides in vivo, researchers have pioneered several techniques to directly or indirectly assay the roles of opioid peptides during behavioral manipulations. In this review, we describe the limitations of the traditional techniques used to study the role of endogenous opioid peptides in food and drug reward and bring focus to the wealth of new techniques to measure endogenous opioid peptides in reward processing.

Diabetic neuropathy is associated with increased pain perception, low serum beta-endorphin and increase insulin resistance among Nigerian cohorts in Ekiti State

IntroductionThere has been an increase in the global prevalence of diabetic polyneuropathy and research evidence suggests that insulin resistance plays an important role in its development and prognosis. However, there seem to be a dearth of information in understanding the likely interplay between beta endorphin, insulin resistance and pain perception especially in the setting of painful diabetic neuropathy. MethodThis study recruited 120 volunteers divided into four groups (30 per group): group 1 healthy volunteer (control); group 2 DM type 2 without neuropathy (DM group); group 3 DM type 2 with painful neuropathy (DPN group); group 4 DM type 2 without painful neuropathy (DN). All subjects were evaluated for pain threshold and neuropathy using an ischemia-induced pain model and biothesiometer respectively. Their beta-endorphin, glycated hemoglobin, fasting plasma insulin, and HOMA values were determined and means compared using ANOVA. ResultSerum beta-endorphin is significantly reduced in DN and DPN (∗p < 0.001) compared with the control and DM group. Also, DPN and DN patients have significantly increased insulin resistance compared to those without neuropathy (∗p < 0.001; ∗p < 0.0001 respectively). There is a significant positive correlation between the pain threshold and beta-endorphin in all the groups except DN group. The correlation between beta-endorphin and insulin resistance was negative and significant in control and DM groups only. Suggestive that the fact that insulin resistance plays an important role in diabetes polyneuropathy, does not alone explain the chronic pain perception noticed in the DPN patients. ConclusionThe present study demonstrates that diabetic neuropathy patients have a poor endogenous opioid peptide system which is associated with increased pain perception and high insulin resistance. However, insulin resistance alone does not explain the chronic pain perception noticed in the DPN patients. Thus, further study is required.

Panicolytic-like effect of µ1-opioid receptor blockade in the inferior colliculus of prey threatened by Crotalus durissus terrificus pit vipers

The endogenous opioid peptide system has been implicated in the neural modulation of fear and anxiety organised by the dorsal midbrain. Furthermore, previous results indicate a fundamental role played by inferior colliculus (IC) opioid mechanisms during the expression of defensive behaviours, but the involvement of the IC µ1-opioid receptor in the modulation of anxiety- and panic attack-related behaviours remains unclear. Using a prey-versus-snake confrontation paradigm, we sought to investigate the effects of µ1-opioid receptor blockade in the IC on the defensive behaviour displayed by rats in a dangerous situation. Specific pathogen-free Wistar rats were treated with microinjection of the selective µ1-opioid receptor antagonist naloxonazine into the IC at different concentrations (1.0, 3.0 and 5.0 µg/0.2 µL) and then confronted with rattlesnakes ( Crotalus durissus terrificus). The defensive behavioural repertoire, such as defensive attention, flat back approach (FBA), startle, defensive immobility, escape or active avoidance, displayed by rats either during the confrontations with wild snakes or during re-exposure to the experimental context without the predator was analysed. The blockade of µ1-opioid receptors in the IC decreased the expression of both anxiety-related behaviours (defensive attention, FBA) and panic attack-related responses (startle, defensive immobility and escape) during the confrontation with rattlesnakes. A significant decrease in defensive attention was also recorded during re-exposure of the prey to the experimental apparatus context without the predator. Taken together, these results suggest that a decrease in µ1-opioid receptor signalling activity within the IC modulates anxiety- and panic attack-related behaviours in dangerous environments.

Age-dependent plasticity in endocannabinoid modulation of pain processing through postnatal development.

Significant age- and experience-dependent remodelling of spinal and supraspinal neural networks occur, resulting in altered pain responses in early life. In adults, endogenous opioid peptide and endocannabinoid (ECs) pain control systems exist which modify pain responses, but the role they play in acute responses to pain and postnatal neurodevelopment is unknown. Here, we have studied the changing role of the ECs in the brainstem nuclei essential for the control of nociception from birth to adulthood in both rats and humans. Using in vivo electrophysiology, we show that substantial functional changes occur in the effect of microinjection of ECs receptor agonists and antagonists in the periaqueductal grey (PAG) and rostroventral medulla (RVM), both of which play central roles in the supraspinal control of pain and the maintenance of chronic pain states in adulthood. We show that in immature PAG and RVM, the orphan receptor, GPR55, is able to mediate profound analgesia which is absent in adults. We show that tissue levels of endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol, within the PAG and RVM are developmentally regulated (using mass spectrometry). The expression patterns and levels of ECs enzymes and receptors were assessed using quantitative PCR and immunohistochemistry. In human brainstem, we show age-related alterations in the expression of key enzymes and receptors involved in ECs function using PCR and in situ hybridisation. These data reveal that significant changes on ECs that to this point have been unknown and which shed new light into the complex neurochemical changes that permit normal, mature responses to pain.

BIBLIOMETRIC ANALYSIS OF ACUPUNCTURE RESEARCH FRONTS AND THEIR WORLDWIDE DISTRIBUTION OVER THREE DECADES.

Background:Considerable research has been conducted on acupuncture worldwide. This study chronologically examined the changing features and research fronts of acupuncture and elucidated the differences among the six most productive countries.Methods:Bibliographic coupling is a powerful tool for identifying the research fronts of a field. Acupuncture-related publications worldwide and from the six most productive countries during 1983-2012 were retrieved from the Science Citation Index Expanded and Social Science Citation Index. To form the research fronts, the 100 most highly cited papers (HCPs) were clustered in terms of references shared.Results:The United States had the highest proportion of HCPs. The effectiveness of acupuncture in areas such as relieving neck and back pain, migraines and headaches, and knee osteoarthritis symptoms was a predominant topic. Initially, the endogenous opioid peptide system was the primary research focus in the acupuncture mechanism research; however, during 1993-2012, researchers focused more on the functional magnetic resonance imaging of brain activity. In addition, acupuncture use and prevalence, the attitudes of health practitioners, and the effects of expectancy and belief were also major topics. Researches from Western countries, including the United States, England, and Germany, showed more interest in clinical trials and economic- and ethics-related studies, whereas those from East Asian countries including China, Japan, and South Korea focused more on mechanism research.Conclusion:Western countries dominated the research fronts of acupuncture. The patterns of the research fronts varied worldwide, indicating continuity and innovation in research in each country.

Interactions of peripheral and central μ opioid systems during emotional stress

Background Numerous studies support an important contribution of endogenous opioid peptide systems in the mechanisms of emotional behavior. It is well known that the structure of opioid receptors (OR) and endogenous opioid peptides in the CNS and in the periphery is identical, but the central and peripheral functions of endogenous opioid systems are considered different, because the blood-brain barrier (BBB) generally prevents the entry of peptides into the brain. We hypothesize that the central and peripheral components of the endogenous opioid system function in close relationship, interacting with each other. The aim of this work was to study an influence of a peripheral administration of the μ opioid receptor ligands, which do not penetrate the BBB, on behavioral parameters as well as on extracellular levels of b-endorphin (BE) in the the cingulate cortex (CC) of rats during acute emotional stress.

Forebrain PENK and PDYN gene expression levels in three inbred strains of mice and their relationship to genotype-dependent morphine reward sensitivity

Vulnerability to drug abuse disorders is determined not only by environmental but also by genetic factors. A body of evidence suggests that endogenous opioid peptide systems may influence rewarding effects of addictive substances, and thus, their individual expression levels may contribute to drug abuse liability. The aim of our study was to assess whether basal genotype-dependent brain expression of opioid propeptides genes can influence sensitivity to morphine reward. Experiments were performed on inbred mouse strains C57BL/6J, DBA/2J, and SWR/J, which differ markedly in responses to morphine administration: DBA/2J and SWR/J show low and C57BL/6J high sensitivity to opioid reward. Proenkephalin (PENK) and prodynorphin (PDYN) gene expression was measured by in situ hybridization in brain regions implicated in addiction. The influence of the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI), which attenuates effects of endogenous PDYN-derived peptides, on rewarding actions of morphine was studied using the conditioned place preference (CPP) paradigm. DBA/2J and SWR/J mice showed higher levels of PDYN and lower levels of PENK messenger RNA in the nucleus accumbens than the C57BL/6J strain. Pretreatment with nor-BNI enhanced morphine-induced CPP in the opioid-insensitive DBA/2J and SWR/J strains. Our results demonstrate that inter-strain differences in PENK and PDYN genes expression in the nucleus accumbens parallel sensitivity of the selected mouse strains to rewarding effects of morphine. They suggest that high expression of PDYN may protect against drug abuse by limiting drug-produced reward, which may be due to dynorphin-mediated modulation of dopamine release in the nucleus accumbens.

Effect of Acute Ethanol Administration on the Release of Opioid Peptides From the Midbrain Including the Ventral Tegmental Area

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

The impact of postnatal environment on opioid peptides in young and adult male Wistar rats

Early environmental influences can change the neuronal development and thereby affect behavior in adult life. The aim in the present study was to thoroughly examine the impact of early environmental factors on endogenous opioids by using a rodent maternal separation (MS) model. The endogenous opioid peptide system is not fully developed at birth, and short- and/or long-term alterations may occur in these neural networks in animals exposed to manipulation of the postnatal environment. Rat pups were subjected to one of five rearing conditions; 15 min (MS15) litter (l) or individual (i), 360 min (MS360) l or i daily MS, or housed under normal animal facility rearing (AFR) conditions during postnatal days 1-21. Measurements of immunoreactive (ir) Met-enkephalin-Arg6Phe7 (MEAP) and dynorphin B (DYNB) peptide levels in the pituitary gland and in a number of brain areas, were performed at three and 10 weeks of age, respectively. MS-induced changes were more pronounced in ir MEAP levels, especially in individually separated rats at three weeks of age and in litter-separated rats at 10 weeks of age. The enkephalin and dynorphin systems have different developmental patterns, dynorphin appearing earlier, which may point at a more sensitive enkephalin system during the early postnatal weeks. The results provide evidence that opioid peptides are sensitive for early environmental factors and show that the separation conditions are critical and also result in changes manifesting at different time points. MS-induced effects were observed in areas related to stress, drug reward and dependence mechanisms. By describing effects on opioid peptides, the study addresses the possible role of a deranged endogenous opioid system in the previously described behavioral consequences of MS.

Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism

It has been suggested that behavioral aberrations observed in autism could be the result of dysfunction of the neuroregulatory role performed by the endogenous opioid peptides. Many of those aberrations have been recently modeled in rats exposed to valproic acid (VPA) on the 12th day of gestation (VPA rats). The aim of the present study was to elucidate functioning of the enkephalinergic system, one of the endogenous opioid peptide systems strongly involved in emotional responses, in VPA rats using both biochemical and behavioral methods. In situ hybridization was used to measure proenkephalin mRNA expression in adult VPA rats' central nucleus of the amygdala, the dorsal striatum, and the nucleus accumbens. Additional groups of animals were examined in a conditioned place aversion to naloxone, the elevated plus maze, and object recognition tests to assess their basal hedonic tone, anxiety, learning and memory, respectively. Prenatal exposure to VPA decreased proenkephalin mRNA expression in the dorsal striatum and the nucleus accumbens but not in the central nucleus of the amygdala. It also increased anxiety and attenuated conditioned place aversion to naloxone but had no impact on learning and memory. The present results suggest that prenatal exposure to VPA may lead to the decreased activity of the striatal enkephalinergic system and in consequence to increased anxiety and disregulated basal hedonic tone observed in VPA rats. Presented results are discussed in light of interactions between enkephalinergic, GABAergic, and dopaminergic systems in the striatum and mesolimbic areas of the brain.

Ethanol-induced effects on opioid peptides in adult male Wistar rats are dependent on early environmental factors

The vulnerability to develop alcoholism is dependent on both genetic and environmental factors. The neurobiological mechanisms underlying these factors are not fully understood but individual divergence in the endogenous opioid peptide system may contribute. We have previously reported that early-life experiences can affect endogenous opioids and also adult voluntary ethanol intake. In the present study, this line of research was continued and the effects of long-term voluntary ethanol drinking on the opioid system are described in animals reared in different environmental settings. Rat pups were subjected to 15 min (MS15) or 360 min (MS360) of daily maternal separation during postnatal days 1–21. At 10 weeks of age, male rats were exposed to voluntary ethanol drinking in a four-bottle paradigm with 5%, 10% and 20% ethanol solution in addition to water for 2 months. Age-matched controls received water during the same period. Immunoreactive (ir) Met-enkephalin-Arg 6Phe 7 (MEAP) and dynorphin B (DYNB) peptide levels were thereafter measured in the pituitary gland and several brain areas. In water-drinking animals, lower ir MEAP levels were observed in the MS360 rats in the hypothalamus, medial prefrontal cortex, striatum and the periaqueductal gray, whereas no differences were seen in ir DYNB levels. Long-term ethanol drinking induced lower ir MEAP levels in MS15 rats in the medial prefrontal cortex and the periaqueductal gray, whereas higher levels were detected in MS360 rats in the hypothalamus, striatum and the substantia nigra. Chronic voluntary drinking affected ir DYNB levels in the pituitary gland, hypothalamus and the substantia nigra, with minor differences between MS15 and MS360. In conclusion, manipulation of the early environment caused changes in the opioid system and a subsequent altered response to ethanol. The altered sensitivity of the opioid peptides to ethanol may contribute to the previously reported differences in ethanol intake between MS15 and MS360 rats.

Intracerebroventricular d-Pen 2, d-Pen 5-enkephalin administration soon after stressor imposition influences behavioral responsivity to a subsequent stressor encounter in CD-1 mice

Endogenous opioid peptide systems diminish stress-induced autonomic nervous system, neuroendocrine (hypothalamic-pituitary-adrenal axis) and behavioral responses, attenuating a collection of physiological symptoms basic to emotional and affective states. Neurogenic stressors may incite specific central changes in opioid peptide availability as well as changes in mu and delta-opioid receptor function. The present investigation evaluated the proactive influence of an intracerebroventricular injection of the opioid receptor agonist d-Pen 2, d-Pen 5-enkephalin (DPDPE) (0 μg, 0.005 μg, 1.0 μg or 2.5 μg) on locomotor behavior of mice following uncontrollable footshock (Shock) or novel shock chamber exposure (No Shock). It was expected that DPDPE administration following Shock on Day 1 would restore locomotor activity up to 1 week and prevent shock-associated behavior of mice encountering a brief session of footshock 18 days later. Exposure to Shock reduced horizontal locomotor and vertical locomotor (rearing) activity of mice while 2.5 μg DPDPE restored behavior. Eighteen days following Shock and DPDPE challenge, mice were exposed to either an abbreviated session of footshock (Mild Stress) or the shock chamber (Cues). Mice in the No Shock and Shock groups administered 2.5 μg DPDPE on Day 1 did not exhibit any locomotor deficits in response to Mild Stress on Day 18. Mice in the Shock group administered 0.005 μg DPDPE on Day 1, did not exhibit exaggerated rearing deficits following ensuing Mild Stressor encounter relative to mice reexposed to Cues on Day 18. Taken together, these data show that (a) footshock differentially affects rearing and locomotor activity, (b) DPDPE administration increases locomotor activity for up to 1 week following footshock and DPDPE administration, (c) reexposure to Mild Stress affects rearing and locomotor performance differently depending on previous stressor history and DPDPE dose, (d) DPDPE affords long-lasting protection to previously non-stressed mice against the deleterious effects of subsequent mild stress on locomotor activity, while a low dose of DPDE is sufficient to prevent shock-induced sensitization of rearing deficits, 18 days following original stressor and drug presentation. Finally, our investigation demonstrates that DPDPE administration alters the behavioral impact of future stressful encounters and emphasizes the importance of investigating opioid mechanisms in chronic stress disorders.

Opioid peptides in cerebrospinal fluid-methods for analysis and their significance in the clinical perspective.

The discovery of the endogenous opioid peptide systems and their subsequent identification in human cerebrospinal fluid near 30 years ago triggered an intensive research to evaluate the function of these compounds in the clinical perspective. However, for this purpose it was necessary to develop reliable techniques with high sensitivity and reproducibility. Furthermore, it was necessary to assess the chemical nature of the opioid activity present in CSF. Therefore, research on opioid peptides in CSF have to a considerable extent been directed to attempts to characterize the peptide activity present in this fluid in order to identify suitable markers of activity in any particular opioid peptide system. In the clinic these markers have been used in attempts to correlate alterations in peptide levels to various neurological diseases. This article reviews the past and ongoing research on opioid peptide systems in CSF from human with particular emphasis on their relevance in the clinical perspective.

Blockade of ventral pallidal opioid receptors induces a conditioned place aversion and attenuates acquisition of cocaine place preference in the rat

Peripheral administration of naloxone is known to produce a conditioned place aversion and to block cocaine-induced conditioned place preference. The ventral pallidum receives a dense enkephalinergic projection from the nucleus accumbens and is implicated as a locus mediating the rewarding and reinforcing effects of psychostimulant and opiate drugs. We sought to provide evidence for the involvement of pallidal opioid receptors in modulating affective state using the place-conditioning paradigm. Microinjection of naloxone (0.01–10 μg) into the ventral pallidum once a day for 3 days dose-dependently produced a conditioned place aversion when tested in the drug-free state 24 h after the last naloxone injection. This effect was reproduced using the μ-opioid receptor selective agonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP, 1 μg). Locomotor activity was reduced following injection of the highest dose of naloxone (10 μg) but elevated following CTOP (1 μg). Daily injection of cocaine (10 mg/kg) for 3 days produced a conditioned place preference 24 h later. This effect of cocaine was attenuated by concomitant intra-ventral pallidal injection of naloxone at a dose (0.01 μg) that had no significant aversive property when injected alone. In contrast, the locomotor activation induced by peripheral cocaine injection was unaffected by naloxone injection into the ventral pallidum. The data implicate endogenous opioid peptide systems within the ventral pallidum as regulators of hedonic status.

Influence of GnRH agonist and neural antagonists on stress-blockade of LH and prolactin surges induced by 17beta-estradiol in ovariectomized rats.

In our previous study, we demonstrated that immobilization stress blocked estrogen-induced luteinizing hormone (LH) surge possibly by inhibiting the synthesis and release of gonadotropin-releasing hormone (GnRH) at the hypothalamic level and by blocking estrogen-induced prolactin (PRL) surge by increasing the synthesis of dopamine receptor at the pituitary level in ovariectomized rats. The present study was performed to determine whether immobilization stress affects pituitary LH responsiveness to GnRH, and whether endogenous opioid peptide (EOP) and dopamine systems are involved in blocking LH and PRL surges during immobilization stress. Immobilization stress was found to inhibit basal LH release and to completely abolish LH surge. However, the intravenous application of GnRH agonist completely restored immobilization-blocked LH surge and basal LH release. Treatment with naloxone did not exert any effect on immobilization-blocked LH surge but increased basal LH release during immobilization stress. Pimozide did not affect immobilization-blocked LH surge or basal LH release. Naloxone also decreased immobilization-induced basal PRL release, but had no effect on immobilization-blocked PRL surge. Immobilization-increased basal PRL levels were augmented by pimozide treatment and immobilization-blocked PRL surge was dramatically restored by pimozide. We conclude that immobilization stress does not impair pituitary LH response to GnRH, and that the immobilization stress-induced blockage of LH surge is probably not mediated by either the opioidergic or the dopaminergic system. However, immobilization-blockade of PRL surge may be partly mediated by the dopaminergic system.

Role of endogenous opioid system in the regulation of the stress response

1. Numerous studies and reviews support an important contribution of endogenous opioid peptide systems in the mediation, modulation, and regulation of stress responses including endocrine (hypothalamopituitary-adrenal, HPA axis), autonomic nervous system (ANS axis), and behavioral responses. Although several discrepancies exist, the most consistent finding among such studies using different species and stressors is that opioids not only diminish stress-induced neuroendocrine and autonomic responses, but also stimulate these effector systems in the non-stressed state. 2. A distinctive feature of the analgesic action of opioids is the blunting of the distressing, affective component of pain without dulling the sensation itself. Therefore, opioid peptides may diminish the impact of stress by attenuating an array of physiologic responses including emotional and affective states. 3. The widespread distribution of enkephalin (ENK) throughout the limbic system (including the extended amygdala, cingulate cortex, entorhinal cortex, septum, hippocampus, and the hypothalamus) is consistent with a direct role in the modulation the stress responses. 4. The predictability of stressful events reduces the impact of a wide range of stressors and ENK appears to play an important role in this process. Therefore, ENK and its receptors could represent a major modulatory system in the adaptation of an organism to stress, balancing the response that the stressor places on the central stress system with the potentially detrimental effects that a sustained stress may produce. Chronic neurogenic stressors will induce changes in specific components of the stress-induced ENKergic system, including ENK, δ- and μ-opioid receptors. 5. This review presents evidences for adaptive cellular mechanisms underlying the response of the central stress system when assaulted by repeated psychogenic stress, and the involvement of ENK in these processes.

Opioid modulation of magnocellular neurosecretory cell activity.

Magnocellular neurosecretory cells of the hypothalamic supraoptic and paraventricular nuclei secrete the hormones, oxytocin and vasopressin, into the systemic circulation from the posterior pituitary gland. Oxytocin is important for parturition and is essential for lactation. Vasopressin regulates body fluid homeostasis. The secretion of these hormones is altered in response to peripheral stimuli that are conveyed via projections from other parts of the brain. Endogenous opioid peptide systems interact with the magnocellular neurosecretory system at several levels to restrain the basal secretion of these hormones as well as their secretory responses to various physiological stimuli. The inhibition of basal secretion can occur at the level of the neurosecretory terminals where endogenous opioids inhibit the release of oxytocin, and at the cell bodies of magnocellular cells to modulate the activity pattern of vasopressin cells. The responses of the magnocellular neurosecretory system to physiological stimuli are also regulated by these mechanisms but in addition probably also by pre-synaptic inhibition of afferent inputs to magnocellular cells as well as direct effects on the cell bodies of afferent input cells to modulate their activity. Here, we review the mechanisms and functional consequences of opioid interactions with oxytocin and vasopressin cells.

Comparison of the Proopiomelanocortin and Proenkephalin Opioid Peptide Systems in Brain Regions of the Alcohol-Preferring C57BL/6 and Alcohol-Avoiding DBA/2 Mice

JAMENSKY, N. T. AND C. GIANOULAKIS. Comparison of the proopiomelanocortin and proenkephalin opioid peptide systems in brain regions of the alcohol-preferring C57BL/6 and alcohol-avoiding DBA/2 mice. ALCOHOL 18(2/3) 177–187, 1999.—Differences in the activity of distinct components of the endogenous opioid system between ethanol-preferring and ethanol-avoiding animals may be important in controlling their voluntary alcohol consumption. The objective of the present studies was to compare the activity of two opioid peptide systems (enkephalin and β-endorphin) in distinct regions of the brain, between the C57BL/6 and DBA/2 mice, using sensitive radioimmunoassays, in situ hybridization, and immunohistochemical techniques. The immunohistochemical studies indicated that there was no significant difference in the number of either β-endorphin or enkephalin immunopositive cells between the C57BL/6 and DBA/2 mice. The in situ hybridization studies demonstrated a 27% higher content of proopiomelanocortin mRNA in the arcuate nucleus of the C57BL/6 than DBA/2 mice, p < 0.02. The content of proenkephalin mRNA was 25% higher in the nucleus accumbens, p < 0.005 and 23% higher in the caudate putamen, p < 0.01, of the C57BL/6 than DBA/2 mice. There was no significant difference in the content of β-endorphin peptides in the distinct brain regions investigated. The content of met-enkephalin-arg 6-phe 7 in the nucleus accumbens and caudate was similar between the two strains of mice, while it was significantly lower in the amygdala, hippocampus, ventral tegmental area, and periaqueductal grey of the C57BL/6 than DBA/2 mice. Thus, there are significant differences in the activity of these two endogenous opioid peptide systems in distinct regions of the brain, between ethanol naive C57BL/6 and DBA/2 mice, which may play a role in controlling their alcohol consumption.