Sex differences in binge-like EtOH drinking, corticotropin-releasing hormone and corticosterone: effects of ß-endorphin.

Binge drinking is an increasingly common pattern of risky use associated with numerous health problems, including alcohol use disorders. Because low basal plasma levels of ß-endorphin (ß-E) and an increased ß-E response to alcohol are evident in genetically at-risk human populations, this peptide is thought to contribute to the susceptibility for disordered drinking. Animal models suggest that the effect of ß-E on consumption may be sex-dependent. Here, we studied binge-like EtOH consumption in transgenic mice possessing varying levels of ß-E: wild-type controls with 100% of the peptide (ß-E +/+), heterozygous mice constitutively modified to possess 50% of wild-type levels (ß-E +/-) and mice entirely lacking the capacity to synthesize ß-E (-/-). These three genotypes and both sexes were evaluated in a 4-day, two-bottle choice, drinking in the dark paradigm with limited access to 20% EtOH. ß-E deficiency determined sexually divergent patterns of drinking in that ß-E -/- female mice drank more than their wild-type counterparts, an effect not observed in male mice. ß-E -/- female mice also displayed elevated basal anxiety, plasma corticosterone and corticotropin-releasing hormone mRNA in the extended amygdala, and all of these were normalized by EtOH self-administration. These data suggest that a heightened risk for excessive EtOH consumption in female mice is related to the drug's ability to ameliorate an overactive anxiety/stress-like state. Taken together, our study highlights a critical impact of sex on neuropeptide regulation of EtOH consumption.

ß-Endorphin and sex differentially modulate the response to EtOH in a site-specific manner.

The effects of alcohol are multifaceted, involving brain circuits regulating reward, motivation, and stress, frequently via the endogenous opioid, beta-endorphin (ß-E). It is currently unknown how alcohol affects neural circuit activation in females and how ß-E affects ethanol's ability to induce neuronal activation. Therefore, we investigated the impact of acute alcohol treatment on neuronal activation in reward- and stress-related brain circuitry in a sex- and ß-E dependent manner. In this study, male and female control (C57BL/6J; ß-E+/+) and ß-E null (-/-) mice were injected intraperitoneally with 2 g/kg ethanol (EtOH) or saline. Post-injection, animals were sacrificed using ketamine/xylazine and perfused with saline followed by 4% paraformaldehyde. Brain sections (35 µm) were immunohistochemically processed for tyrosine hydroxylase (TH), dopamine's rate-limiting enzyme, and c-fos, a neuronal activation marker. The number of c-fos immunoreactive cell nuclei, TH-immunoreactivity, and TH/c-fos-ir cells were quantified in the nucleus accumbens (NAc), ventral tegmental area (VTA), paraventricular nucleus (PVN), central nucleus of the amygdala (CeA), paraventricular thalamic nucleus (PVA) and Edinger-Westphal nucleus (EW). In females, EtOH increased c-fos expression in the CeA, PVN, EW and NAc shell, while c-fos expression in the VTA, and TH expression in the VTA and NAc, depended on a genotype and treatment interaction. In males, EtOH increased c-fos in the CeA and PVN. EtOH also increased the number of double-labeled cells in the Arc, but only in females. These results suggest that the neurons in females are inherently more sensitive to EtOH, emphasizing the importance of studying the relationship between sex and alcohol addiction.

Serotonin 5-HT2C receptor-independent expression of hypothalamic NOR1, a novel modulator of food intake and energy balance, in mice.

NOR1, Nur77 and Nurr1 are orphan nuclear receptors and members of the NR4A subfamily. Here, we report that the expression of hypothalamic NOR1 was remarkably decreased in mildly obese beta-endorphin-deficient mice and obese db/db mice with the leptin receptor mutation, compared with age-matched wild-type mice, whereas there were no genotypic differences in the expression of hypothalamic Nur77 or Nurr1 in these animals. The injection of NOR1 siRNA oligonucleotide into the third cerebral ventricle significantly suppressed food intake and body weight in mice. On the other hand, the decreases in hypothalamic NOR1 expression were not found in non-obese 5-HT2C receptor-deficient mice. Moreover, systemic administration of m-chlorophenylpiperazine (mCPP), a 5-HT2C/1B receptor agonist, had no effect on hypothalamic NOR1 expression, while suppressing food intake in beta-endorphin-deficient mice. These findings suggest that 5-HT2C receptor-independent proopiomelanocortin-derived peptides regulate the expression of hypothalamic NOR1, which is a novel modulator of feeding behavior and energy balance.

Exercise-induced promotion of hippocampal cell proliferation requires beta-endorphin.

Adult hippocampal neurogenesis is influenced by a variety of stimuli, including exercise, but the mechanisms by which running affects neurogenesis are not yet fully understood. Because beta-endorphin, which is released in response to exercise, increases cell proliferation in vitro, we hypothesized that it could exert a similar effect in vivo and mediate the stimulatory effects of running on neurogenesis. We thus analyzed the effects of voluntary wheel-running on adult neurogenesis (proliferation, differentiation, survival/death) in wild-type and beta-endorphin-deficient mice. In wild-type mice, exercise promoted cell proliferation evaluated by sacrificing animals 24 h after the last 5-bromo-2'-deoxyuridine (BrdU) pulse and by using endogenous cell cycle markers (Ki67 and pH(3)). This was accompanied by an increased survival of 4-wk-old BrdU-labeled cells, leading to a net increase of neurogenesis. Beta-endorphin deficiency had no effect in sedentary mice, but it completely blocked the running-induced increase in cell proliferation; this blockade was accompanied by an increased survival of 4-wk-old cells and a decreased cell death. Altogether, adult neurogenesis was increased in response to exercise in knockout mice. We conclude that beta-endorphin released during running is a key factor for exercise-induced cell proliferation and that a homeostatic balance may regulate the final number of new neurons.

Direct evidence for the involvement of endogenous beta-endorphin in the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state.

Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective mu-opioid receptor agonist [d-Ala(2), N-MePhe(4), Gly-ol(5)] enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5'-o-(3-[(35)S]thio) triphosphate ([(35)S]GTPgammaS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the beta-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous mu-opioid peptide beta-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous beta-endorphin to cause the dysfunction of mu-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.

Essential role of mu opioid receptor in the regulation of delta opioid receptor-mediated antihyperalgesia.

Analgesic effects of delta opioid receptor (DOR) -selective agonists are enhanced during persistent inflammation and arthritis. Although the underlying mechanisms are still unknown, membrane density of DOR was shown to be increased 72 h after induction of inflammation, an effect abolished in mu opioid receptor (MOR) -knockout (KO) mice [Morinville A, Cahill CM, Kieffer B, Collier B, Beaudet A (2004b) Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain. Pain 109:266-273]. In this study, we demonstrated a crucial role of MOR in DOR-mediated antihyperalgesia. Intrathecal administration of the DOR selective agonist deltorphin II failed to induce antihyperalgesic effects in MOR-KO mice, whereas it dose-dependently reversed thermal hyperalgesia in wild-type mice. The antihyperalgesic effects of deltorphin II were blocked by naltrindole but not d-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) suggesting that this agonist was mainly acting through DOR. SNC80-induced antihyperalgesic effects in MOR-KO mice were also attenuated as compared with littermate controls. In contrast, kappa opioid receptor knockout did not affect deltorphin II-induced antihyperalgesia. As evaluated using mice lacking endogenous opioid peptides, the regulation of DOR's effects was also independent of beta-endorphin, enkephalins, or dynorphin opioids known to be released during persistent inflammation. We therefore conclude that DOR-mediated antihyperalgesia is dependent on MOR expression but that activation of MOR by endogenous opioids is probably not required.

The absence of endogenous beta-endorphin selectively blocks phosphorylation and desensitization of mu opioid receptors following partial sciatic nerve ligation.

Phosphorylation of specific sites in the second intracellular loop and in the C-terminal domain have previously been suggested to cause desensitization and internalization of the mu-opioid receptor (MOP-R). To assess sites of MOP-R phosphorylation in vivo, affinity-purified, phosphoselective antibodies were raised against either phosphothreonine-180 in the second intracellular loop (MOR-P1) or the C-terminal domain of MOP-R containing phosphothreonine-370 and phosphoserine-375 (MOR-P2). We found that MOR-P2-immunoreactivity (IR) was significantly increased within the striatum of wild-type C57BL/6 mice after injection of the agonist fentanyl. Pretreatment with the antagonist naloxone blocked the fentanyl-induced increase. Furthermore, mutant mice lacking MOP-R showed only non-specific nuclear MOR-P2-IR before or after fentanyl treatment, confirming the specificity of the MOR-P2 antibodies. To assess whether MOP-R phosphorylation occurs following endogenous opioid release, we induced chronic neuropathic pain by partial sciatic nerve ligation (pSNL), which caused a significant increase in MOR-P2-IR in the striatum. pSNL also induced signs of mu opioid receptor tolerance demonstrated by a rightward shift in the morphine dose response in the tail withdrawal assay and by a reduction in morphine conditioned place preference (CPP). Mutant mice selectively lacking all forms of the beta-endorphin peptides derived from the proopiomelanocortin (Pomc) gene did not show increased MOR-P2-IR, decreased morphine antinociception, or reduced morphine CPP following pSNL. In contrast gene deletion of either proenkephalin or prodynorphin opioids did not block the effects of pSNL. These results suggest that neuropathic pain caused by pSNL in wild-type mice activates the release of the endogenous opioid beta-endorphin, which subsequently induces MOP-R phosphorylation and opiate tolerance.

[Plasma concentrations of beta-endorphins in the children of alcoholic patients]. / Niveles de beta-endorfinas en hijos de padres alcohólicos.

BACKGROUND: Of the factors identified in different studies as the possible causes of alcoholism, heredity appears to be the most important. However, environmental factors can increase or decrease the risk of an individual developing alcohol dependence. METHOD: To clarify the possible influence of heredity on alcoholism, we studied the plasma concentration of beta-endorphins in 25 families with alcoholic members: 27 children whose father was alcoholic and 7 whose father and mother were both alcoholics. The results were compared with finding in an age-matched control group of no-drinking adults and normal children in non-drinking families. RESULTS: The children of alcoholic parents had significantly lower beta-endorphin levels (p < 0.001) than control individuals, and concentrations were especially low when both parents were alcoholics. CONCLUSION: We conclude that plasma beta-endorphin concentration may have predictive value in identifying persons likely to become alcoholics.

Beta-endorphin involvement in the regulatory response to body sodium overload.

The present study was performed to examine the role of the endogenous beta-endorphinergic system on blood pressure regulation, sympathetic and brain activity during body sodium overload. Beta-endorphin knockout (beta end-/-), heterozygous (beta end+/-) and wild-type (beta end+/+) mice were submitted for two weeks to either a normal- or a high-sodium diet (NSD and HSD, respectively), and systolic blood pressure (SBP), urinary catecholamines (as an index of sympathetic nervous system activity), and the brain pattern of Fos-like immunoreactivity (as a marker of neuronal activation) were evaluated in each group. HSD caused a significant increase in SBP in beta end-/- mutant mice compared with beta end+/+ mice kept in the same experimental conditions (P < 0.01), but no statistical differences were observed between beta end+/- and beta end+/+ on a HSD. Moreover, when animals from the three genetic lines were fed with a NSD no changes in SBP were evidenced. With regard to brain activity, beta end-/- mice maintained on a HSD showed a significant increase in Fos-like immunoreactive neurons in the median preoptic nucleus (P < 0.01) compared with beta end+/- and beta end+/+ animals. Additionally, beta end-/- mice had higher levels of urinary epinephrine excretion (P < 0.05) on a HSD in comparison to beta end+/+ and beta end+/- animals in the same experimental conditions. No differences, however, were registered in norepinephrine and dopamine urinary excretion in animals from the three genetic lines after two weeks on either a HSD or a NSD. In summary, our results indicate that the beta-endorphinergic system may play a part in the compensatory response to sodium overload, since the absence of beta-endorphin causes an increase in systolic blood pressure, and increases median preoptic nucleus neural activity and urinary epinephrine excretion.

ß-endorphin regulates alcohol consumption induced by exercise restriction in female mice.

Animal models have long been used to study the mechanisms underlying the complex association between alcohol and stress. Female mice prevented from running on a home-cage activity wheel increase voluntary ethanol consumption. ß-endorphin is an endogenous opioid involved in negatively regulating the stress response and has also been implicated in the risk for excessive drinking. The present study investigates the role of ß-endorphin in moderating free-choice consumption of ethanol in response to a blocked activity wheel. Female, transgenic mice with varying levels of the opioid peptide were given daily 2-h access to 20% ethanol with rotations on a running wheel blocked on alternate days. Subjects with low ß-endorphin exhibited enhanced stress sensitivity by self-administering larger quantities of ethanol on days when wheel running was prevented. ß-endorphin levels did not influence voluntary activity on the running wheel. There were genotypic differences in plasma corticosterone levels as well as corticotropin-releasing hormone mRNA content in multiple brain regions associated with the stress response in these free drinking and running subjects. Susceptibility to stress is enhanced in female mice with low levels of ß-endorphin, and better understanding of the role for this opioid in mitigating the response to stressors may aid in the development of interventions and treatments for excessive use of alcohol in women.

Selective reward deficit in mice lacking beta-endorphin and enkephalin.

It has been impossible to unequivocally identify which endogenous opioids modulate the incentive value of rewarding stimuli because these peptides are not highly selective for any single opioid receptor subtype. Here, we present evidence based on the measurement of instrumental behavior of beta-endorphin and enkephalin knock-out mice that both opioid peptides play a positive role. A progressive ratio schedule was used to measure how hard an animal would work for food reinforcers. The loss of either opioid reduced responding under this schedule, regardless of the palatability of the three different formulas of reinforcers used. The phenotype of mice lacking both endogenous opioids was nearly identical to the phenotype of mice mutant for either individual opioid. Responses were tested in nondeprived and deprived feeding states but were reduced in beta-endorphin- and enkephalin-deficient mice only when they were maintained under nondeprived conditions. Other operant manipulations ruled out variables that might contribute nonspecifically to this result such as differences in acquisition, early satiation, motor performance deficit, and reduced resistance to extinction. In contrast to the effects on instrumental performance, the loss of either or both endogenous opioids did not influence preference for water flavored with sucrose or saccharin in a two-bottle free-choice drinking paradigm. We conclude that both beta-endorphin and enkephalin positively contribute to the incentive-motivation to acquire food reinforcers. Because the attenuation of operant responding was observed only during a nondeprived motivational state, the hedonics of feeding are likely altered rather than energy homeostasis.

Deficit in beta-endorphin peptide and tendency to alcohol abuse.

Human and animal studies suggest that there is a correlation between endogenous opioid peptides, especially beta-endorphin, and alcohol abuse. It has been proven that the consumption of alcohol activates the endogenous opioid system. Consumption of alcohol results in an increase in beta-endorphin level in those regions of the human brain, which are associated with a reward system. However, it has also been observed that habitual alcohol consumption leads to a beta-endorphin deficiency. It is a well-documented phenomenon that people with a genetic deficit of beta-endorphin peptide are particularly susceptible to alcoholism. The plasma level of beta-endorphin in subjects genetically at high risk of excessive alcohol consumption shows lower basal activity of this peptide. Its release increases significantly after alcohol consumption. Clinical and laboratory studies confirm that certain genetically determined factors might increase the individual's vulnerability to alcohol abuse.

A role for the endogenous opioid beta-endorphin in energy homeostasis.

Proopiomelanocortin (POMC) neurons in the hypothalamus are direct targets of the adipostatic hormone leptin and contribute to energy homeostasis by integrating peripheral and central information. The melanocortin and beta-endorphin neuropeptides are processed from POMC and putatively coreleased at axon terminals. Melanocortins have been shown by a combination of pharmacological and genetic methods to have inhibitory effects on appetite and body weight. In contrast, pharmacological studies have generally indicated that opioids stimulate food intake. Here we report that male mice engineered to selectively lack beta-endorphin, but that retained normal melanocortin signaling, were hyperphagic and obese. Furthermore, beta-endorphin mutant and wild-type mice had identical orexigenic responses to exogenous opioids and identical anorectic responses to the nonselective opioid antagonist naloxone, implicating an alternative endogenous opioid tone to beta-endorphin that physiologically stimulates feeding. These genetic data indicate that beta-endorphin is required for normal regulation of feeding, but, in contrast to earlier reports suggesting opposing actions of beta-endorphin and melanocortins on appetite, our results suggest a more complementary interaction between the endogenously released POMC-derived peptides in the regulation of energy homeostasis.

Disparate spinal and supraspinal opioid antinociceptive responses in beta-endorphin-deficient mutant mice.

The role of endogenous opioid systems in the analgesic response to exogenous opiates remains controversial. We previously reported that mice lacking the peptide neurotransmitter beta-endorphin, although unable to produce opioid-mediated stress-induced antinociception, nevertheless displayed intact antinociception after systemic administration of the exogenous opiate morphine. Morphine administered by a peripheral route can activate opioid receptors in both the spinal cord and brain. However, beta-endorphin neuronal projections are confined predominantly to supraspinal nociceptive nuclei. Therefore, we questioned whether the absence of beta-endorphin would differentially affect antinociceptive responses depending on the route of opiate administration. Time- and dose-response curves were obtained in beta-endorphin-deficient and matched wild-type C57BL/6 congenic control mice using the tail-immersion/withdrawal assay. Null mutant mice were found to be more sensitive to supraspinal (i.c.v.) injection of the micro-opioid receptor-selective agonists, morphine and D-Ala(2)-MePhe(4)-Gly-ol(5) enkephalin. In contrast, the mutant mice were less sensitive to spinal (i.t.) injection of these same drugs. Quantitative receptor autoradiography revealed no differences between genotypes in the density of mu, delta, or kappa opioid receptor binding sites in either the spinal cord or pain-relevant supraspinal areas. Thus we report that the absence of a putative endogenous ligand for the mu-opioid receptor results in opposite changes in morphine sensitivity between discrete areas of the nervous system, which are not simply caused by changes in opioid receptor expression.

Reduced sodium appetite and increased oxytocin gene expression in mutant mice lacking beta-endorphin.

Central opioid and oxytocinergic systems have been involved in the regulatory control of sodium appetite. In addition, previous studies support the existence of a functional interaction between opioid peptides and oxytocinergic pathways, and suggest that beta-endorphin neurons would modulate the activity of central oxytocinergic pathways, its pituitary secretion and sodium appetite. To investigate the role of this opioid peptide in the control of oxytocin (OT) synthesis and sodium appetite regulation we used mice with gene dosage-dependent variations in brain beta-endorphin content, expressing either 100%, 50%, or 0% of normal beta-endorphin content. Our results show that beta-endorphin knockout (KO) and heterozygous (HT) mutant mice consume approximately a 50% less 2% NaCl solution compared with wild type mice (WT), after furosemide and low sodium diet treatment. These data suggest that beta-endorphin may facilitate induced sodium appetite, giving new evidence about the role of beta-endorphin on sodium appetite behavior. Our data also indicate that OT mRNA levels evaluated by in situ hybridization significantly increased within the hypothalamic paraventricular nucleus of WT animals after induced sodium ingestion, giving support to former evidence indicating an inhibitory role for central OT in the control of sodium appetite. Moreover, beta-endorphin mutated mice have similar higher levels of OT mRNA expression after the different conditions analyzed: basal, control or experimental, compared with WT mice. Both control HT and KO mice showed higher OT mRNA expression levels than control WT group and these levels did not change after induced sodium intake. Taken together, our data suggest that the reduced sodium ingestion observed in beta-endorphin deficient mice could be due to a higher expression of the OT gene. This conclusion would support the hypothesis that OT inhibits sodium intake and provides new evidence about beta-endorphin modulation of OT synthesis and sodium appetite.

Is withdrawal-induced anxiety in alcoholism based on beta-endorphin deficiency?

RATIONALE: Associations between several psychopathological alterations and lowered beta-endorphin(beta E) plasma levels have already been stated in former studies. However, whereas single measures during static conditions generally failed in linking beta E levels with psychopathology, dynamic changes of beta E in particular have been shown to be associated with spells of anxiety and depression. During alcohol withdrawal, a decreased secretion of beta E with a delayed normalization has been reported, but up to now only few data became available regarding the interaction of plasma beta E and psychopathological parameters. OBJECTIVES: The aim of our study was to test the hypothesis whether beta E during acute alcohol withdrawal is associated with anxiety, depression, and craving. METHODS: We observed self-rated anxiety, depression, and craving during alcohol withdrawal and assessed beta E levels (RIA) in a consecutive sample of 60 alcoholics on day 1 and day 14 after onset of withdrawal, and in 30 healthy volunteers. To control for mutual interactions of beta E and the pituitary-adrenocortical hormone secretion, plasma corticotropin (ACTH) and cortisol were also determined. RESULTS: In accordance with prior studies, beta E was significantly lowered on day 1 and day 14 of alcohol withdrawal relative to controls. Plasma levels of ACTH correlated significantly with beta E in alcoholics at both time points and in controls, without differing significantly between the groups. Self-rated anxiety, depression, and alcohol craving decreased significantly between day 1 and day 14. Levels of beta E were inversely correlated with anxiety day 1 (r=-0.58) and day 14 (r=-0.71). Partial correlation coefficients controlling for ACTH plasma levels revealed that this correlation was largely independent from ACTH. In addition, a significant inverse relationship was found between beta E and craving on day 14 (r=-0.28). No association appeared between beta E and depression. CONCLUSIONS: Our results give first evidence that lowered beta E during alcohol withdrawal may contribute to anxiety as a common disturbance during this state.

Ethanol oral self-administration is increased in mutant mice with decreased beta-endorphin expression.

The relationship between ethanol (EtOH) administration and the endogenous opioid system has been studied for many years and a considerable body of evidence supports the contention that EtOH modulates the production and/or release of endogenous opioid peptides. However, substantially less is known about the converse influence: the effect that opioids have on EtOH sensitivity. In this study, we used the beta-endorphin deficient mutant mouse line C57BL/6-Pomc1(tm1Low) to investigate the possible role of a specific opioid peptide on EtOH consumption. Homozygous knockout mice (entirely lacking beta-endorphin), heterozygous mice (50% beta-endorphin expression) and sibling wildtype mice from the same strain were evaluated in a two-bottle free choice paradigm for oral self-administration of EtOH. Across varying EtOH concentrations only the heterozygous mice were found to consistently drink more than wildtype mice. These data support the hypothesis that beta-endorphin modulates the response to EtOH.

Beta-endorphin modulates the acute response to a social conflict in male mice but does not play a role in stress-induced changes in sleep.

Beta-endorphin is an endogenous opioid peptide that is released during stress and has been associated with many physiological functions. In this experiment beta-endorphin deficient mice were used to study the role of endorphins in the acute physiological and behavioral responses to a social conflict, as well as their role in social stress-induced changes in sleep. Adult male beta-endorphin deficient and wild type mice were subjected to the stress of a 1 h social conflict with an aggressive dominant conspecific. After the conflict, the beta-endorphin deficient mice had higher corticosterone levels but the peak increase in body temperature was not different from that in wild type animals. In fact, body temperature returned to baseline levels faster in the beta-endorphin deficient mice. During their interaction with the aggressive conspecific several of the beta-endorphin deficient mice showed clear signs of counter aggression whereas this was not seen in any of the wild type mice. Overall, the beta-endorphin deficient mice and wild type mice had fairly similar sleep patterns under baseline conditions and also showed similar amounts of NREM sleep, REM sleep and EEG slow-wave energy after the social conflict. In addition, no differences were found in the sleep patterns of mice that showed counter aggression and mice that did not. In conclusion, the results suggest that beta-endorphin modulates the acute endocrine, thermoregulatory and behavioral response to a social conflict but the data do not support a major role for beta-endorphin in the regulation of sleep or social stress-induced alterations in sleep.

[Beta-endorphin levels in patients with pain syndromes in the areas of the face and head]. / Issledovanie urovnia beta-éndorfina u bo'lnykh s bolevymi sindromami v oblasti litsa i golovy.

Blood plasma beta-endorphin concentrations were measured in 87 patients with various facial and head pain syndromes: trigeminal neuralgia or neuropathy Horner syndrome and migraine, facial autonomic pains. beta-endorphin concentrations were measured before and after treatment. In the groups under investigation, the neuropeptide showed opposite changes in plasma levels after the therapy depending on the type of the syndrome.

[New aspects of pathogenesis and treatment of neurostomatological diseases with the predominant pain syndrome]. / Novye aspekty patogeneza i lecheniia neirostomatologicheskikh zabolevanii s vedushchim algicheskim sindromom.

Somatosensory evoked potentials, biochemical, immunological, pharmacokinetic and psychological research methods were used to examine 308 patients suffering from neuralgia of the trigeminal and glossopharyngeal nerves, neuropathy of the trigeminal nerve, neuralgias of the face and painful dysfunction of the temporomandibular articulation. New mechanisms of the pathogenesis of the diseases indicated were revealed. That made it possible to improve and devise new treatment methods.