Spinal interleukin-10 produces antinociception in neuropathy through microglial ß-endorphin expression, separated from antineuroinflammation.

Interleukin 10 (IL-10) is antinociceptive in various animal models of pain without induction of tolerance, and its mechanism of action was generally believed to be mediated by inhibition of neuroinflammation. Here we reported that intrathecal IL-10 injection dose dependently attenuated mechanical allodynia and thermal hyperalgesiain male and female neuropathic rats, with ED50 values of 40.8 ng and 24 ng, and Emax values of 61.5% MPE and 100% MPE in male rats. Treatment with IL-10 specifically increased expression of the ß-endorphin (but not prodynorphin) gene and protein in primary cultures of spinal microglia but not in astrocytes or neurons. Intrathecal injection of IL-10 stimulated ß-endorphin expression from microglia but not neurons or astrocytes in both contralateral and ipsilateral spinal cords of neuropathic rats. However, intrathecal injection of the ß-endorphin neutralizing antibody, opioid receptor antagonist naloxone, or µ-opioid receptor antagonist CTAP completely blocked spinal IL-10-induced mechanical antiallodynia, while the microglial inhibitor minocycline and specific microglia depletor reversed spinal IL-10-induced ß-endorphin overexpression and mechanical antiallodynia. IL-10 treatment increased spinal microglial STAT3 phosphorylation, and the STAT3 inhibitor NSC74859 completely reversed IL-10-increased spinal expression of ß-endorphin and neuroinflammatory cytokines and mechanical antiallodynia. Silence of the Bcl3 and Socs3 genes nearly fully reversed IL-10-induced suppression of neuroinflammatory cytokines (but not expression of ß-endorphin), although it had no effect on mechanical allodynia. In contrast, disruption of the POMC gene completely blocked IL-10-stimulated ß-endorphin expression and mechanical antiallodynia, but had no effect on IL-10 inhibited expression of neuroinflammatory cytokines. Thus this study revealed that IL-10 produced antinociception through spinal microglial ß-endorphin expression, but not inhibition of neuroinflammation.

Mediation of beta-endorphin in andrographolide-induced plasma glucose-lowering action in type I diabetes-like animals.

In the present study, we investigated the mechanism(s) for glucose-lowering action of andrographolide in streptozotocin-induced diabetic rats (STZ-diabetic rats). Andrographolide lowered plasma glucose concentrations in a dose-dependent manner and increased plasma beta-endorphin-like immunoreactivity (BER) dose-dependently in diabetic rats. Both of these responses to andrographolide were abolished by the pretreatment of animals with prazosin or N-(2-(2-cyclopropylmethoxy) ethyl) 5-choro-alpha-dimethyl-1H-indole-3-thylamine (RS17053) at doses sufficient to block alpha1-adrenoceptors (ARs). Also, andrographolide enhanced BER release from isolated rat adrenal medulla in a concentration-related manner that could be abolished by alpha1-ARs antagonists. Bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of andrographolide, including the plasma glucose-lowering effect and the plasma BER-elevating effect. Andrographolide failed to lower plasma glucose in the presence of opioid micro-receptor antagonists and in the opioid micro-receptor knockout diabetic mice. Treatment of STZ-diabetic rats with andrographolide resulted in the reduced expression of phosphoenolpyruvate carboxykinase (PEPCK) in liver and an increased expression of the glucose transporter subtype 4 (GLUT 4) in soleus muscle. These effects were also blocked by opioid micro-receptor antagonists. In conclusion, our results suggest that andrographolide may activate alpha1-ARs to enhance the secretion of beta-endorphin which can stimulate the opioid micro-receptors to reduce hepatic gluconeogenesis and to enhance the glucose uptake in soleus muscle, resulting in a decrease of plasma glucose in STZ-diabetic rats. However, the roles of other endogenous opioid peptides or the mixture of several opioid peptides in the activation of opioid micro-receptors associated with the plasma glucose-lowering action of andrographolide, should be considered and need more investigation in the future.

Pharmacogenetic treatments for drug addiction: alcohol and opiates.

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

The effect of calcitonin on beta-endorphin levels in postmenopausal osteoporotic patients with back pain.

The purpose of this study was to evaluate the efficacy of calcitonin on beta-endorphin levels in female patients experiencing back pain associated with postmenopausal osteoporosis. The secondary purpose was to assess the pain and quality of life in these patients. There were 30 patients with a mean age of 58.2+/-5.4 years in the treatment group and 26 patients with a mean age of 58.8+/-5.2 years in the placebo group in this randomized, placebo-controlled study. The patients subcutaneously received 100 IU salmon calcitonin or placebo injections and 1,000 mg elementary calcium for 2 weeks. Baseline plasma beta-endorphin levels were measured and repeated after 2 weeks. Patients' pain and quality of life (QOL) were evaluated by using the Visual Analogue Scale, Modified Face Scale, Beck Depression Index, and Nottingham Health Profile. Patients' global assessment of disease activity was also performed at baseline and at the end of the first and second week. We found that plasma beta-endorphin levels in the treatment group were significantly higher than the placebo group at the end of the second week (p<0.001). Although pain and QOL scores were improved at the end of the second week in both groups (p<0.05), the improvement in the treatment group was more significant when compared with the placebo group (p<0.05). Therefore, calcitonin is an analgesic agent, as it increases the plasma beta-endorphin levels in patients with postmenopausal osteoporosis, which consequently improves QOL.

No change in serum melatonin, or plasma beta-endorphin levels after sevoflurane anesthesia.

STUDY OBJECTIVE: To investigate the effect of sevoflurane as single anesthetic on melatonin and beta-endorphin plasma levels during the first 24 hours postoperatively. DESIGN: Prospective, open-cohort study. SETTING: University hospital. PATIENTS: 13 ASA physical status I and II, adults, scheduled for dilatation and curettage of the uterus, and 13 healthy volunteers. INTERVENTIONS: Patients received general anesthesia with sevoflurane. MEASUREMENTS: Melatonin and beta-endorphin plasma levels were determined before anesthesia, immediately after, and two, 4, 8, and 24 hours after the end of anesthesia. Melatonin and beta-endorphin were also measured in 13 healthy subjects (controls) not undergoing anesthesia at similar times during the day. Systolic and diastolic blood pressure, heart rate, bispectral index, and oxygen saturation via pulse oximeter (SpO(2)) were recorded before and after anesthesia. Quality of sleep postoperatively was also assessed. MAIN RESULTS: Melatonin levels (pg/mL) in the patients and controls were 8.2 +/- 7.9 versus 15.2 +/- 15.0 before anesthesia and 7.7 +/- 7.9 versus 11.1 +/- 7.0, 6.5 +/- 6.1 versus 15.6 +/- 16.3, and 19.5 +/- 17.9 versus 23.7 +/- 23.3 at the end of anesthesia and 4 and 24 hours after the end of anesthesia, respectively (P = 0.057). At the same time points, beta-endorphin plasma levels (pmol/L) in patients and controls were 5.2 +/- 2.0 versus 4.0 +/- 2.3, 5.4 +/- 3.3 versus 3.9 +/- 2.5, 4.9 +/- 1.2 versus 4.4 +/- 1.7, and 3.7 +/- 2.6 versus 4.2 +/- 1.8, respectively (P= 0.285). The quality of sleep assessed clinically was not altered. CONCLUSION: Sevoflurane as a single anesthetic for minor gynecological procedures did not influence significantly melatonin or beta-endorphin plasma levels. Sleep quality assessed clinically was not influenced.

Progesterone increased ß-endorphin innervation of the locus coeruleus, but ovarian steroids had no effect on noradrenergic neurodegeneration.

With the decline of ovarian steroids levels at menopause, many women experience an increase in anxiety and stress sensitivity. The locus coeruleus (LC), a central source of noradrenaline (NE), is activated by stress and is inhibited by ß-endorphin. Moreover, increased NE has been implicated in pathological anxiety syndromes. Hormone replacement therapy (HRT) in menopause appears to decrease anxiety and vulnerability to stress. Therefore, we questioned the effect of HRT on the inhibitory ß-endorphin innervation of the LC. In addition, we found that progesterone protects serotoninergic neurons in monkeys, leading us to question whether ovarian steroids are also neuroprotective in LC neurons in monkeys. Adult Rhesus monkeys (Macaca mulatta) were ovariectomized, and either treated with Silastic capsules that contained estradiol, estradiol+progesterone, progesterone alone or that were empty (ovariectomized; control). After 1month, the LC was obtained and processed for immunohistochemistry for ß-endorphin and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL). The density of ß-endorphin axons was determined with image analysis using ImageJ. The TUNEL-positive neurons were counted in the entire LC. Progesterone-alone significantly increased the density of the ß-endorphin axons in the LC (p<0.01). No significant differences between groups in the number of TUNEL-positive cells in the LC were found. In conclusion, we found that HRT increases the inhibitory influence of ß-endorphin in the LC, which could, in turn, contribute to reduce anxiety and increase stress resilience. In addition, we did not find compelling evidence of neurodegeneration or neuroprotection by HRT in the LC of Rhesus monkeys.

Withdrawal following sufentanil/propofol and sufentanil/midazolam. Sedation in surgical ICU patients: correlation with central nervous parameters and endogenous opioids.

PURPOSE: Patients in the ICU after long-term administration of an opioid/hypnotic often develop delirium. To assess the nature of this phenomenon, patients in a surgical ICU following ventilatory support and sedation with an opioid/hypnotic/sedative were studied. METHODOLOGY: Following sufentanil/midazolam (group 1; n =14) or sufentanil/propofol (group 2; n =15) sedation, patients were evaluated for changes in mean arterial blood pressure and heart rate, the activity of the central nervous system (sensory evoked potentials, spectral edge frequency of EEG), and the endogenous opioids plasma concentrations (beta-endorphin, met-enkephalin). Data obtained were correlated with the individual intensities of withdrawal symptoms 6-, 12-, and 24 h following sedation. RESULTS: Following a mean duration of ventilation of 7.7 days (+/-3.6 SD) in groups 1 and 3.5 (+/-1.7 SD) in group 2, withdrawal intensities peaked within the 6th hour after cessation. Plasma beta-endorphin and met-enkephalin levels were low during sedation, and only the sufentanil/midazolam group demonstrated a postinhibitory overshoot. Withdrawal symptom intensities demonstrated an inverse correlation with beta-endorphin and met-enkephalin levels, a direct linear correlation with amplitude height of the evoked potential, and blood pressure and heart rate changes. Withdrawal intensities did not correlate with EEG power spectral edge frequency. CONCLUSION: The endorphinergic system is suppressed when a potent exogenous opioid like sufentanil is given over a long period of time. Following sedation, abstinence symptoms seem to be related to postinhibitory increased endorphin synthesis. This is mostly seen in the combination of sufentanil/midazolam. In addition, an increase in the amplitude of the sensory-evoked potential suggests a postinhibitory excitatory state within the nociceptive system.

Response of neuropeptide Y-induced feeding to mu-, delta- and kappa-opioid receptor antagonists in the neonatal chick.

It is known that opioid antagonists reduce the orexigenic effect of neropeptide Y (NPY) in mammals. We studied the effect of three opioid antagonists on NPY-induced feeding in male broiler chicks. Beta-funaltrexamine (beta-FNA), naloxonazine (NAL), ICI-174,864 (ICI) or nor-binaltorphimine (nor-BNI), antagonists of mu-, mu1-, delta- or kappa-receptors, and NPY were co-injected in chicks. Food intake was measured 30 min after treatment. Co-injection of beta-FNA or NAL was effective in reducing NPY-induced feeding, whereas ICI and nor-BNI had little effect on NPY-induced feeding. These data suggest that the mu-opioid receptor, especially the mu1-opioid has some relation to NPY-induced feeding, and implies that an endogenous ligand, such as beta-endorphin, participates in the orexigenic effect of NPY in neonatal chicks.

Changes in the beta-endorphin plasma level after repeated treatment with acamprosate in rats selectively bred for high and low alcohol preference.

The aim of this study was to evaluate the beta-endorphin (beta-endorphin) plasma level in Warsaw Low Preferring (WLP) and Warsaw high-preferring (WHP) rats after repeated administration of acamprosate, one of most effective drug in the treatment of alcoholism. Treatment with acamprosate in dose 200mg/kg, p.o. for 10 days induced an increase in plasma beta-endorphin levels. A single injection of ethanol also results in the increase of beta-endorphin level. Moreover, it was found that single injection of ethanol to WHP rats resulted in lower increase of plasma beta-endorphin content in rats earlier treated with acamprosate. In WLP rats, repeated acamprosate treatment prevents the ethanol-induced increase in plasma beta-endorphin level. It may be concluded that acamprosate modulates the endogenous opioid system.

Differential effects of aging on neuroendocrine responses to physostigmine in normal men.

We assessed the effects of age on cholinergic regulation of the hypothalamic-pituitary-adrenal axis and other neuroendocrine systems by measuring the plasma cortisol and beta-endorphin responses to an infusion of the centrally active cholinesterase inhibitor physostigmine (0.0125 mg/kg) in 12 healthy older men (68 +/- 1.7 yr) and 9 healthy young men (25 +/- 1.4 yr). We also measured the responses to physostigmine of plasma GH, arginine vasopressin, epinephrine, and norepinephrine (NE). As estimated by comparing calculated areas under the curve, older subjects had greater cortisol (P = 0.02) and beta-endorphin (P less than 0.01) secretory responses, but a reduced GH (P less than 0.01) secretory response. The arginine vasopressin response did not differ between groups. By analysis of variance, older subjects also had a greater epinephrine response (P = 0.01). Older subjects had higher basal NE concentrations (P less than 0.05), but NE responses to physostigmine did not differ between groups. These findings suggest age-related enhancement of the cholinergic stimulatory regulation of the hypothalamic-pituitary-adrenal axis and adrenal medulla. They also confirm previous reports of reduced GH secretory response with aging in normal men.

Enhanced analgesia and suppression of plasma beta-endorphin by the S(+)-isomer of ibuprofen.

BACKGROUND: Peripheral nociceptive barrage after tissue injury results in acute pain and a variety of physiologic responses, including pituitary secretion of beta-endorphin. This study evaluated whether administration of the pharmacologically active S(+)-isomer of ibuprofen suppresses acute pain and plasma beta-endorphin levels in the oral surgery model of acute pain. METHODS: Subjects in a single-dose, double-blind, parallel-group study received either 200 mg S(+)-ibuprofen, 400 mg S(+)-ibuprofen, 400 mg racemic ibuprofen, or placebo. Both doses of S(+)-ibuprofen resulted in significantly greater analgesia over the first 60 minutes in comparison to racemic ibuprofen and placebo; the 400 mg dose of S(+)-ibuprofen also produced greater analgesia at 2 and 3 hours. Plasma levels of immunoreactive beta-endorphin decreased over time coincident with the onset of analgesia in all groups but were significantly less than placebo after both doses of S(+)-ibuprofen from 30 to 120 minutes. CONCLUSIONS: These findings show that, compared with racemic ibuprofen, administration of the S(+)-isomer of ibuprofen results in faster analgesic onset, greater peak analgesia, similar duration of action, and a low incidence of adverse effects, while suppressing nociceptive activation of the pituitary-adrenal axis.

Ibuprofen elevates immunoreactive beta-endorphin levels in humans during surgical stress.

Release of beta-endorphin is modulated by physiologic stress and a variety of hormonal and pharmacologic factors. Prostaglandin E2 inhibits release of beta-endorphin and corticotropin from pituitary corticotroph cells, suggesting that suppression of prostaglandin levels should increase beta-endorphin release. This hypothesis was tested by administration of 600 mg ibuprofen before surgical stress in humans in comparison to placebo and methylprednisolone. Plasma samples were analyzed for immunoreactive beta-endorphin with concurrent measurement of pain and apprehension. Levels of immunoreactive beta-endorphin increased during surgery in the placebo group but were significantly greater in the group of patients pretreated with ibuprofen. Methylprednisolone suppressed intraoperative immunoreactive beta-endorphin, compared with both placebo and ibuprofen. Parallel in vivo and in vitro studies indicate that nonsteroidal anti-inflammatory drug potentiation of endorphin release is mediated at the level of the pituitary corticotroph cell. These results show that ibuprofen enhances pituitary release of beta-endorphin by corticotroph cells in response to stress.

Effects of dopamine D1 and D2 receptor agonists and antagonists on basal and ethanol-modulated beta-endorphin secretion from hypothalamic neurons in primary cultures.

In the present study, we determined the effects of dopamine receptor agonists and antagonists on basal and ethanol-modulated beta-endorphin (beta-EP) secretion from hypothalamic neurons in primary cultures. Treatment with various concentrations of dopamine D1 agonist SKF 38393 and D1 antagonist SCH 23390 did not affect basal IR-beta-EP release. However, dopamine D2 receptor agonist LY 141865 reduced basal immunoreactive (IR)-beta-EP release in a concentration dependent manner. D2 receptor antagonist, sulpiride, on the other hand, stimulated basal IR-beta-EP release and blocked LY 141865-induced inhibition of IR-beta-EP release in a concentration dependent manner. When the actions of these DA receptor agents on ethanol-modulated IR-beta-EP release were studied, both D1 and D2 receptor agents failed to affect ethanol-modulated IR-beta-EP release. These data suggest that the endogenous secretion of beta-EP from hypothalamic neurons is under the influence of an inhibitory dopaminergic system involving the D2 receptor. Furthermore, ethanol's effects on beta-EP secretion are not mediated by dopamine.

Regulation of cellular alpha-MSH and beta-endorphin during stimulated secretion from intermediate pituitary cells: involvement of aspartyl and cysteine proteases in the control of cellular levels of alpha-MSH and beta-endorphin.

The regulation of cellular levels of alpha-melanocyte stimulating factor (alpha-MSH) and beta-endorphin in response to stimulated secretion from intermediate pituitary cells in primary culture was investigated in this study. Regulation of the cell content of alpha-MSH and beta-endorphin occurred in two phases consisting of (a) initial depletion of cellular levels of these peptide hormones during short-term secretion (3 h) induced by isoproterenol, forskolin, or phorbol myristate acetate (PMA) which was followed by (b) long-term (24 h) increases in cellular levels of alpha-MSH and beta-endorphin in response to stimulated secretion induced by isoproterenol and PMA. In short-term experiments (3 h), cellular levels of alpha-MSH and beta-endorphin were reduced by 30-50% during stimulated secretion of these peptide hormones by isoproterenol (agonist for the beta-adrenergic receptor), forskolin that activates protein kinase A (PKA), and PMA that activates protein kinase C (PKC). Moreover, dopamine inhibited isoproterenol-induced depletion of cellular alpha-MSH and beta-endorphin. During long-term incubation of cells (24 h) with isoproterenol, cellular alpha-MSH and beta-endorphin were increased to twice that of controls (unstimulated cells). Treatment with PMA for 24 h also increased cellular levels of alpha-MSH and beta-endorphin. Moreover, cellular levels of alpha-MSH and beta-endorphin were decreased during long-term treatment of cells with an aspartyl protease inhibitor, pepstatin A, and with the cysteine protease inhibitor E64c. These results implicate aspartyl and cysteine proteases in the cellular production of alpha-MSH and beta-endorphin that requires proteolytic processing of their common precursor proopiomelanocortin (POMC). These findings demonstrate the parallel regulation of cellular levels of alpha-MSH and beta-endorphin during their cosecretion, which may involve aspartyl and cysteine proteases in the metabolism of these peptide hormones.

Estradiol valerate and alcohol intake: a comparison between Wistar and Lewis rats and the putative role of endorphins.

Studies show that estrogens can influence alcohol consumption; however, findings are variable and an etiology remains unknown. Furthermore, estrogen administration can alter several neurotransmitter systems implicated in alcohol consumption, including the beta-endorphin (beta-EP) system. The present studies investigate (a) whether estradiol valerate (EV) alters voluntary alcohol consumption in Wistar and Lewis rats, (b) if an effect of EV on drinking is associated with changes in hypothalamic or pituitary beta-EP content, and (c) whether differences in alcohol drinking between treatment and rat groups are related to locomotor or defensive behavior/anxiety scores. Of 30 Wistar and 30 Lewis rats used in this study, half were injected with 2 mg EV in 0.2 ml sesame oil, while the remainder were injected with the vehicle only. After 8 weeks, all animals were tested in the open field and elevated plus maze. A week later, 4-6 animals in each group were sacrificed. The remaining animals were tested for voluntary alcohol drinking for 24 days prior to being sacrificed on the last day. Radioimmunoassay was used to estimate hypothalamic and pituitary beta-EP content. Wistar and Lewis rats injected with EV showed an increase in alcohol drinking, but their behavior scores and beta-EP levels remained unaltered. This result suggests that any EV effect on drinking is unrelated to changes in beta-EP or behavioral performance. Furthermore, Wistar rats show higher alcohol drinking, locomotor and defensive behavior scores, and hypothalamic beta-EP than Lewis rats. Higher alcohol drinking by Wistar rats might be due to higher behavioral scores or endogenous opioid activity/sensitivity.

Neuropeptide Y stimulates beta-endorphin release in the basal hypothalamus: role of gonadal steroids.

Recent pharmacological and morphological studies have raised the likelihood of a regulatory link between the neuropeptide Y (NPY) and beta-endorphin (beta-END) networks in the hypothalamus. To evaluate this link we have examined the effects of NPY administration on the in vivo release of beta-END by push-pull perfusion of the basal hypothalamus. Results showed that centrally injected NPY stimulated the in vivo release of beta-END. This effect was evident only in the absence of testicular steroids since NPY failed to alter beta-END release in intact rats. These data suggest that the well-documented effects of NPY such as inhibition of pituitary gonadotropin release in gonadectomized rats and stimulation of feeding may be mediated, in part, by stimulation of beta-END.

Androgenic-anabolic steroids blunt morphine-induced c-fos expression in the rat striatum: possible role of beta-endorphin.

Self-administration of large doses of androgenic-anabolic steroids (AAS) in a significant portion of the population suggests that these agents are drugs of abuse. However, acute administration of AAS did not induce striatal immediate-early genes (IEG) expression in male rats, indicating that AAS do not share a common mechanism of action with other drugs of abuse. Surveys have indicated that people who abuse AAS are more likely to self-administer other drugs of abuse than do people who do not take AAS. In the present study, chronic administration of AAS blunted the striatal c-fos response to morphine, indicating that AAS can alter the molecular responses to at least one drug of abuse. Chronic administration of AAS also increased the content of beta-endorphin in the midline thalamus, suggesting a possible mechanism by which AAS may modulate the response to morphine through regulation of thalamo-striatal neurons.

Interrelationships between mu opioid and melanocortin receptors in mediating food intake in rats.

The present study examined the interrelationships between feeding responses produced by mu opioid receptor agonists and melanocortin-3 or 4 (MC-3/4) receptor antagonists. Feeding induced by the mu-sensitive opioid peptide, beta-endorphin (betaEND, 10 microg, i.c.v.) was significantly and dose-dependently reduced by pretreatment with the MC-3/4 receptor agonist, melanotan-II (MTII: 0.01-10 nmol, i.c.v.). Moreover, the selective mu opioid antagonist, beta-funaltrexamine (betaFNA: 2-20 mug, i.c.v.), significantly and dose-dependently reduced feeding and weight gain elicited by the potent MC-3/4 receptor antagonist, SHU-9119 (0.5 nmol, i.c.v.), especially at those intake periods (24-48 h) when SHU-9119 produced maximal ingestive effects. These data extend previous findings demonstrating interactions between opioid and melanocortin receptors in the mediation of food intake.

Brain opioid receptor adaptation and expression after prenatal exposure to buprenorphine.

Previous in vivo studies revealed that buprenorphine can down-regulate mu and up-regulate delta2 and kappa1 opioid receptors in adult and neonatal rat brain. To assess gestational effects of buprenorphine on offspring, pregnant rats were also administered this drug and opioid receptor binding parameters (Kd and Bmax values) were measured by homologous binding assays of postnatal day 1 (P1) brain membranes. Buprenorphine concentrations of 2.5 mg/kg injected into dams elicited an up-regulation of kappa1 opioid receptors as detected with the kappa1-selective agonist 3H-U69593. Parallel studies with the mu-selective agonist [D-ala2, mephe4,gly-ol5] enkephalin revealed a buprenorphine-induced down-regulation in receptor density at 0.3, 0.6 or 2.5 mg/kg drug treatment. A greater down-regulation of mu receptors for P1 males than for their female counterparts was observed. Buprenorphine did not cause a reduction in binding affinity in these experiments. Changes in opioid receptor adaptation induced by buprenorphine were further supported by data from cross-linking of 125I-beta-endorphin to brain membrane preparations. RT-PCR analysis of opioid receptor expression was also estimated in P1 brains. However, significant changes in neither mu nor kappa receptor message were detected in P1 brains as a result of prenatal buprenorphine treatment under the conditions of these experiments. Since buprenorphine is being evaluated in clinical trials for the treatment of heroin abuse, the in utero actions of the drug have ramifications for its use in the treatment of maternal drug abuse.

The effect of haloperidol on met-enkephalin, beta-endorphin, cholecystokinin and substance P in the pituitary, the hypothalamus and the striatum of rats during aging.

1. Haloperidol increased the Met-enk level in the striatum at all age groups. However, the Met-enk level was decreased in AL of young and middle-aged rats by the drug. 2. Haloperidol elevated the beta-end level in AL and CCK level in NIL in young rats only. 3. The SP content in NIL was decreased by haloperidol in all age groups. 4. With regard to the effect of aging, Met-enk level in AL of middle-aged rats was higher than that in young rats. The beta-end level in AL also increased in old rats. 5. Aging modified the haloperidol effect on beta-end level in AL and CCK level in NIL as the effect was only observed in young rats. 6. In addition, aging caused a blunted response of Met-enk level to haloperidol in the striatum but an increased response of SP content to haloperidol in the NIL.