norbinaltorphimine and Body-Weight

Intraplantar administration of complete Freund's adjuvant (CFA) and formalin are two noxious stimuli commonly used to produce sustained pain-related behaviors in rodents for research on neurobiology and treatment of pain. One clinically relevant manifestation of pain is depression of behavior and mood. This study compared effects of intraplantar CFA and formalin on depression of positively reinforced operant behavior in an assay of intracranial self-stimulation (ICSS) in rats. Effects of CFA and formalin on other physiological and behavioral measures, and opioid effects on formalin-induced depression of ICSS, were also examined.. There were four main findings. First, consistent with previous studies, both CFA and formalin produced similar paw swelling and mechanical hypersensitivity. Second, CFA produced weak and transient depression of ICSS, whereas formalin produced a more robust and sustained depression of ICSS that lasted at least 14 days. Third, formalin-induced depression of ICSS was reversed by morphine doses that did not significantly alter ICSS in saline-treated rats, suggesting that formalin effects on ICSS can be interpreted as an example of pain-related and analgesic-reversible depression of behavior. Finally, formalin-induced depression of ICSS was not associated with changes in central biomarkers for activation of endogenous kappa opioid systems, which have been implicated in depressive-like states in rodents, nor was it blocked by the kappa antagonist norbinaltorphimine.. These results suggest differential efficacy of sustained pain stimuli to depress brain reward function in rats as assessed with ICSS. Formalin-induced depression of ICSS does not appear to engage brain kappa opioid systems.

Topics: Analgesics, Opioid; Animals; Body Weight; Conditioning, Operant; Disease Models, Animal; Formaldehyde; Freund's Adjuvant; Hyperalgesia; Inhibition, Psychological; Male; Morphine; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Self Stimulation

Food intake and, subsequently, body weight are influenced by endogenous opioids acting in the central nervous system. Agonists for the opioid receptor increase food intake, whereas antagonists reduce food intake. Body weight, however, is the result of food consumed and energy expended. Although much has been reported about the effect of opioid antagonism on food intake, less has been reported about its effect on energy expended. This study investigated the effect of selective antagonism of the kappa opioid receptor on food intake, body weight, and indicators of energy expenditure in male obese Zucker rats (n=10). Energy expenditure was measured by indirect calorimetry, whereas general activity and body temperature were measured by implanted radio frequency telemetry. Central administration of 30 microg of the kappa opioid receptor (KOR) antagonist norbinaltorphamine resulted in a significant 34% reduction in food intake (p =.001), a small reduction in body weight, a reduction in resting energy expenditure (p = .06), a reduction in respiratory quotient (p =.06), a 14% reduction in general activity, and a reduction in core body temperature. Reduction in body weight as a result of KOR inhibition in this study was related to a decrease in food intake but not related to an increase in energy expended or activity.

Topics: Analysis of Variance; Animals; Body Temperature; Body Weight; Calorimetry, Indirect; Cardiac Catheterization; Disease Models, Animal; Drug Evaluation, Preclinical; Energy Intake; Energy Metabolism; Injections, Intravenous; Male; Motor Activity; Naltrexone; Narcotic Antagonists; Obesity; Rats; Rats, Zucker; Receptors, Opioid, kappa; Respiration; Telemetry

Toward understanding why infant rats ingest high levels of ethanol without initiation procedures, the authors tested effects of mu and kappa receptor antagonists on ethanol reinforcement in neonatal rats. After an intracisternal injection of CTOP (micro antagonist), nor-Binaltorphimine (kappa antagonist), or saline, newborn (3-hr-old) rats were given conditioning pairings of an odor with intraorally infused ethanol or a surrogate nipple with ethanol administered intraperitoneally (to minimize ethanol's gustatory attributes). In each case, these opioid antagonists reduced or eliminated ethanol's reinforcement effect. The same effects occurred with saccharin as the reinforcer in olfactory conditioning. The results imply that activation of mu and kappa receptors, apparently acting jointly, is necessary for reinforcement or that antagonists of this activity impair basic conditioning.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Body Weight; Bottle Feeding; Central Nervous System Depressants; Cesarean Section; Conditioning, Classical; Ethanol; Female; Male; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Sex Factors; Somatostatin

Kappa opioid receptor (KOR) agonists interfere with the reinforcing effects of drugs of abuse. KOR agonists decrease heroin, cocaine, and ethanol self-administration, and block heroin and cocaine conditioned place preference (CPP) in rats. However, KOR agonists also produce emesis and dysphoria, making it difficult to determine if their effects on self-administration are due to an action on reward mechanisms or are secondary to the drug's direct aversive effects. Assuming that endogenous KOR ligands modulate circuits involved in drug and alcohol reward, selective KOR antagonists can be used to clarify these issues. If KOR antagonists increase drug self-administration then it is likely that endogenous KOR agonists directly modulate drug intake.. To determine the effects of nor-BNI, the highly selective KOR antagonist, on ethanol consumption and CPP.. Thirty-eight male Lewis rats were given free access to ethanol until stable self-administration was achieved. Animals were then administered a single injection of nor-BNI (10 mg kg(-1)) while ethanol intake was monitored.. A single injection of nor-BNI induces a long-lasting increase in ethanol consumption, but does not induce a CPP. A high/low split revealed that this effect was primarily due to an increase in drinking in nor-BNI-treated high drinkers, which drank significantly more than saline-treated high drinkers and also drank significantly more when compared to their own pretreatment baseline.. Blocking the KOR system increases ethanol self-administration, suggesting that the decrease in self-administration seen with KOR agonists is due to a direct modulation of reward circuitry.

Topics: Alcohol Drinking; Animals; Body Weight; Choice Behavior; Conditioning, Psychological; Drinking; Female; Male; Naltrexone; Rats; Rats, Inbred Lew; Receptors, Opioid, kappa; Sex Characteristics

Previous research in our laboratory has established a restraining role of the hippocampal kappa-opioid receptor system in the neural control of blood pressure. Chronic or acute hippocampal administration of kappa-agonists has been shown to reduce blood pressure. Isolation of male Sprague-Dawley rats provokes an increase in blood pressure, which has been proposed as a valid model of mild emotionally induced hypertension. It was the purpose of this study to investigate the blood pressure effects of dorsal hippocampal administration of nor-binaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist; in conscious male Sprague-Dawley rats subjected to isolation-induced hypertension. Chronic bi-hippocampal microinjection of nor-BNI (10 nmol per side, twice a day for 13 days) caused increases in systolic blood pressure in grouped rats from a mean of 125 to 148 mmHg, and in isolated rats from a mean of 125 to 151 mmHg. This hypertension was similar in magnitude to the increase observed after rats were isolated for 7 days and treated with vehicle in a similar fashion (mean systolic blood pressure 144 mmHg). The increases in blood pressure were accompanied by bradycardia. No significant responses were seen in the blood pressure of grouped rats treated with vehicle. The hypotensive response to a single hippocampal microinjection of the kappa-agonist U62, 066E (10 or 20 nmol) was prevented in anesthetized rats treated previously with nor-BNI, indicating that in the nor-BNI treated rats there was effective blockade of dorsal hippocampal receptors. These data suggest that the rat hippocampal kappa-opioid receptor system and the endogenous neuropeptide dynorphin may be involved in the central neural regulation of blood pressure.

Topics: Anesthesia; Animals; Blood Pressure; Body Weight; Heart Rate; Hippocampus; Hypertension; Male; Microinjections; Naltrexone; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Social Isolation; Stress, Psychological

The obese Zucker rat (OZR) exhibits a hyperphagic eating pattern similar to the obese binge eater. Dynorphin, an endogenous agonist of the kappa receptor, is associated with regulation offood intake. Lessened sensitivity to opioid antagonists and/or increased central dynorphin levels may contribute to the hyperphagic eating pattern observed in the OZR. This study examined the temporal effect of a single intracerebroventricular (ICV) dose of nor-binaltorphimine (NBNI), a specific and long-lasting kappa opioid antagonist, on food intake, body weight, and satiety measures (meal size and the shape of the cumulative food intake curve [CFIC]) in adult male OZRs. Analysis of individual subjects revealed a differential response to opioid antagonism with respect to weight loss, reduction in food intake, and change in the slope of the CFIC, with some responding and others responding poorly. Repeated-measures analysis of variance showed a significant decrease in body weight (P = 0.001) and food intake (P = 0.03) in responders compared to poor responders and controls. Satiation was influenced to a greater extent in responders, who showed a significant reduction in meal size and a greater change in the CFICfor the largest meal of the day toward a pattern of satiation. These data suggest that a differential response to chronic opioid antagonism may exist in the OZR.

Topics: Animals; Body Weight; Brain; Bulimia; Energy Intake; Feeding Behavior; Hyperphagia; Injections, Intraventricular; Models, Animal; Naltrexone; Narcotic Antagonists; Obesity; Rats; Rats, Zucker; Satiation

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

Topics: Analgesia; Animals; Arteries; Blood Pressure; Body Temperature; Body Weight; Brain; Chronic Disease; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The profile of actions of dihydroetorphine (DHE) concerning antinociception, tolerance and dependence was compared with those of morphine in mice. DHE at 1, 5, 10 or 20 micrograms/kg produced an antinociceptive effect in a dose dependent manner and 10 micrograms/kg was nearly equipotent to that of 10 mg/kg of morphine. The antinociceptive effect of both drugs was completely suppressed by 1 mg/kg of naloxone, while neither 10 mg/kg of naltrindole nor 1 mg/kg of nor-binaltorphimine had any suppressive effect. Mice tolerant to morphine antinociception were tolerant to DHE and vice versa. The naloxone-sensitive, locomotor accelerating activity was progressively enhanced by daily administration of DHE and morphine and a cross reverse tolerance developed between these compounds, suggesting that common mechanisms, especially mediating opioid receptors, underlay the activity enhancement. The development of physical dependence as evidenced by naloxone precipitated withdrawal signs, however, was not observed with daily treatment with DHE, 10, 20 and 100 micrograms/kg for 6 d. Thus, we demonstrated that DHE produces the antinociceptive effect mediated through mu opioid receptors without causing development of a physical dependence, suggesting that it is safe to use in the clinical therapy of patients suffering severe pain such as that accompanying cancer.

Topics: Analgesics; Animals; Body Weight; Drug Tolerance; Etorphine; Male; Mice; Mice, Inbred Strains; Morphine; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Substance-Related Disorders

The present study was conducted to evaluate the influence of chronic kappa receptor blockade on the neuroendocrine effects of the selective kappa 1 opioid agonist U-50,488H, on the hypothalamo-pituitary-adrenocortical (HPA) axis. Male Sprague-Dawley rats were chronically treated with naloxone (3 mg kg-1 day-1 for 7 days) or distilled water by s.c. implantation of osmotic minipumps and the response of the HPA axis to U-50,488H or saline was assessed before and 24 h after pump removal. Chronic infusion of naloxone reduced body weight gain and blocked the increase in corticosterone secretion induced by U-50,488H, indicating occupation of kappa opioid receptors. Significantly higher plasma corticosterone levels after U-50,488H administration at doses of 5 or 15 mg/kg were observed 1 day after cessation of naloxone treatment compared with those in corresponding control rats. The enhanced responsiveness of the HPA axis to U-50,488H (15 mg/kg) was antagonized by norbinaltorphimine (5 mg/kg), suggesting a role for kappa receptors in mediating supersensitivity to the kappa agonist. The findings of the present study demonstrated that chronic blockade of the kappa receptor results in augmentation of kappa agonist-induced stimulation of the HPA axis activity (functional supersensitivity).

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Body Weight; Corticosterone; Dose-Response Relationship, Drug; Hyperalgesia; Hypothalamo-Hypophyseal System; Male; Naloxone; Naltrexone; Pituitary-Adrenal System; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sensitivity and Specificity; Sodium Chloride

The effects of a highly selective kappa antagonist, nor-binaltorphimine (nor-BNI), on the development of tolerance to morphine analgesia and physical dependence on morphine were examined. Pretreatment with nor-BNI (5 mg/kg s.c.) 2 h prior to injection of morphine or a selective kappa agonist, U-50,488H, significantly antagonized the analgesic effect of U-50,488H, but not morphine analgesia in mice. The development of tolerance to morphine analgesia was significantly potentiated by pretreatment of mice with nor-BNI 2 h prior to morphine treatment during chronic morphine treatment for 5 days. Additionally, the pretreatment with nor-BNI during chronic treatment with the high dose of morphine for 5 days significantly potentiated the naloxone-induced body weight loss in morphine-dependent mice and rats. These findings suggest that inactivation of the kappa opioid system may potentiate the development of tolerance to morphine analgesia in mice and may aggravate the naloxone-precipitated body weight loss in morphine-dependent mice and rats.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Analgesics; Analysis of Variance; Animals; Behavior, Animal; Body Weight; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence; Naltrexone; Pyrrolidines; Rats

Chronic treatment with naloxone (Nx) or naltrexone (Ntx) induces paradoxical analgesia. In the present study, the effects of chronic treatment with opioid receptor antagonists, such as nor-binaltorphimine (nor-BNI) for kappa and naltrindole (NTI) for delta receptors, on analgesic response using the hot plate test and on morphine physical dependence in rats were examined. The hot plate latency was significantly increased by pretreatment with Nx (5 mg/kg, s.c.), nor-BNI (20 mg/kg, i.p.) or NTI (20 mg/kg, i.p.) for 5 days. After chronic pretreatment with these antagonists, the rats were treated with morphine-admixed food (0.5 mg/g of food) for 3 days. Chronic pretreatment with Nx and NTI significantly increased Nx precipitated body weight loss in morphine dependent rats, while chronic pretreatment with nor-BNI produced small increase. These results indicate that chronic treatment with nor-BNI or NTI as well as with Nx induces obviously paradoxical analgesia, and that chronic blockade of mu or delta may enhance the development of physical dependence on morphine.

Topics: Animals; Body Weight; Indoles; Male; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Substance-Related Disorders