clocinnamox and norbinaltorphimine

Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined.. The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE. The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 μg), naltrindole (60 μg) and nor-binaltorfimina (200 μg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 μg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng).. These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes.

Topics: Analgesics; Animals; Cinnamates; Dinoprostone; Disease Models, Animal; Male; Mice; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Opioid Peptides; Pain; Receptors, Opioid; Serotonin

The aim of this study was to investigate this involvement in not inflammatory model of pain and which opioid receptor subtype mediates noradrenaline-induced peripheral antinociception. Noradrenaline is involved in the intrinsic control of pain-inducing pro-nociceptive effects in the primary afferent nociceptors. However, inflammation can induce various plastic changes in the central and peripheral noradrenergic system that, upon interaction with the immune system, may contribute, in part, to peripheral antinociception.. Hyperalgesia was induced by intraplantar injection of prostaglandin E. Intraplantar injection of NA induced peripheral antinociception against hyperalgesia induced by PGE. Besides the α

Topics: Analgesics; Animals; Cinnamates; Dinoprostone; Dose-Response Relationship, Drug; Hyperalgesia; Leucine; Male; Morphine Derivatives; Naltrexone; Norepinephrine; Opioid Peptides; Pain Measurement; Prazosin; Propranolol; Rats; Yohimbine

It is generally believed that NMDA receptor antagonism accounts for most of the anesthetic and analgesic effects of ketamine, however, it interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors. Interestingly, it was shown that at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal antinociception. In this study, we investigated the involvement of endogenous opioids in ketamine-induced central antinociception. The nociceptive threshold for thermal stimulation was measured in Swiss mice using the tail-flick test. The drugs were administered via the intracerebroventricular route. Our results demonstrated that the opioid receptor antagonist naloxone, the μ-opioid receptor antagonist clocinnamox and the δ-opioid receptor antagonist naltrindole, but not the κ-opioid receptor antagonist nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner. Additionally, the administration of the aminopeptidase inhibitor bestatin significantly enhanced low-dose ketamine-induced central antinociception. These data provide evidence for the involvement of endogenous opioids and μ- and δ-opioid receptors in ketamine-induced central antinociception. In contrast, κ-opioid receptors not appear to be involved in this effect.

Topics: Aminopeptidases; Analgesics; Animals; Brain; Cinnamates; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hot Temperature; Ketamine; Leucine; Male; Mice; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptive Pain; Opioid Peptides; Pain Perception; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

The development of antinociceptive tolerance to morphine is one of the major problems in its clinical use. Therefore, exploring effective measures to prevent morphine tolerance is of great clinical relevance. We evaluated whether pentazocine could prevent morphine tolerance in mice.. Five groups of male ICR mice received repeated subcutaneous (s.c.) injections of morphine at a high dose (10 mg x kg(-1)) or saline, concomitantly with s.c. injections of pentazocine at low, subanalgesic doses (0.1, 0.3, or 1.0 mg x kg(-1)) or saline, respectively, once daily for 14 days. On day 15, mice received co-injections of morphine and pentazocine 120 min after pretreatment with nor-binaltorphimine (5 mg x kg(-1)), a selective kappa-opioid receptor antagonist. The tail pressure threshold was measured before and 60 min after the daily drug co-injections.. Repeated s.c. co-injections of morphine and saline resulted in a progressive decrease in morphine-induced antinociception, due to the development of morphine tolerance. Co-injections of pentazocine (0.1, 0.3, and 1.0 mg x kg(-1)) with morphine potentiated the morphine-induced antinociception dose-dependently by preventing the development of morphine tolerance. Nor-binaltorphimine completely inhibited the chronic antinociception maintained by co-injections of morphine and pentazocine.. When chronically co-administered with morphine, pentazocine at low, subanalgesic doses dose-dependently potentiated morphine-induced antinociception in morphine-tolerant mice, through its kappa-opioid-receptor-mediated tolerance-preventing activity. Because pentazocine is the only agonist-antagonist analgesic that has an effective oral formulation suitable for chronic administration, the results of the present study warrant clinical trials of pentazocine to assess its tolerance-preventing activity in patients with cancer pain.

Topics: Analgesics, Opioid; Animals; Cinnamates; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Pain Measurement; Pentazocine; Pressure; Receptors, Opioid, kappa

Previously, we found that processed Aconiti tuber (PAT) could inhibit morphine tolerance in mice. In the present study, we investigated mechanisms underlying this effect. Mice received subcutaneous (s.c.) morphine (10 mg/kg) and oral PAT at a subanalgesic dose (0.3 g/kg), once a day for 12 days. Additional PAT-treated groups received morphine and PAT, at 120 min after pretreatment with s.c. clocinnamox mesylate (C-CAM) (0.5 mg/kg), or nor-binaltorphimine (nor-BNI) (5 mg/kg). The antinociceptive effect was assessed with the tail pressure test, at 60 min after the daily s.c. morphine injections were given. In the placebo-treated group, repeated morphine injections caused morphine tolerance, and morphine antinociception was abolished by day 6, whereas in PAT-treated groups, significant antinociception was maintained until day 12, suggesting that PAT inhibited morphine tolerance, thereby sustaining morphine antinociception. C-CAM, a selective mu-opioid receptor (MOR) antagonist, blocked morphine antinociception whereas nor-BNI, a selective kappa-opioid receptor (KOR) antagonist, did not. However, both C-CAM and nor-BNI could block the antinociception maintained by the morphine-PAT combination. Results of the study suggested that chronic treatment with PAT at a subanalgesic dose maintained MOR-mediated morphine antinociception by attenuating development of morphine tolerance, and that this tolerance-attenuating effect of PAT was mediated by KOR.

Topics: Aconitum; Analgesics, Opioid; Animals; Cinnamates; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Drugs, Chinese Herbal; Male; Mice; Morphine; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Pain Threshold; Plant Tubers; Receptors, Opioid, kappa; Time Factors

We have investigated effects of micro- and kappa-opioid agonists and antagonists on plasma oxytocin levels and noradrenaline content in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of 20-day pregnant rats. beta-Endorphin, oxytocin, estrogen and progesterone profiles in late pregnant and parturient rats were also sought. Stage of estrous cycle was monitored by vaginal smear, and pro-estrous animals were left overnight with male. In the first set of experiments, pregnant rats were monitored and decapitated on days 20 and 21 and after the delivery of second pup. In the second set, 20-day pregnant rats were intracerebroventricularly infused with morphine (50 microg/10 microl), U50,488H (kappa-agonist; 50 microg/10 microl), clocinnamox (micro-antagonist; 50 microg/10 microl) and norbinaltorphimine (kappa-antagonist; 50 microg/10 microl). Controls received saline alone. Serum estrogen and progesterone levels were measured by enzyme immunoassay, and plasma oxytocin and beta-endorphin by radioimmunoassay. Noradrenaline and its metabolite (3,4-dihydroxyphenylglycol) were determined in micropunched hypothalamic nuclei by HPLC-ECD. In parturient rats, oxytocin levels were increased (p < 0.05) and beta-endorphin decreased (p < 0.01) compared to 20-day pregnant animals. Serum progesterone concentrations progressively declined towards parturition (p < 0.001). Clocinnamox raised oxytocin levels (p < 0.01) while U50,488H caused decreases (p < 0.05). Noradrenaline content was elevated by clocinnamox in the SON (p < 0.01) and PVN (p < 0.05) compared to control values. Other agonists and antagonists had no significant effect on the noradrenergic neurotransmission or oxytocin secretion. We suggest that noradrenaline may mediate the inhibitory effects of micro-opioids on oxytocin release. Our findings have also shown that kappa-opioid receptors are not involved in modulation of oxytocin neurons in late pregnant rats.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Cinnamates; Enzyme-Linked Immunosorbent Assay; Estrogens; Female; Methoxyhydroxyphenylglycol; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Narcotics; Norepinephrine; Oxytocin; Paraventricular Hypothalamic Nucleus; Pregnancy; Progesterone; Rats; Rats, Wistar; Receptors, Opioid, kappa; Receptors, Opioid, mu; Supraoptic Nucleus

Some opioid antagonists increase the release of adrenocorticotropic hormone (ACTH) and cortisol in humans and, therefore, may indicate that endogenous opioids modulate hypothalamic-pituitary-adrenal axis activity. The type of opioid receptor that may be related to these endocrine effects is unknown. The purpose of this experiment was to evaluate the ability of different opioid antagonists to increase ACTH and cortisol plasma levels in rhesus monkeys. Eight monkeys received intramuscular injections of various antagonists: 0.0032-1.0 mg/kg naltrexone, 0.1-3.2 mg/kg naltrindole (delta-selective), 0.032-0.32 mg/kg clocinnamox (mu-selective), and 1-3.2 mg/kg nor-binaltorphimine (kappa-selective). Naltrexone, 0.1-1.0 mg/kg, increased ACTH levels, whereas naltrindole and clocinnamox failed to increase ACTH levels. Nor-binaltorphimine, 1-3.2 mg/kg, increased ACTH concentrations on the day of injection, but not at a time when other assays continue to demonstrate kappa-antagonism (24 h). Cortisol concentrations generally followed the same pattern as the ACTH concentrations, but the incremental differences in cortisol release between doses were less clear. Thus, opioid modulation of ACTH and cortisol plasma levels is not clearly associated with a particular opioid receptor. Although the kappa-antagonist increased ACTH and cortisol release on the day of injection, some evidence suggests that this endocrine effect may be due to mechanisms other than those mediated by the kappa-receptor. Alternatively, the naltrexone-induced increase of ACTH and cortisol plasma levels may be caused by activity at multiple opioid receptors or some uncharacterized receptor. Finally, the increased release of ACTH and cortisol may be a response to naltrexone's aversive properties.

Topics: Adrenocorticotropic Hormone; Animals; Cinnamates; Dose-Response Relationship, Drug; Female; Hydrocortisone; Hypothalamo-Hypophyseal System; Macaca mulatta; Male; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Pituitary-Adrenal System