naltrindole and clocinnamox

Ketamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective μ- and δ-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not κ-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced β-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for μ- and δ-opioid receptors and for the endogenous opioid β-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.

Topics: Analgesics; Animals; Cinnamates; Dinoprostone; Ketamine; Male; Mice; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu

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

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