Stress-induced analgesia and morphine responses are changed in catechol-O-methyltransferase-deficient male mice.

Catechol-O-methyltransferase (COMT) polymorphisms modulate pain and opioid analgesia in human beings. It is not clear how the effects of COMT are mediated and only few relevant animal studies have been performed. Here, we used old male Comt gene knock-out mice as an animal model to study the effects of COMT deficiency on nociception that was assessed by the hot plate and tail flick tests. Stress-induced analgesia was achieved by forced swim. Morphine antinociception was measured after 10 mg/kg of morphine subcutaneously. Morphine tolerance was produced with subcutaneous morphine pellets and withdrawal provoked with subcutaneous naloxone. In the hot plate test, morphine-induced antinociception was significantly greater in the COMT knock-out mice, compared to the wild-type mice. This may be due to increased availability of opioid receptors as suggested by previous human studies. In the tail flick test, opioid-mediated stress-induced analgesia was absent and morphine-induced analgesia was decreased in COMT knock-out mice. In the hot plate test, stress-induced analgesia developed to all mice regardless of the COMT genotype. There were no differences between the genotypes in the baseline nociceptive thresholds, morphine tolerance and withdrawal. Our findings show, for the first time, the importance of COMT activity in stress- and morphine-induced analgesia in mice. COMT activity seems to take part in the modulation of nociception not only in the brain, as suggested earlier, but also at the spinal/peripheral level.

Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats.

BACKGROUND: The pharmacology of oxycodone is poorly understood despite its growing clinical use. The discrepancy between its good clinical effectiveness after systemic administration and the loss of potency after spinal administration led the authors to study the pharmacodynamic effects of oxycodone and its metabolites using in vivo and in vitro models in rats. METHODS: Male Sprague-Dawley rats were used in hot-plate, tail-flick, and paw-pressure tests to study the antinociceptive properties of morphine, oxycodone, and its metabolites oxymorphone and noroxycodone. Mu-opioid receptor agonist-stimulated GTPgamma[S] autoradiography was used to study G-protein activation induced by morphine, oxycodone, and oxymorphone in the rat brain and spinal cord. Spontaneous locomotor activity was measured to assess possible sedation or motor dysfunction. Naloxone and the selective kappa-opioid receptor antagonist nor-binaltorphimine were used to study the opioid receptor selectivity of the drugs. RESULTS: Oxycodone showed lower efficacy and potency to stimulate GTPgamma[S] binding in the spinal cord and periaqueductal gray compared with morphine and oxymorphone. This could relate to the fact that oxycodone produced only weak naloxone-reversible antinociception after intrathecal administration. It also suggests that the metabolites may have a role in oxycodone-induced analgesia in rats. Intrathecal oxymorphone produced strong long-lasting antinociception, whereas noroxycodone produced antinociception with very high doses only. Subcutaneous administration of oxycodone and oxymorphone produced thermal and mechanical antinociception that was reversed by naloxone but not by nor-binaltorphimine. Oxymorphone was more potent than oxycodone, particularly in the hot-plate and paw-pressure tests. CONCLUSIONS: The low intrathecal potency of oxycodone in rats seems be related to its low efficacy and potency to stimulate mu-opioid receptor activation in the spinal cord.

Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat.

We studied the effects of the commonly used mu-opioid receptor agonists morphine, oxycodone, methadone and the enantiomers of methadone in thermal and mechanical models of acute pain and in the spinal nerve ligation model of neuropathic pain in rats. Subcutaneous administration of morphine, oxycodone, and methadone produced a dose-dependent antinociceptive effect in the tail flick, hotplate, and paw pressure tests. l-methadone, racemic methadone, and oxycodone had a similar dose-dependent antinociceptive effect, whereas the dose-response curve of morphine was shallower. In the spinal nerve ligation model of neuropathic pain, subcutaneous administration of morphine, oxycodone, methadone and l-methadone had antiallodynic effects in tests of mechanical and cold allodynia. l-methadone showed the strongest antiallodynic effect of the tested drugs. d-methadone was inactive in all tests. Morphine 5.0 mg/kg, oxycodone 2.5 mg/kg, and l-methadone 1.25 mg/kg decreased spontaneous locomotion 30 min after drug administration. In conclusion, in acute nociception all mu-opioid receptor agonists produced antinociception, with morphine showing the weakest effect. In nerve injury pain, l-methadone showed the greatest antiallodynic potency in both mechanical and cold allodynia compared with the other opioids. Opioids seem to have different profiles in different pain models. l-methadone should be studied for neuropathic pain in humans.