Additive and subadditive antiallodynic interactions between μ-opioid agonists and N-methyl D-aspartate antagonists in male rhesus monkeys

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Abstract

μ-Opioid agonists are clinically effective analgesics, but also produce undesirable effects such as sedation and abuse potential that limit their clinical utility. Glutamatergic systems also modulate nociception and N-methyl D-aspartate (NMDA) receptor antagonists have been proposed as one useful adjunct to enhance the therapeutic effects and/or attenuate the undesirable effects of μ-opioid agonists. Whether NMDA antagonists enhance the antiallodynic effects of μ-agonists in preclinical models of thermal hypersensitivity (i.e. capsaicin-induced thermal allodynia) are unknown. The present study determined the behavioral effects of racemic ketamine, (+)-MK-801, (−)-nalbuphine, and (−)-oxycodone alone and in fixed proportion mixtures in assays of capsaicin-induced thermal allodynia and schedule-controlled responding in rhesus monkeys. Ketamine, nalbuphine, and oxycodone produced dose-dependent antiallodynia. MK-801 was inactive up to doses that produced undesirable effects. Ketamine, but not MK-801, enhanced the potency of μ-agonists to decrease rates of operant responding. Ketamine and nalbuphine interactions were additive in both procedures. Ketamine and oxycodone interactions were additive or subadditive depending on the mixture. Furthermore, oxycodone and MK-801 interactions were subadditive on antiallodynia and additive on rate suppression. These results do not support the broad clinical utility of NMDA receptor antagonists as adjuncts to μ-opioid agonists for thermal allodynic pain states.

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