Additive and sub-additive antiallodynic interactions between mu-opioid agonists and N-Methyl D-Aspartate antagonists in male rhesus monkeys

摘要

Mu-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 undesirable effects of mu-opioid agonists. Whether NMDA antagonists enhance the antiallodynic effects of mu 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 mu agonists to decrease rates of operant responding. Ketamine and nalbuphine interactions were additive in both procedures. Ketamine and oxycodone interactions were additive or sub-additive depending upon the mixture. Furthermore, oxycodone and MK-801 interactions were sub-additive on anti-allodynia and additive on rate suppression. These results do not support the broad clinical utility of NMDA receptor antagonists as adjuncts to mu-opioid agonists for thermal allodynic pain states.