Potentiation of morphine-induced antinociception in acute spinal rats by the NMDA antagonist dextrorphan

Neurophysiologic and behavioral evidence indicates that excitatory amino acid (EAA) antagonists may provide a new class of selective analgesics for opiate resistant, neuropathic pain syndromes. Therapeutic applications have been limited because of unacceptable side effects of most EAA blockers. However, dextrorphan, a metabolite of the antitussive drug, dextromethorphan, is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of EAA receptor with few side effects and a moderate analgesic effect in animals with peripheral neuropathy. It may therefore, have clinical benefit, either alone or in combination with opiates, for neuropathic pain. In this study a subeffective dose of dextrorphan (15 mg/kg) was combined with several doses of morphine (1.5, 3.0 and 6.0 mg/kg) and assessed in an animal model of central injury, the tail flick response of the acute spinal rat. At doses which were individually ineffective, the combination of dextrorphan and morphine (15 and 1.5 mg/kg, respectively) produced a significant antinociceptive response. The same dose of dextrorphan also increased the antinociceptive response to 3.0 and 6.0 mg/kg of morphine. Coadministration of low doses of an NMDA antagonist and an opiate, might have clinical benefit for the relief of pain with reduced risk of undesirable side effects.