The analgesic action of topical diclofenac may be mediated through peripheral NMDA receptor antagonism

The analgesic mechanism underlying the efficacy of topical diclofenac in the treatment of musculoskeletal pain is incompletely understood. The present study investigated whether intramuscular injection of diclofenac (0.1 mg/ml, ∼340 μM) could attenuate jaw-closer muscle nociceptor discharge and mechanical sensitization induced by activation of peripheral 5-hydroxytryptamine (serotonin) or excitatory amino acid receptors in anesthetized Sprague-Dawley rats. Diclofenac inhibited nociceptor discharge evoked by NMDA, but had no effect on nociceptor discharge evoked by 5-hydroxytryptamine or AMPA. Subsequent experiments revealed that diclofenac-mediated inhibition of NMDA-evoked nociceptor discharge was competitive. Intramuscular injection of 5-hydroxytryptamine, NMDA and AMPA also decreased nociceptor mechanical threshold, however, only the mechanical sensitization produced by NMDA was reversed by diclofenac. Co-administration of the proinflammatory prostaglandin PGE2 did not alter the ability of diclofenac to significantly attenuate NMDA-evoked nociceptor discharge or NMDA-induced mechanical sensitization. Intramuscular injection of either diclofenac or the competitive NMDA receptor antagonist dl-2-amino-5-phosphonovalerate (50 mM) alone could elevate nociceptor mechanical threshold for a 30 min period post-injection. The present study indicates that in vivo, diclofenac can exert a selective, competitive inhibition of peripheral NMDA receptors at muscle concentrations achievable after topical administration of diclofenac containing preparations. This property may contribute to the analgesic effect of topical diclofenac when used for muscle pain.