Antihyperalgesic activity of epibatidine in the formalin model of facial pain

A growing body of evidence supports a nicotinic cholinergic approach to pain management, as neuronal nicotinic receptor agonists have shown efficacy across animal models of both inflammatory and neuropathic pain. However, most of these investigations have focused on the spinal system, and there is to date no report of nicotinic receptor-mediated antinociception in any pain model involving the trigeminal field of innervation. Thus, the purpose of the present studies was to evaluate whether the neuronal nicotinic receptor agonist epibatidine possesses antihyperalgesic activity in the formalin model of facial pain. Adult, male, Sprague--Dawley rats received a 50-microl, subcutaneous injection of 5% formalin into one vibrissal pad and the consequent, facial grooming behavior was monitored. Consistent with previous investigations using the formalin model, animals exhibited two periods of nocifensive grooming: (1) an acute phase that began immediately, peaked at 3 min and almost completely abated by 6 min, and (2) a tonic phase that began between 6 and 9 min, peaked at 21 min and slowly diminished over the ensuing 24 min. The subcutaneous administration of epibatidine (1--5 microg/kg) 5 min prior to the formalin injection led to a significant, dose-dependent reduction of both the acute and tonic phases of hyperalgesia. Separate groups of animals receiving epibatidine either 15, 30 or 60 min prior to the formalin injection exhibited a progressively diminishing antihyperalgesic response that was no longer significant in either phase by 30 min. Finally, pretreatment with the selective neuronal nicotinic receptor antagonist mecamylamine completely abolished the antihyperalgesic effect of epibatidine in both phases. Taken together, these studies demonstrate that in both the acute and tonic phases of the formalin model of facial pain, epibatidine produces a neuronal nicotinic receptor-mediated antihyperalgesia that is both dose- and time-dependent. These results support the rationale for exploring the clinical efficacy of nicotinic agonists as analgesics to treat certain types of trigeminal pain in humans.