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.