Pain
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Clonidine, an alpha-2 adrenergic agonist, is an extremely potent antinociceptive agent. However, the therapeutic utility of systemic clonidine for the treatment of pain is limited by centrally mediated side effects including sedation, hypotension and rebound hypertension. Given that alpha-2 adrenoceptors are expressed on the peripheral and central terminals of nociceptive fibers, we administered clonidine topically in order to avoid central effects. ⋯ Tolerance to the antinociceptive actions of clonidine was not blocked by topical administration of the NMDA antagonist, ketamine. In conclusion, topical administration of clonidine elicits antinociception by blocking the emerging pain signals at peripheral terminals via alpha-2 adrenoceptors without producing the undesirable central side effects observed following the systemic administration. The ineffectiveness of topical ketamine to block topical clonidine antinociceptive tolerance suggests that peripheral NMDA receptors do not mediate local clonidine antinociceptive tolerance.