Topical clonidine antinociception

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. Here, we demonstrate that topical administration of clonidine to mice (via tail immersion) elicited antinociception in the radiant heat tail-flick test. The magnitude of antinociception was dependent upon the duration of exposure to the clonidine solution. Further, the antinociceptive activity of clonidine was limited to the portion of the tail exposed to drug solution suggesting that the actions of clonidine were locally mediated. Systemic pretreatment with the alpha-2 receptor antagonist, yohimbine, blocked the antinociceptive activity of topical clonidine. Concentrations of clonidine administered locally that were antinociceptive did not impair motor coordination as measured by the rota-rod test. However, doses of clonidine administered systemically that produced antinociception significantly impaired motor coordination. Repeated daily topical administration of clonidine resulted in antinociceptive tolerance. 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.