Peripheral nerve injury alters the α 2 adrenoceptor subtype activated by clonidine for analgesia

Abstract

Background: Previous studies suggest that the α 2A adrenoceptor subtype is the target for spinally administered α2-adrenergic agonists, i.e., clonidine, for pain relief. However, ST 91, a preferential α2 NON-A adrenoceptor subtype agonist, induces antinociception, and intrathecally administered α 2c antisense oligodeoxynucleotide decreases antinociception induced by clonidine in the rat, suggesting non-A sites may be important as well. Therefore, the authors examined the subtype of α2 adrenoceptor activated by clonidine and ST 91 in normal rats and those with nerve injury-induced hypersensitivity. Methods: The same mechanical stimulus was applied to normal rats and those following spinal nerve ligation, and the effect of intrathecal clonidine and ST 91 on withdrawal threshold to the stimulus was determined. To further examine subtypes, animals were spinally pretreated. with vehicle, BRL 44408 (an α 2A subtype-preferring antagonist), and ARC 239 (an α2 NON-A subtype-preferring antagonist). Results: In normal animals, clonidine's effect was diminished by pretreatment with either antagonist, whereas ST 91's antinociceptive effect was solely blocked by pretreatment with ARC 239. In nerve-injured animals, the antihypersensitivity action of both clonidine and ST 91 was blocked by administration of ARC 239, whereas BRL 44408 was ineffective. Conclusions: These data agree with previous studies supporting that the α 2A adrenoceptor is important to the antinociceptive effect of clonidine in normal animals. Nerve injury alters this and results in a total reliance on α2 NON-A adrenoceptors.