The differential in vivo contribution of spinal α(2A)- and α(2C)-adrenoceptors in tonic and acute evoked nociception in the rat.

Spinal α(2)-adrenoceptor induces analgesia by neuronal inhibition of primary afferent fibers. This family receptor coupled to G (i/o) proteins can be subdivided into three functional subtypes: α(2A), α(2B,) and α(2C)-adrenoceptors, and current evidence on spinal analgesia supports the relevance of α(2A) and seems to exclude the role of α(2B), but the functional contribution of α(2C)-adrenoceptors remains elusive. The present study was designed to pharmacologically dissect the contribution of spinal α(2)-adrenoceptor subtypes modulating tonic or acute peripheral nociception. Using male Wistar rats, we analyzed the effect of spinal clonidine (a non-selective α(2A/)α(2B/)α(2C)-adrenoceptor agonist) and/or selective subtype α(2)-adrenoceptor antagonists on: 1) tonic nociception induced by subcutaneous formalin (flinching behavior) or 2) acute nociception induced by peripheral electrical stimulus in in vivo extracellular recordings of spinal dorsal horn second-order wide dynamic range (WDR) neurons. Clonidine inhibited the nocifensive behavior induced by formalin, an effect blocked by BRL 44408 (α(2A)-adrenoceptor antagonist) but not by imiloxan (α(2B)-adrenoceptor antagonist) or JP 1302 (α(2C)-adrenoceptor antagonist). Similarly, spinal BRL 44408 reversed the clonidine-induced inhibition of nociceptive WDR activity. Interestingly, spinal JP 1302 per se produced behavioral antinociception (an effect blocked by bicuculline, a preferent GABA(A) channel blocker), but no correlation was found with the electrophysiological experiments. These data imply that, at the spinal level, 1) presynaptic α(2A)-adrenoceptor activation produces antinociception during acute or tonic nociceptive stimuli; and 2) under tonic nociceptive (inflammatory) input, spinal α(2C)-adrenoceptors are pronociceptive, probably by the inactivation of GABAergic transmission. This result supports a differential role of α(2A) and α(2C)-adrenoceptors modulating nociception.