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.