The differential in vivo contribution of spinal α2A- and α2C-adrenoceptors in tonic and acute evoked nociception in the rat

Abstract

Spinal α2-adrenoceptor induces analgesia by neuronal inhibition of primary afferent fibers. This family receptor coupled to Gi/o proteins can be subdivided into three functional subtypes: α2A, α2B, and α2C-adrenoceptors, and current evidence on spinal analgesia supports the relevance of α2A and seems to exclude the role of α2B, but the functional contribution of α2C-adrenoceptors remains elusive. The present study was designed to pharmacologically dissect the contribution of spinal α2-adrenoceptor subtypes modulating tonic or acute peripheral nociception. Using male Wistar rats, we analyzed the effect of spinal clonidine (a non-selective α2A/α2B/α2C-adrenoceptor agonist) and/or selective subtype α2-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 (α2A-adrenoceptor antagonist) but not by imiloxan (α2B-adrenoceptor antagonist) or JP 1302 (α2C-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 GABAA channel blocker), but no correlation was found with the electrophysiological experiments. These data imply that, at the spinal level, 1) presynaptic α2A-adrenoceptor activation produces antinociception during acute or tonic nociceptive stimuli; and 2) under tonic nociceptive (inflammatory) input, spinal α2C-adrenoceptors are pronociceptive, probably by the inactivation of GABAergic transmission. This result supports a differential role of α2A and α2C-adrenoceptors modulating nociception.

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations

“…As for spinal alpha-2B, it did not play a role in tonic inflammatory and acute nociception. 47 The net impact of non-selective alpha 2-adrenoceptor agonists is antinociception in acute and neuropathic pain conditions, suggesting the significance of alpha 2A-adrenoreceptors over alpha 2C-adrenoreceptors.…”

Understanding of Spinal Wide Dynamic Range Neurons and Their Modulation on Pathological Pain

“… 109 Spinal application of α2-adrenoceptor agonists can effectively decrease the noxious discharges of WDR neurons through both pre-synaptic and post-synaptic mechanisms. 30 Significantly, opto-activation of local LC noradrenergic neurons was found to mitigate, rather than abolish, the DNIC effects in an α1 adrenergic receptors-dependent manner. 110 Overall, the suppressive action of LC on WDR is achieved through direct projections to the dorsal horn as well as indirect engagement in DNIC.…”