AUTHOR=López-Córdoba Gustavo , Martínez-Lorenzana Guadalupe , Lozano-Cuenca Jair , Condés-Lara Miguel , González-Hernández Abimael 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1023611

DOI=10.3389/fphar.2022.1023611

ISSN=1663-9812

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