López-Córdoba Gustavo, Martínez-Lorenzana Guadalupe, Lozano-Cuenca Jair, Condés-Lara Miguel, González-Hernández Abimael
Departamento de Neurobiología Del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.
Departamento de Biología Celular, Secretaría de Salud, Instituto Nacional de Perinatología, Mexico City, Mexico.
Front Pharmacol. 2022 Nov 23;13:1023611. doi: 10.3389/fphar.2022.1023611. eCollection 2022.
Spinal α-adrenoceptor induces analgesia by neuronal inhibition of primary afferent fibers. This family receptor coupled to G proteins can be subdivided into three functional subtypes: α, α and α-adrenoceptors, and current evidence on spinal analgesia supports the relevance of α and seems to exclude the role of α, but the functional contribution of α-adrenoceptors remains elusive. The present study was designed to pharmacologically dissect the contribution of spinal α-adrenoceptor subtypes modulating tonic or acute peripheral nociception. Using male Wistar rats, we analyzed the effect of spinal clonidine (a non-selective ααα-adrenoceptor agonist) and/or selective subtype α-adrenoceptor antagonists on: 1) tonic nociception induced by subcutaneous formalin (flinching behavior) or 2) acute nociception induced by peripheral electrical stimulus in 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-adrenoceptor antagonist) but not by imiloxan (α-adrenoceptor antagonist) or JP 1302 (α-adrenoceptor antagonist). Similarly, spinal BRL 44408 reversed the clonidine-induced inhibition of nociceptive WDR activity. Interestingly, spinal JP 1302 produced behavioral antinociception (an effect blocked by bicuculline, a preferent GABA channel blocker), but no correlation was found with the electrophysiological experiments. These data imply that, at the spinal level, 1) presynaptic α-adrenoceptor activation produces antinociception during acute or tonic nociceptive stimuli; and 2) under tonic nociceptive (inflammatory) input, spinal α-adrenoceptors are pronociceptive, probably by the inactivation of GABAergic transmission. This result supports a differential role of α and α-adrenoceptors modulating nociception.
脊髓α-肾上腺素能受体通过对初级传入纤维的神经元抑制作用诱导镇痛。这个与G蛋白偶联的受体家族可细分为三种功能亚型：α1、α2和α3-肾上腺素能受体，目前关于脊髓镇痛的证据支持α2的相关性，似乎排除了α1的作用，但α3-肾上腺素能受体的功能贡献仍不明确。本研究旨在从药理学角度剖析脊髓α-肾上腺素能受体亚型对紧张性或急性外周伤害感受的调节作用。我们使用雄性Wistar大鼠，分析了脊髓可乐定（一种非选择性α1α2α3-肾上腺素能受体激动剂）和/或选择性α3-肾上腺素能受体拮抗剂对以下方面的影响：1）皮下注射福尔马林诱导的紧张性伤害感受（退缩行为），或2）在脊髓背角二阶广动力范围（WDR）神经元的细胞外记录中，外周电刺激诱导的急性伤害感受。可乐定抑制了福尔马林诱导的伤害性防御行为，该效应被BRL 44408（α3-肾上腺素能受体拮抗剂）阻断，但未被咪洛昔安（α1-肾上腺素能受体拮抗剂）或JP 1302（α2-肾上腺素能受体拮抗剂）阻断。同样，脊髓注射BRL 44408可逆转可乐定诱导的对伤害性WDR活动的抑制。有趣的是，脊髓注射JP 1302产生行为性抗伤害感受（该效应被优先作用于GABA通道的阻断剂荷包牡丹碱阻断），但在电生理实验中未发现相关性。这些数据表明，在脊髓水平，1）突触前α3-肾上腺素能受体激活在急性或紧张性伤害性刺激期间产生抗伤害感受；2）在紧张性伤害性（炎症性）输入下，脊髓α1-肾上腺素能受体可能通过GABA能传递失活而具有促伤害感受作用。这一结果支持了α2和α3-肾上腺素能受体在调节伤害感受方面的不同作用。
