Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China.
Acta Pharmacol Sin. 2024 Jun;45(6):1160-1174. doi: 10.1038/s41401-024-01234-7. Epub 2024 Mar 4.
Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-β-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.
烟碱型乙酰胆碱受体（nAChRs）通过不同的受体亚型、神经元类型和位置调节疼痛通路，产生不同的结果。但是，在表达丰富的中脑网状部（SNr）的α4β2 nAChRs 是否有潜力减轻疼痛状态下的痛觉过敏仍然未知。我们观察到，将 nAChR 拮抗剂注射到 SNr 会降低未接受处理的小鼠的痛觉阈值，而将 nAChR 激动剂注射到 SNr 则会减轻因辣椒素注射到后腿、脊髓神经损伤、慢性缩窄性损伤或慢性尼古丁暴露而引起的痛觉过敏。对 pedunculopontine 核（PPN）到 SNr 的胆碱能传入进行光遗传学刺激可以模拟 nAChR 激动剂的镇痛作用，但当 SNr GABA 能神经元上的α4 nAChRs 下调和向 SNr 注射二氢-β-erythroidine 时，这种镇痛作用会减弱。慢性尼古丁引起的痛觉过敏依赖于 SNr GABA 能神经元上的α4 nAChRs，并且与 SNr 中 ACh 释放的减少有关。无论是激活 SNr 中的α4 nAChRs 还是光遗传学刺激 PPN-SNr 胆碱能投射都可以减轻慢性尼古丁引起的痛觉过敏。有趣的是，无论是在接受辣椒素注射到后腿还是接受 SNI 后，机械刺激诱导的 ACh 释放都明显减弱。这些结果表明，SNr 中的 GABA 能神经元上的α4 nAChRs 介导了一个胆碱能镇痛回路，这些受体可能是治疗急性和慢性疼痛以及慢性尼古丁暴露引起的痛觉过敏的有效治疗靶点。
