Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, USA.
Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, Turkey.
Eur J Pain. 2018 Jan;22(1):84-93. doi: 10.1002/ejp.1092. Epub 2017 Aug 14.
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The α4β2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of α4β2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for α4β2 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at α4β2 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine-induced antinociception.
The present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotine-evoked antiallodynic response.
We found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour dose- and time-dependently without motor impairment. Our data revealed that this effect was mediated by the α4β2 nAChRs by using competitive α4β2 antagonist dihydro-β-erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to α4β2 nAChRs.
The present results suggest that allosteric modulation of α4β2 nAChR may provide new strategies in chronic neuropathic pain.
α4β2 nAChRs are involved in pain modulation. dFBr, a PAM at α4β2 nAChRs, potentiates the nicotine response dose-dependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of α4β2* nAChR may provide new strategies in chronic neuropathic pain.
神经元烟碱型乙酰胆碱受体（nAChRs）是配体门控离子通道。α4β2 亚型 nAChRs 在介导疼痛和几种烟碱诱发的反应中发挥重要作用。α4β2 nAChRs 的激动剂和部分激动剂在动物疼痛模型中显示出疗效。此外，具有高亲和力的非选择性 nAChR 激动剂尼古丁的镇痛特性是众所周知的。越来越多的证据表明，变构调节 nAChRs 是实验性疼痛的一种替代治疗策略。去甲(formyl)氟溴烷（dFBr）是α4β2 nAChRs 的正变构调节剂（PAM），可增强激动剂反应而不激活受体。我们假设 dFBr 可能通过增加内源性胆碱能张力或增强烟碱诱发的抗痛觉过敏反应来增强尼古丁引起的镇痛作用。
本研究探讨了 dFBr 是否可以通过增加内源性胆碱能张力或增强烟碱诱发的抗痛觉过敏反应来减轻小鼠慢性缩窄性损伤（CCI）引起的神经病理性疼痛。
我们发现，单独给予皮下 dFBr 并不能减轻疼痛行为。然而，dFBr 与尼古丁联合使用可显著逆转神经病理性疼痛行为，且具有剂量和时间依赖性，而无运动障碍。我们的数据表明，这种效应是通过竞争性α4β2 拮抗剂二氢-β-erythroidine 介导的α4β2 nAChRs 来介导的。此外，dFBr 未能增强吗啡的抗痛觉过敏作用，这表明 dFBr 的作用是独特的α4β2 nAChRs。
本研究结果表明，α4β2 nAChR 的变构调节可能为慢性神经病理性疼痛提供新的策略。
α4β2 nAChRs 参与疼痛调节。dFBr 是α4β2 nAChRs 的 PAM，可剂量依赖性增强神经病理性疼痛中的烟碱反应。因此，本研究结果表明，α4β2* nAChR 的变构调节可能为慢性神经病理性疼痛提供新的策略。
