ABSTRACT

Clinical intervention of pain is often accompanied by changes in affective behaviors, so both assays of affective and sensorial aspects of nociception play an important role in the development of novel analgesics. Although positive allosteric modulation (PAM) of α7 nicotinic acetylcholine receptors (nAChRs) has been recognized as a novel approach for the relief of sensorial aspects of pain, their effects on affective components of pain remain unclear. Therefore, we investigated whether PAM-4, a highly selective α7-nAChR PAM, attenuates inflammatory and neuropathic pain, as well as the concomitant depressive/anxiety comorbidities. The anti-nociceptive activity of PAM-4 was assessed in mice using the formalin test and chronic constriction injury (CCI)-induced neuropathic pain model. The anxiolytic- and antidepressant-like activity of PAM-4 was evaluated using the marble burying test and forced swimming test. Acute systemic administration of PAM-4 dose-dependently reversed formalin-induced paw licking behavior and CCI-induced mechanical allodynia without development of any motor impairment. PAM-4 reversed the decreased swimming time and number of buried marbles in CCI-treated mice, suggesting that this ligand attenuates chronic pain-induced depression-like behavior and anxiogenic-like effects. The effects of PAM-4 were inhibited by the α7-selective antagonist methyllycaconitine, indicating molecular mechanism mediated by α7-nAChRs. Indeed, electrophysiological recordings showed the PAM-4 enhances human α7 nAChRs with higher potency and efficacy compared to rat α7 nAChRs. These findings suggest that PAM-4 reduces both sensorial and affective behaviors induced by chronic pain in mice by α7-nAChR potentiation. PAM-4 deserves further investigations for the management of chronic painful conditions with comorbidities.

摘要

疼痛的临床干预通常伴随着情感行为的变化，因此伤害感受的情感和感觉方面的测定在新型镇痛药的开发中发挥着重要作用。尽管 α7 烟碱型乙酰胆碱受体 (nAChRs) 的正变构调节 (PAM) 已被认为是缓解疼痛感觉方面的一种新方法，但它们对疼痛的情感成分的影响仍不清楚。因此，我们研究了 PAM-4（一种高度选择性的 α7-nAChR PAM）是否能减轻炎症和神经性疼痛以及伴随的抑郁/焦虑合并症。使用福尔马林试验和慢性收缩损伤 (CCI) 诱导的神经性疼痛模型在小鼠中评估 PAM-4 的抗伤害活性。使用大理石掩埋试验和强迫游泳试验评估 PAM-4 的抗焦虑和抗抑郁样活性。急性全身给药 PAM-4 剂量依赖性地逆转福尔马林诱导的舔爪行为和 CCI 诱导的机械异常性疼痛，而不会发生任何运动障碍。PAM-4 逆转了 CCI 治疗小鼠游泳时间和埋藏弹珠数量的减少，表明这种配体减弱了慢性疼痛引起的抑郁样行为和焦虑样作用。PAM-4的作用被α7选择性拮抗剂甲基利乌头碱抑制，表明α7-nAChRs介导的分子机制。事实上，电生理记录显示，与大鼠 α7 nAChRs 相比，PAM-4 增强人 α7 nAChRs 具有更高的效力和功效。这些发现表明，PAM-4 可通过 α7-nAChR 增强降低小鼠慢性疼痛引起的感觉和情感行为。PAM-4 值得进一步研究以管理慢性疼痛和合并症。