Department of Pharmacology and Physiology, College of Osteopathic Medicine, Oklahoma State University Center for Health Sciences, Tahlequah, Oklahoma 74464, United States.
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia.
ACS Chem Neurosci. 2020 Nov 4;11(21):3603-3614. doi: 10.1021/acschemneuro.0c00476. Epub 2020 Oct 19.
The main objective of this study was to determine whether ()-3-furan-2-yl---tolyl-acrylamide (PAM-2) and its structural derivative DM489 produce anti-neuropathic pain activity using the streptozotocin (STZ)- and oxaliplatin-induced neuropathic pain animal models. To assess possible mechanisms of action, the pharmacological activity of these compounds was determined at α7 and α9α10 nicotinic acetylcholine receptors (nAChRs) and Ca2.2 channels expressed alone or coexpressed with G protein-coupled GABA receptors. The animal results indicated that a single dose of 3 mg/kg PAM-2 or DM489 decreases STZ-induced neuropathic pain in mice, and chemotherapy-induced neuropathic pain is decreased by PAM-2 (3 mg/kg) and DM489 (10 mg/kg). The observed anti-neuropathic pain activity was inhibited by the α7-selective antagonist methyllycaconitine. The coadministration of oxaliplatin with an inactive dose (1 mg/kg) of PAM-2 decreased the development of neuropathic pain after 14, but not 7, days of cotreatment. The electrophysiological results indicated that PAM-2 potentiates human (h) and rat (r) α7 nAChRs with 2-7 times higher potency than that for hCa2.2 channel inhibition and an even greater difference compared to that for rα9α10 nAChR inhibition. These results support the notion that α7 nAChR potentiation is likely the predominant molecular mechanism underlying the observed anti-nociceptive pain activity of these compounds.
本研究的主要目的是确定（）-3-呋喃-2-基--对甲苯基丙烯酰胺（PAM-2）及其结构衍生物 DM489 是否通过链脲佐菌素（STZ）和奥沙利铂诱导的神经病理性疼痛动物模型产生抗神经病理性疼痛活性。为了评估可能的作用机制，测定了这些化合物在单独表达或与 G 蛋白偶联 GABA 受体共表达的 α7 和 α9α10 烟碱型乙酰胆碱受体（nAChR）和 Ca2.2 通道中的药理学活性。动物实验结果表明，单次给予 3mg/kg PAM-2 或 DM489 可减轻 STZ 诱导的小鼠神经病理性疼痛，而 PAM-2（3mg/kg）和 DM489（10mg/kg）可减轻化疗诱导的神经病理性疼痛。观察到的抗神经病理性疼痛活性被 α7 选择性拮抗剂甲基lycaconitine 抑制。奥沙利铂与无活性剂量（1mg/kg）的 PAM-2 共同给药可降低神经病理性疼痛的发生，而在 14 天而非 7 天的共同治疗后。电生理结果表明，PAM-2 增强了人（h）和大鼠（r）α7 nAChR 的活性，其效力比 hCa2.2 通道抑制高 2-7 倍，与 rα9α10 nAChR 抑制的差异更大。这些结果支持这样的观点，即α7 nAChR 增强可能是这些化合物观察到的抗伤害性疼痛活性的主要分子机制。
