Arias Hugo R, Tae Han-Shen, Micheli Laura, Yousuf Arsalan, Ghelardini Carla, Adams David J, Di Cesare Mannelli Lorenzo
Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK, USA.
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, 2522, Australia.
Neuropharmacology. 2020 Sep 15;175:108194. doi: 10.1016/j.neuropharm.2020.108194. Epub 2020 Jun 12.
The primary aim of this study was to determine the anti-neuropathic activity of (±)-18-methoxycoronaridine [(±)-18-MC] and (+)-catharanthine in mice by using the oxaliplatin-induced neuropathic pain paradigm and cold plate test. The results showed that both coronaridine congeners induce anti-neuropathic pain activity at a dose of 72 mg/kg (per os), whereas a lower dose (36 mg/kg) of (+)-catharanthine decreased the progress of oxaliplatin-induced neuropathic pain. To determine the underlying molecular mechanism, electrophysiological recordings were performed on α9α10, α3β4, and α4β2 nAChRs as well as voltage-gated calcium (Ca2.2) channels modulated by G protein-coupled γ-aminobutyric acid type B receptors (GABARs). The results showed that (±)-18-MC and (+)-catharanthine competitively inhibit α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly block Ca2.2 channels without activating GABARs. Considering the potency of the coronaridine congeners at Cav2.2 channels and α9α10 nAChRs, and the calculated brain concentration of (+)-catharanthine, it is plausible that the observed anti-neuropathic pain effects are mediated by peripheral and central mechanisms involving the inhibition of α9α10 nAChRs and/or Ca2.2 channels.
本研究的主要目的是通过使用奥沙利铂诱导的神经性疼痛模型和冷板试验，确定（±）-18-甲氧基冠狗牙花定碱[（±）-18-MC]和（+）-长春花碱在小鼠中的抗神经性活性。结果表明，两种冠狗牙花定碱同系物在剂量为72mg/kg（口服）时均诱导抗神经性疼痛活性，而较低剂量（36mg/kg）的（+）-长春花碱可减缓奥沙利铂诱导的神经性疼痛进展。为了确定潜在的分子机制，对α9α10、α3β4和α4β2烟碱型乙酰胆碱受体（nAChRs）以及由G蛋白偶联的B型γ-氨基丁酸受体（GABARs）调节的电压门控钙（Ca2.2）通道进行了电生理记录。结果表明，（±）-18-MC和（+）-长春花碱竞争性抑制α9α10 nAChRs，其效力高于对α3β4和α4β2 nAChRs的抑制，并且直接阻断Ca2.2通道而不激活GABARs。考虑到冠狗牙花定碱同系物对Cav2.2通道和α9α10 nAChRs的效力，以及计算出的（+）-长春花碱的脑内浓度，观察到的抗神经性疼痛作用可能是由涉及抑制α9α10 nAChRs和/或Ca2.2通道的外周和中枢机制介导的。
