Bagher Amina M, Binmahfouz Lenah S, Shaik Rasheed A, Eid Basma G
Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Saudi Pharm J. 2023 Feb;31(2):255-264. doi: 10.1016/j.jsps.2022.12.011. Epub 2022 Dec 29.
Chemotherapy-induced peripheral neuropathy (CIPN) is one of chemotherapies' most often documented side effects. Patients with CIPN experience spontaneous burning, numbness, tingling, and neuropathic pain in their feet and hands. Currently, there is no effective pharmacological treatment to prevent or treat CIPN. Activating the cannabinoid receptor type 1 (CB) by orthosteric agonists has shown promising results in alleviating the pain and neuroinflammation associated with CIPN. However, the use of CB orthosteric agonists is linked to undesirable side effects. Unlike the CB orthosteric agonists, CB positive allosteric modulators (PAMs) don't produce any psychoactive effects, tolerance, or dependence. Previous studies have shown that CB PAMs exhibit antinociceptive effects in inflammatory and neuropathic rodent models. This study aimed to investigate the potential benefits of the newly synthesized GAT229, a pure CB PAM, in alleviating neuropathic pain and slowing the progression of CIPN. GAT229 was evaluated in a cisplatin-induced (CIS) mouse model of peripheral neuropathic pain (3 mg/kg/d, 28 d, i.p.). GAT229 attenuated and slowed the progression of thermal hyperalgesia and mechanical allodynia induced by CIS, as evaluated by the hotplate test and von Frey filament test. GAT229 reduced the expression of proinflammatory cytokines in the dorsal root ganglia (DRG) neurons. Furthermore, GAT229 attenuated nerve injuries by normalizing the brain-derived neurotrophic factor and the nerve growth factor mRNA expression levels in the DRG neurons. The CB receptor antagonist/inverse agonist AM251 blocked GAT229-mediated beneficial effects. According to our data, we suggest that CB PAMs might be beneficial in alleviating neuropathic pain and slowing the progression of CIPN.
化疗引起的周围神经病变（CIPN）是化疗最常记录的副作用之一。CIPN患者会在手脚出现自发性灼痛、麻木、刺痛和神经性疼痛。目前，尚无有效的药物治疗方法来预防或治疗CIPN。通过正构激动剂激活1型大麻素受体（CB1）已显示出在减轻与CIPN相关的疼痛和神经炎症方面有前景的结果。然而，使用CB1正构激动剂会带来不良副作用。与CB1正构激动剂不同，CB1正向变构调节剂（PAMs）不会产生任何精神活性作用、耐受性或依赖性。先前的研究表明，CB1 PAMs在炎症性和神经性啮齿动物模型中表现出抗伤害感受作用。本研究旨在调查新合成的纯CB1 PAM——GAT229在减轻神经性疼痛和减缓CIPN进展方面的潜在益处。在顺铂诱导（CIS）的周围神经性疼痛小鼠模型（3 mg/kg/d，28天，腹腔注射）中对GAT229进行评估。通过热板试验和von Frey细丝试验评估，GAT229减轻并减缓了CIS诱导的热痛觉过敏和机械性异常性疼痛的进展。GAT229降低了背根神经节（DRG）神经元中促炎细胞因子的表达。此外，GAT229通过使DRG神经元中脑源性神经营养因子和神经生长因子mRNA表达水平正常化，减轻了神经损伤。CB1受体拮抗剂/反向激动剂AM251阻断了GAT229介导的有益作用。根据我们的数据，我们认为CB1 PAMs可能有助于减轻神经性疼痛和减缓CIPN的进展。
