化疗引起的周围神经病变(CIPN)是化疗中最常见的副作用之一。CIPN患者经历自燃,麻木,刺痛,和他们的脚和手的神经性疼痛。目前,没有有效的药物治疗来预防或治疗CIPN。通过正构激动剂激活1型大麻素受体(CB1)在减轻与CIPN相关的疼痛和神经炎症方面显示出有希望的结果。然而,使用CB1正位激动剂与不良副作用有关。与CB1正构激动剂不同,CB1正变构调节剂(PAMs)不会产生任何精神活性作用,容忍度,或依赖。先前的研究表明,CB1PAM在炎症和神经性啮齿动物模型中表现出镇痛作用。本研究旨在调查新合成的GAT229,一种纯的CB1PAM的潜在益处,减轻神经性疼痛和减缓CIPN的进展。在顺铂诱导的(CIS)外周神经性疼痛小鼠模型中评估GAT229(3mg/kg/d,28d,i.p.)。GAT229减弱并减缓了CIS诱导的热痛觉过敏和机械性异常性疼痛的进展,通过热板测试和vonFrey灯丝测试进行评估。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神经元中的脑源性神经营养因子和神经生长因子mRNA表达水平正常化来减轻神经损伤。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CB1PAMs可能有助于缓解神经性疼痛和减缓CIPN的进展.
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 (CB1) by orthosteric agonists has shown promising results in alleviating the pain and neuroinflammation associated with CIPN. However, the use of CB1 orthosteric agonists is linked to undesirable side effects. Unlike the CB1 orthosteric agonists, CB1 positive allosteric modulators (PAMs) don\'t produce any psychoactive effects, tolerance, or dependence. Previous studies have shown that CB1 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 CB1 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 CB1 receptor antagonist/inverse agonist AM251 blocked
GAT229-mediated beneficial effects. According to our data, we suggest that CB1 PAMs might be beneficial in alleviating neuropathic pain and slowing the progression of CIPN.