Chemotherapy-induced peripheral neuropathy (CIPN) affects ~68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and Group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca²⁺ activity of the large population of dorsal root ganglia (DRG) neurons in vivo. For the latter, we used a genetically-encoded Ca²⁺ indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions at the level of the intact DRG neuronal ensemble. We found that CIPN increased spontaneous Ca²⁺ activity in DRG neurons, increased number of Ca²⁺ transients, and increased hyper-responses to mechanical, thermal, and chemical stimuli. We found that mechanical and thermal pain caused by CIPN was significantly attenuated by the mGluR8 agonist, (S)–3,4-DCPG, the Group II mGluR agonist, LY379268, and the H1 histamine receptor antagonist, meclizine. DRG neuronal Ca²⁺ activity elevated by CIPN was attenuated by LY379268 and meclizine, but not by (S)–3,4-DCPG. Furthermore, meclizine and LY379268 attenuated cisplatin-induced weight loss. These results suggest that Group II mGluR agonist, mGluR8 agonist, and meclizine are promising candidates as new treatment options for CIPN, and studies of their mechanisms are warranted.

SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition that affects most chemotherapy patients and persists several months or longer after treatment ends. Research on CIPN mechanism is extensive but has produced only few clinically useful treatments. Using in vivo GCaMP Ca²⁺ imaging in live animals over 1800 neurons/dorsal root ganglia (DRG) at once, we have characterized the effects of the chemotherapeutic drug, cisplatin and three treatments that decrease CIPN pain. Cisplatin increases sensory neuronal Ca²⁺ activity and develops various sensitization. Metabotropic glutamate receptor (mGluR) agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca²⁺ activity and reduces pain hypersensitivity. Our results and experiments provide insights into cellular effects of cisplatin and drugs preventing CIPN pain.

化疗引起的周围神经病变 (CIPN) 影响约 68% 接受化疗的患者，导致衰弱性神经性疼痛并降低生活质量。顺铂是一种常用的铂类化疗药物，已知可引起 CIPN，可能是通过对初级感觉神经元造成氧化应激损伤。人们普遍认为代谢型谷氨酸受体 (mGluR) 参与疼痛处理和疼痛缓解。 Meclizine 是一种 H1 组胺受体拮抗剂，已知具有神经保护作用，包括抗氧化作用。在这里，我们使用顺铂诱导的 CIPN 小鼠模型，使用雄性和雌性小鼠来测试 mGluR8 和 II 组 mGluR 的激动剂以及氯苯甲嗪作为减轻顺铂诱导的疼痛的干预措施。我们进行了行为疼痛测试，并对体内大量背根神经节 (DRG) 神经元的 Ca ²⁺活性进行了成像。对于后者，我们使用了基因编码的 Ca ²⁺指示剂 Pirt-GCaMP3，它使我们能够在完整的 DRG 神经元群水平上监测不同的药物干预。我们发现 CIPN 增加了 DRG 神经元中自发的 Ca ²⁺活性，增加了 Ca ²⁺瞬变的数量，并增加了对机械、热和化学刺激的过度反应。我们发现，mGluR8 激动剂 (S)–3,4-DCPG、II 组 mGluR 激动剂 LY379268 和 H1 组胺受体拮抗剂氯苯甲嗪可显着减轻 CIPN 引起的机械性和热痛。 CIPN 升高的 DRG 神经元 Ca ²⁺活性被 LY379268 和氯苯甲嗪减弱，但 (S)–3,4-DCPG 没有减弱。此外，meclizine 和 LY379268 减弱了顺铂引起的体重减轻。 这些结果表明，II 组 mGluR 激动剂、mGluR8 激动剂和氯苯甲嗪是有希望作为 CIPN 新治疗选择的候选药物，并且有必要对其机制进行研究。

意义声明化疗引起的周围神经病变 (CIPN) 是一种痛苦的病症，影响大多数化疗患者，并在治疗结束后持续数月或更长时间。 CIPN 机制的研究非常广泛，但产生的临床有用的治疗方法却很少。通过对活体动物的超过 1800 个神经元/背根神经节 (DRG) 进行一次体内GCaMP Ca ²⁺成像，我们表征了化疗药物顺铂和三种减轻 CIPN 疼痛的治疗方法的效果。顺铂可增加感觉神经元 Ca ²⁺活性并产生各种敏化作用。代谢型谷氨酸受体 (mGluR) 激动剂 LY379268 或 H1 组胺受体拮抗剂美其嗪可降低顺铂对神经元 Ca ²⁺活性的影响并降低疼痛超敏反应。我们的结果和实验提供了关于顺铂和预防 CIPN 疼痛的药物的细胞效应的见解。