Shannonhouse John, Bernabucci Matteo, Gomez Ruben, Son Hyeonwi, Zhang Yan, Ai Chih-Hsuan, Ishida Hirotake, Kim Yu Shin
Department of Oral & Maxillofacial Surgery, School of Dentistry.
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854.
J Neurosci. 2022 Aug 3;42(31):6020-6037. doi: 10.1523/JNEUROSCI.1064-21.2022.
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 Ca activity of the large population of dorsal root ganglia (DRG) neurons For the latter, we used a genetically-encoded Ca 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 Ca activity in DRG neurons, increased number of Ca 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 Ca 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. 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 GCaMP Ca 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 Ca activity and develops various sensitization. Metabotropic glutamate receptor (mGluR) agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca 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，导致使人衰弱的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，已知会导致CIPN，可能是通过对初级感觉神经元造成氧化应激损伤。代谢型谷氨酸受体（mGluRs）被广泛推测参与疼痛处理和疼痛缓解。美克洛嗪是一种已知具有神经保护作用（包括抗氧化作用）的H1组胺受体拮抗剂。在此，我们使用雄性和雌性小鼠建立顺铂诱导的CIPN小鼠模型，以测试mGluR8和II组mGluR的激动剂以及美克洛嗪作为减轻顺铂诱导疼痛的干预措施。我们进行了行为疼痛测试，并对大量背根神经节（DRG）神经元的钙活性进行成像。对于后者，我们使用了一种基因编码的钙指示剂Pirt-GCaMP3，这使我们能够在完整的DRG神经元群体水平监测不同的药物干预。我们发现CIPN增加了DRG神经元的自发钙活性，增加了钙瞬变的数量，并增加了对机械、热和化学刺激的超敏反应。我们发现，mGluR8激动剂（S）-3,4-DCPG、II组mGluR激动剂LY379268和H1组胺受体拮抗剂美克洛嗪可显著减轻CIPN引起的机械性和热性疼痛。CIPN升高的DRG神经元钙活性被LY379268和美克洛嗪减弱，但未被（S）-3,4-DCPG减弱。此外，美克洛嗪和LY379268减轻了顺铂诱导的体重减轻。这些结果表明，II组mGluR激动剂、mGluR8激动剂和美克洛嗪有望成为CIPN的新治疗选择，有必要对其作用机制进行研究。化疗引起的周围神经病变（CIPN）是一种疼痛性疾病，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。对CIPN机制的研究广泛，但仅产生了少数临床上有用的治疗方法。通过在活体动物中对超过1800个神经元/背根神经节（DRG）同时进行GCaMP钙成像，我们已经表征了化疗药物顺铂以及三种减轻CIPN疼痛的治疗方法的作用。顺铂增加感觉神经元钙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组胺受体拮抗剂美克洛嗪可降低顺铂对神经元钙活性的影响并降低疼痛超敏反应。我们的结果和实验为顺铂和预防CIPN疼痛的药物的细胞作用提供了见解。
