Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, 147002, Patiala, India.
Laboratory of Experimental Cardiology, Institute of Cardiology, Kyevskaya 111, 634012, Tomsk, Russia.
Fundam Clin Pharmacol. 2020 Jun;34(3):336-344. doi: 10.1111/fcp.12519. Epub 2019 Dec 2.
Preconditioning is a well-documented strategy that induces hepatic protection, renal protection, cardioprotection, and neuroprotection but its mechanism still remains to be elucidated. Hence, the present study investigated the protective mechanism underlying pain attenuating effects of vincristine-preconditioning in chemotherapeutic agent-induced neuropathic pain. Neuropathic pain was induced by administration of vincristine (50 µg/kg, i.p.) for 10 days in rats. Vincristine-preconditioning was induced by administration of vincristine (2, 5, and 10 µg/kg, i.p) for 5 days before administration of pain-inducing dose of vincristine (50 µg/kg, i.p.). Vincristine-preconditioning (10 µg/kg, i.p) for 5 days significantly reduced vincristine (50 µg/kg, i.p.) induced pain-related behaviors including paw cold allodynia, mechanical hyperalgesia, and heat hyperalgesia. However, vincristine (2 and 5 µg/kg, i.p) did not significantly ameliorate the vincristine (50 µg/kg, i.p.) induced neuropathic pain in rats. Furthermore, to explore the involvement of calcium channels in pain attenuating mechanism of vincristine-preconditioning, T-type calcium channel blocker, ethosuximide (100 and 200 mg/kg, i.p.) and L-type calcium channel blocker, amlodipine (5 and 10 mg/kg, i.p.) were used. Pretreatment with T-type calcium channel blocker, ethosuximide significantly abolished vincristine-preconditioning-induced protective effect. However, pretreatment with L-type calcium channel blocker, amlodipine did not alter vincristine-preconditioning-induced pain-related behaviors. This indicates that vincristine-preconditioning has protective effect on pain-related parameters due to opening of calcium channels, particularly T-type calcium channels that lead to entry of small magnitude of intracellular calcium through these channels and prevent the deleterious effects of high-dose vincristine.
预处理是一种经过充分证明的策略，可诱导肝保护、肾保护、心脏保护和神经保护，但它的机制仍有待阐明。因此，本研究探讨了长春新碱预处理减轻化疗药物诱导的神经病理性疼痛的镇痛作用的保护机制。通过给大鼠腹腔注射长春新碱（50μg/kg）10 天来诱导神经病理性疼痛。长春新碱预处理通过给大鼠腹腔注射长春新碱（2、5 和 10μg/kg）5 天来诱导，然后再给予疼痛诱导剂量的长春新碱（50μg/kg，腹腔注射）。5 天腹腔注射长春新碱预处理（10μg/kg）显著减轻长春新碱（50μg/kg，腹腔注射）引起的痛觉相关行为，包括爪冷觉过敏、机械性痛觉过敏和热痛觉过敏。然而，长春新碱（2 和 5μg/kg，腹腔注射）并没有显著改善大鼠长春新碱（50μg/kg，腹腔注射）诱导的神经病理性疼痛。此外，为了探讨钙通道在长春新碱预处理的镇痛机制中的作用，使用了 T 型钙通道阻滞剂乙琥胺（100 和 200mg/kg，腹腔注射）和 L 型钙通道阻滞剂氨氯地平（5 和 10mg/kg，腹腔注射）。T 型钙通道阻滞剂乙琥胺预处理显著消除了长春新碱预处理诱导的保护作用。然而，L 型钙通道阻滞剂氨氯地平预处理并没有改变长春新碱预处理诱导的痛觉相关行为。这表明长春新碱预处理对痛觉相关参数具有保护作用，这是由于钙通道的开放，特别是 T 型钙通道的开放，导致小幅度的细胞内钙通过这些通道进入，从而防止了高剂量长春新碱的有害作用。
