Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy

Paclitaxel and vincristine are chemotherapeutic drugs that often evoke along-lasting painful peripheral neuropathy. Using drugs that reduce intracellular or extracellular calcium ions (Ca2+), we investigated the hypothesis that impaired Ca2+ regulation contributes to die chemotherapy-evoked neuropathic pain syndrome. For comparison, we also tested rats with painful peripheral neuropathy caused by nerve trauma and to the antihuman immunodeficiency virus nucleoside analog 2',3'-dideoxycytidune (ddC). Normal naive (without neuropathy), paclitaxel-treated, and vincristine-treated rats received the following intrathecal injections: TMB-8 (46 nmol), Quin-2 (1.8 nmol), EGTA (0.7 mu mol), EGTA-AM (0.1 mu mol), and their vehicle controls. Chronic constriction injury (CCI) rats were examined after TMB-8 and Quin-2 injections, and ddC-treated rats were examined after receiving TMB-8. Mechano-allodynia and mechano-hyperalgesia were evaluated after each injection. Drug effects on heat hyperalgesia were also tested in CCI rats. All four Ca2+-reducing drugs significantly inhibited mechano-allodynia and mechano-hyperalgesia in the rats treated with paclitaxel, vincristine, or ddC, but no effects were seen in the CCI or naive rats. We conclude that a similar abnormality of cellular Ca2+ homeostasis contributes to the pain caused by paclitaxel, vincristine, and ddC, but not posttraumatic painful peripheral neuropathy.