T cell-dependent modulation of pain behaviors in a rat model of recurring paclitaxel-induced peripheral neuropathy.

Advances in preventing or treating chemotherapy-induced peripheral neuropathy (CIPN) have been limited because most preclinical models do not capture the repeated cycles of chemotherapy exposure common in clinical practice. Consequently, the mechanisms driving CIPN across successive chemotherapy cycles remain incompletely understood. Here, we investigated the contribution of T cells to recurrent paclitaxel (PTX)-induced peripheral neuropathy (PIPN) using homozygous RNU rats (T cell-deficient) and heterozygous littermates (T cell-competent). PTX (8 mg/kg total) was administered intraperitoneally over two treatment cycles to model repeated chemotherapy exposure and its effects on neuropathic pain. Pain sensitivity testing with von Frey filaments, dry-ice, and acetone assays revealed distinct pain phenotypes across cycles. Mechanical allodynia was transient, resolving between cycles, with a smaller reduction in mechanical withdrawal threshold during the observed period following the second cycle, independent of T cell status. In contrast, cold hyperalgesia persisted in T cell-competent rats but did not reach significance in T cell-deficient rats, whereas cold allodynia was transient, resolving between cycles, and developed exclusively in T cell-competent rats. T cell frequencies in peripheral neural tissues were higher after the second PTX cycle than after the first, while natural killer cell populations showed T cell- and tissue-specific differences across cycles. CD163