Paclitaxel (PTX), a commonly used chemotherapeutic, frequently leads to chemotherapy-induced peripheral neuropathy (CIPN), characterized by persistent pain and neuronal hypersensitivity. While its effects on peripheral nerves are well-documented, paclitaxel also influences central nervous system pathways, particularly spinal synaptic transmission, through Toll-like receptor 4 (TLR4) activation and subsequent sensitization of transient receptor potential vanilloid 1 (TRPV1) receptors. In this study, we used an in vitro model of paclitaxel-induced neuropathic pain to investigate the role of glial activation in TRPV1 receptor function. Using whole-cell patch-clamp recordings from superficial dorsal horn neurons in acute spinal cord slices, we evaluated the effects of minocycline (MX), a glial cell inhibitor, and ISO-1, a macrophage migration inhibitory factor (MIF) antagonist, on paclitaxel-induced synaptic changes. Our results demonstrate that acute paclitaxel application enhances nociceptive signaling and impairs capsaicin-induced TRPV1 receptor tachyphylaxis, leading to sustained hyperactivity. Minocycline preincubation effectively mitigated paclitaxel-induced sensitization, restoring normal nociceptive signaling, whereas acute minocycline treatment failed to prevent these changes. ISO-1 in vitro co-incubation with paclitaxel did not affect the paclitaxel-induced changes. These findings offer novel insight into the intricate interactions among neuroinflammatory mediators, glial cell activation, and TRPV1 receptor sensitization in paclitaxel-induced neuropathic pain. The differential effects of acute versus prolonged pre-incubation minocycline application suggest the importance of sustained glial inhibition for effective outcomes and neuropathic pain management.

Laboratory of Pain Research Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

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