Mitochondrial Dysfunction is Part of a Novel Mechanism for Chemotherapy-Induced Neuropathic Pain

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, persistent complication of cancer treatment, yet the mechanisms sustaining pain remain unclear. Mitochondrial dysfunction has been implicated in chronic pain, but its role in spinal cord dysfunction after chemotherapy, and whether it can be reversed, is unknown. Here, we show that paclitaxel-induced persistent mechanical allodynia was associated with spinal cord (L1-L6) mitochondrial dysfunction 18 days after the last injection, including reduced oxygen consumption and membrane potential (Ψm) in the non-phosphorylated state, ATP-linked respiration, maximal respiration, and electron transfer capacity. Paclitaxel also increased susceptibility to mitochondrial permeability transition pore (mPTP)-induction, lowering calcium retention capacity at 3, 8, and 13 days after the last injection. Acute ex-vivo paclitaxel exposure had a similar effect, and cyclosporin A, an mPTP blocker, significantly reversed it. Consistent with a causal role for mitochondrial impairment, hyperbaric oxygen therapy (HBOT), initiated after allodynia developed, improved oxygen consumption and Ψm and progressively enhanced mechanical thresholds. Likewise, intrathecal delivery of healthy mitochondria to the spinal cord attenuated established allodynia in paclitaxel-treated rats and reduced mechanical and thermal hypersensitivity in other pain models, sciatic nerve crush and capsaicin. These findings identify persistent spinal mitochondrial dysfunction and increased mPTP susceptibility as features of CIPN and support mitochondrial protection as a therapeutic strategy for CIPN and other pain conditions.