The Kv4.3 channel on c-low threshold mechanoreceptors in DRG is a key mediator transforming tactile stimuli into nociceptive signals in chemotherapy-induced neuropathy

Oxaliplatin, a chemotherapeutic agent commonly used in colorectal cancer treatment, frequently induces chemotherapy-induced peripheral neuropathy (CIPN), with mechanical allodynia as a dose-limiting neurological complication. However, the precise pathophysiological mechanism underlying this sensory dysfunction remains inadequately elucidated. This study identifies Kv4.3 channel dysfunction in C-low threshold mechanoreceptors (C-LTMRs), a subset of tyrosine hydroxylase-positive (TH⁺) sensory neurons in the dorsal root ganglia (DRG), as the critical driver of oxaliplatin-induced mechanical allodynia. Using electrophysiological, pharmacological, and genetic approaches in mouse models, we have demonstrated that oxaliplatin selectively alters the firing pattern of C-LTMRs and enhances their excitability, particularly in response to low-intensity stimuli. This effect is mediated by Kv4.3 channel dysfunction within C-LTMRs, which underlies the pathological conversion of innocuous touch to pain. Critically, pharmacological inhibition or neuron-specific knockdown of Kv4.3 channels exacerbated mechanical allodynia, while Kv4.3 channel activation reversed neuronal hyperexcitability and alleviated oxaliplatin-induced mechanical allodynia. Thus, Kv4.3 dysfunction constitutes a core pathogenic mechanism of oxaliplatin-induced mechanical allodynia. Targeted enhancement of the Kv4.3 channel activity in C-LTMRs represents a promising precision analgesic strategy for this condition.