CGRP expression and signaling sensitization in a mouse model of chronic oxaliplatin-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and dose-limiting side effect of oxaliplatin treatment, yet its molecular mechanisms remain incompletely understood. Calcitonin gene-related peptide alpha (CGRPα, encoded by Calca) is a neuropeptide implicated in several chronic pain conditions and has been proposed to mediate CIPN-related hypersensitivity. Here, we investigated the role of CGRPα in a mouse model of chronic oxaliplatin-induced neuropathy. Mice treated with oxaliplatin over 8 weeks developed cold allodynia and reduced sensory nerve conduction velocity, recapitulating hallmark clinical symptoms of chronic CIPN. However, contrary to expectations, we observed no increase in Calca mRNA expression or protein levels in the dorsal root ganglia (DRG) of male mice and a significant decrease in female mice. The proportion of CGRP-expressing neurons remained unchanged. RNA-seq revealed a two-fold upregulation of Ramp1, a subunit of the CGRP receptor complex. These results suggest that CGRPα signaling may be enhanced not by increased peptide expression, but rather by increased calcium-dependent release from existing neurons and increased CGRP receptor sensitization. This is consistent with known effects of oxaliplatin-induced oxidative stress, which can activate TRPA1 channels and promote calcium-dependent vesicular release of neuropeptides. Although additional validation of this model is needed, our data support a revised rationale of CGRP involvement in CIPN based on sensitization and neuropeptide release, rather than upregulation, and point to TRPA1-CGRP interactions as a potential therapeutic target in oxaliplatin-induced neuropathic pain.