VARENICLINE-ACTIVATED PSAM⁴-GLYR AS A REVERSIBLE ANALGESIC APPROACH TO PACLITAXEL-INDUCED NEUROPATHY

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and dose-limiting complication of paclitaxel treatment, characterised by mechanical and cold hypersensitivity arising from dysfunction across peripheral sensory neuron subtypes. Here, we test whether reversible chemogenetic silencing of defined sensory neuron populations alleviates CIPN without impairing motor function. Using transgenic mice expressing the inhibitory PSAM⁴-GlyR channel in either nociceptor-enriched (Nav1.8-Cre) or pan-sensory (Advillin-Cre) dorsal root ganglion neurons, neuropathy was induced by repeated paclitaxel administration. Activation of PSAM⁴-GlyR was achieved via systemic varenicline, an FDA-approved ligand. Behavioural assays assessed mechanical (von Frey, Randall–Selitto), thermal (Hargreaves), and cold (dry ice) sensitivity, alongside motor coordination (rotarod) and locomotion (open field). Paclitaxel produced robust mechanical and cold hypersensitivity with minimal effects on motor performance. Chemogenetic activation of PSAM⁴-GlyR reversibly normalised sensory thresholds across modalities in both Nav1.8 and Advillin cohorts, with comparable efficacy and no impairment of motor coordination, speed, or distance travelled. Preliminary histological analysis revealed reduced intraepidermal nerve fibre density following paclitaxel, while in vivo GCaMP imaging confirmed stimulus-evoked sensory neuron activity suitable for mechanistic interrogation. Ongoing work quantifies DRG calcium responses to hot, cold, and mechanical stimulation in CIPN mice before and after varenicline administration. Higher-order behavioural assays including social interaction, burrowing behaviour, and novelty-suppressed feeding assess the impact of chemogenetic sensory silencing on affective and motivational dimensions of pain. These findings demonstrate that reversible silencing of peripheral sensory neurons alleviates CIPN while preserving motor function and support chemogenetic neuromodulation as a precise, non-sedative strategy for treating cancer therapy–associated sensory neuropathic pain.