Nav1.8 Variant I206M as a Latent Susceptibility Factor in Postaxotomy Ocular Pain

Background and Objectives: A small proportion of patients develop persistent ocular pain after corneal refractive surgery, which injures the distal axons of trigeminal ganglia neurons innervating the eye. In this study, we investigate the role of a low-frequency Nav1.8 variant, c.618A > G (p.I206M), in the pathogenesis of persistent ocular pain after corneal refractive surgery. Methods: . We characterized its functional effects using patch-clamp electrophysiology, computer simulations, and multielectrode array recordings of transfected rat trigeminal neurons. Results: p.I206M produced a hyperpolarizing shift in activation of ∼5 mV without significant effects on current density, inactivation, persistent currents, or recovery kinetics. Modeling predicted a small increase in excitability, attenuated under simulated heterozygous conditions. MEA recordings indicated a significant increase in firing frequency in trigeminal neuron firing at 33 and 37°C for p.I206M vs reference (wild-type) neurons. Discussion: Although subtle, the p.I206M activation shift may lower the excitability threshold of trigeminal neurons. In the context of axotomy-induced remodeling of the electrogenisome, such variants may act as latent susceptibility factors for chronic ocular pain. Together with prior findings of Nav1.7, TRPV1, and TRPM8 variants in this same cohort, these results support a multihit model, in which rare gain-of-function ion channel variants combine with nerve injury to drive persistent pain after injury, in this instance a second injury, to distal trigeminal axons. Given recent clinical validation of Nav1.8 as an analgesic target, this work further highlights the translational significance of Nav1.8 in human pain disorders.