Cav3.2 channels modulate allodynia but TRP channels are the primary mediators in prenatal valproic acid-induced sensory dysfunction.

Prenatal exposure to valproic acid (pre-VPA) in rodents is a well-established model of autism spectrum disorder associated with altered sensory processing. We examined the contribution of peripheral ion channels to pre-VPA-induced mechanical and cold allodynia. Pregnant C57BL (WT) and Cav3.2-/- mice were exposed to VPA or saline, and offspring were assessed at 4 and 8 weeks. Sensory behavior was evaluated with von Frey (mechanical allodynia), Hargreaves (thermal hyperalgesia), and acetone (cold allodynia) tests. The effect of systemic delivery of inhibitors of various ion channels expressed in the afferent pain pathway (T-type calcium channels, TRPM3, TRPM8, TRPA1, TRPV1, high voltage activated calcium channels and sodium channels) was tested in male mice. This was complemented by current-clamp recordings in dorsal root ganglion (DRG) neurons. WT and Cav3.2-/- pre-VPA males developed mechanical allodynia at 4 and 8 weeks, while only Cav3.2-/- pre-VPA females showed this phenotype. Thermal sensitivity was unaltered. Cold allodynia occurred at 4 weeks in WT and Cav3.2-/- males and WT females. A967079, ononetin, AMTB, gabapentin, and VPA reduced mechanical allodynia in 8-week-old pre-VPA males, while Z944 and II-2 were ineffective. In the acetone assay at 4 weeks, A967079, ononetin, and AMTB were effective, whereas gabapentin, VPA, and II-2 showed no effect. Electrophysiology revealed normal rheobase but reduced firing frequency in DRG neurons from pre-VPA WT males, suggesting the possibility of central sensitization rather than peripheral hyperactivity. Our findings demonstrate that prenatal VPA induces mechanical and cold allodynia that is overcome by TRPA1, TRPM3, and TRPM8 blockers.