Cellular/Molecular The Voltage-Gated Sodium Channel Nav1.9 Is an Effector of

We used a mouse with deletion of exons 4, 5, and 6 of the SCN11A (sodium channel, voltage-gated, type XI, ) gene that encodes the voltage-gated sodium channel Nav1.9 to assess its contribution to pain. Nav1.9 is present in nociceptor sensory neurons that express TRPV1, bradykininB2, andpurinergic P2X3 receptors. InNav1.9 /mice, the non-inactivating persistent tetrodotoxin-resistant sodium TTXr-Per current is absent, whereas TTXr-Slow is unchanged. TTXs currents are unaffected by the mutation of Nav1.9. Pain hypersen-sitivity elicited by intraplantar administration of prostaglandin E2, bradykinin, interleukin-1, capsaicin, and P2X3 and P2Y receptor agonists, but not NGF, is either reduced or absent in Nav1.9 / mice, whereas basal thermal and mechanical pain sensitivity is un-changed. Thermal, but not mechanical, hypersensitivity produced by peripheral inflammation (intraplanatar complete Freund’s adju-vant) is substantially diminished in thenull allelemutantmice,whereas hypersensitivity in twoneuropathic painmodels is unchanged in the Nav1.9 /mice. Nav1.9 is, we conclude, an effector of the hypersensitivity produced by multiple inflammatory mediators on noci-ceptor peripheral terminals and therefore plays a key role in mediating peripheral sensitization. Key words: sensory neuron; peripheral sensitization; inflammation; nociceptor; pain; sodium channe