Disruption of the Nav1.8/Ankyrin-3 interaction in nociceptors reduces pathological pain-like behaviors in mice.

Treating chronic neuropathic pain is challenging due to its complex pathophysiology. Persistent changes in the somatosensory system prolong heightened states of stimulus-evoked and spontaneous pain. Nociceptor dorsal root ganglion (DRG) neurons are key contributors to neuropathic pain due to pathological plasticity following injury, leading to spontaneous ectopic and stimulus-evoked firing. Preclinical strategies to inhibit Nav1.8, a nociceptor-specific voltage-gated sodium channel, are successful in reducing neuropathic pain but have yet to produce similar results in clinical settings. Here, we evaluate the pharmacotherapeutic potential of the Nav1.8/Ank3 interaction in neuropathic pain, utilizing electrophysiology, biochemistry, and proteomic approaches. We report that Nav1.8/Ank3 interactions are necessary for maintaining pathological nociceptor hyperexcitability in neuroma pain and that inhibition of this interaction with a short lipidated peptide (SLiP) is sufficient to alleviate neuropathic pain-like behaviors in mice. This work highlights the value of reevaluating targets for pharmacological intervention to produce analgesia specific to pathological states.