Neuropathic Pain Develops Normally in Mice Lacking both Na_v1.7 and Na_v1.8

Abstract

Two voltage gated sodium channel α-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Nav1.7 and Nav1.8 is uncertain. Here we show that deleting Nav1.7 has no effect on the development of neuropathic pain. Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Nav1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Nav1.7 or Nav1.8 alone or in combination.

Nociceptors: the sensors of the pain pathway

“…These mice are unresponsive to acute noxious mechanical (pressure-induced, not punctate) and cold stimuli and defective in the development of inflammatory pain, but are normal with regard to acute responsiveness to heat stimuli and the ability to develop neuropathic pain (120). These data are remarkably consistent with gene-deletion studies (103). The sensitivity of C-MH fibers innervating hairy skin to cold, heat, and mechanical stimuli is reduced in mice constitutively lacking MrgprD-expressing cells reported to be TRPV1 and peptide negative (121).…”

“…Since enhanced excitability of primary sensory neurons in inflammatory and pathologic pain states is a major contributor to the perception of pain, specific pharmacological agents that specifically dampen aberrant activity are desirable in the design of pain therapeutics. To this end, an understanding of species-specific differences is critical, as exemplified by the dramatically different phenotypes in mice and humans lacking Na v 1.7: although mice lacking Na v 1.7 show a mechanosensory (pinch) and formalin-induced (5%) pain phenotype (103), humans lacking Na v 1.7 are insensitive to pain altogether (104).…”

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

“…Increasing their expression in slow neurons might promote hyperexcitability. However, in sensory neuron-specific knockouts of Na v 1.7, Na v 1.8 or double-knockout mice, neuropathic pain-like behavior still develops after nerve injury (18)(19)(20). It must be noted that compensatory effects in the expression of the different Na v isoforms in genetically modified animals during development cannot be excluded.…”

“…Not only are Na v 1.7 and Na v 1.8 important in inherited pain disorders, but also in acquired pain disorders, where their increased expression has already been linked to diverse chronic pain symptoms (14)(15)(16). Studies using knockout mice have implicated Na v 1.7 and Na v 1.8 in acute and inflammatory pain (17)(18)(19)(20), but their involvement in hyperexcitability and neuropathic pain remains to be determined.…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…[73][74][75][76] Surprisingly, neuropathic pain is still present in mice lacking Na v 1.7 or Na v 1.8 (established using a Na v 1.8-driven knock-out strategy) and neuropathic pain behavior is even maintained in mice in which nearly all Na v 1.8-positive nociceptors have been ablated. [77][78][79] Because Na v 1.8-expressing nociceptors also express and release BDNF in the spinal cord, perhaps it is the absence of BDNF that changes pain behavior in mice lacking Na v 1.8-positive sensory neurons, given the role of BDNF and TrkB in the establishment of some types of persistent pain behavior (although maybe not all types of neuropathic pain-at least not in mice). 62 Nevertheless, increased expression of sodium channels on nerve terminals and axons would be one mechanism contributing to hyperexcitability and, through increased depolarization, increased intracellular calcium due to activation of voltage-dependent calcium channels.…”