Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7

Abstract

Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7-null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids.

Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain

“…Although loss-of-function mutations in Nav1.7 lead to complete inability to perceive pain (2,3), gain-of-function of Nav1.7 results in debilitating painful disorders (4 -7). Based on all available evidence, Nav1.7 is currently recognized as a prominent target for the development of new analgesic drugs, although recent evidence suggests additional involvement in regulating endogenous opioid systems (8,9). Nav1.7 belongs to the family of voltage-gated sodium channels that includes nine known members (Nav1.1-Nav1.9) with specific tissue localization and functional differences.…”

Differential aging‐related changes in neurophysiology and gene expression in IB4‐positive and IB4‐negative nociceptive neurons

“…It is particularly interesting that in IB4+ neurons from this age group there is a significant decrease in the mRNA expression of PENK, low levels of which have been implicated in pronociceptive states (Minett et al., 2015). Combined with the observed increase in excitability, it is likely that IB4+ neurons from middle‐aged mice are particularly vulnerable to proalgesic inputs.…”

Sodium Channels in Pain and Cancer

“…Interestingly, pain induced by the chemotherapeutic agent oxaliplatin and cancer-induced bone pain still occurs in Na v 1.7-null mice (Minett et al, 2014). In humans, an example of pain developing in a congenital indifference to pain Na v 1.7-null female has recently been described (Minett et al, 2015).…”