Neuron
Volume 109, Issue 9, 5 May 2021, Pages 1497-1512.e6
Journal home page for Neuron

Article
A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7

https://doi.org/10.1016/j.neuron.2021.03.012Get rights and content
Under a Creative Commons license
open access

Highlights

  • Loss of sodium channel NaV1.7 abolishes pain without silencing peripheral nociceptors

  • Synaptic input to dorsal horn is compromised by an opioid-dependent mechanism

  • Impaired neurotransmission from olfactory sensory neurons is opioid independent

  • Blocking opioid receptors reverses analgesia in mice and humans lacking NaV1.7

Summary

Deletion of SCN9A encoding the voltage-gated sodium channel NaV1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of NaV1.7 in sensory neurons of mice also abolishes pain, suggesting that the locus of analgesia is the nociceptor. Here we demonstrate, using in vivo calcium imaging and extracellular recording, that NaV1.7 knockout mice have essentially normal nociceptor activity. However, synaptic transmission from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also reversed substantially by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid independent. Male and female humans with NaV1.7-null mutations show naloxone-reversible analgesia. Thus, inhibition of neurotransmitter release is the principal mechanism of anosmia and analgesia in mouse and human Nav1.7-null mutants.

Keywords

pain
analgesia
sodium channels
NaV1.7
human genetics
endogenous opioids
neurotransmitter release

Cited by (0)

7

Lead contact