The mechanism of analgesia in Nav1.7 null mutants
macdonald, d.; sikandar, s.; weiss, j.; pyrski, m.; luiz, a.; millet, q.; emery, e.; mancini, f.; Iannetti, G. D.; alles, s.; zhao, j.; cox, j.; brownstone, R.; Zufall, f.; wood, j.
Show abstract
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 the locus of analgesia is the nociceptor. Here we demonstrate that NaV1.7 knockout mice have essentially normal nociceptor activity using in vivo calcium imaging and extracellular recording. However, glutamate and substance P release from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also substantially reversed 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 opioid-dependent inhibition of neurotransmitter release is the principal mechanism of NaV1.7 null analgesia in mice and humans.
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