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Deletion of SCN9A encoding the voltage-gated sodium channel Na_V1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of Na_V1.7 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 Na_V1.7 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 Na_V1.7-null mutations show naloxone-reversible analgesia. Thus, inhibition of neurotransmitter release is the principal …