Sodium channel Nav1.7, encoded by the SCN9A gene, is a well validated target that plays a key role in controlling pain sensation. Loss-of-function mutations of Nav1.7 can cause a syndrome of profound congenital insensitivity to pain (CIP) in humans. Better understanding of how the loss of Nav1.7 leads to loss of pain sensibility would help to decipher the fundamental mechanisms of nociception and inform strategies for development of novel analgesics. Utilizing a recently described rat Nav1.7 loss-of-function model with deficient nociception but intact olfactory function, we investigated the involvement of endogenous opioid and cannabinoid systems in this rodent model of Nav1.7-related CIP. We found that both the opioid receptor antagonist naloxone and cannabinoid receptor blockers SR141716A (rimonabant) and SR144528 fail to restore acute pain sensitivity in Nav1.7 loss-of-function rats. We observed, however, that following rimonabant administration, Nav1.7 loss-of-function but not WT rats displayed abnormal behaviours, such as enhanced scratching, caudal self-biting and altered facial expressions; the underlying mechanism is still unclear. Dorsal root ganglion (DRG) neurons from Nav1.7 loss-of-function rats, although hypo-excitable compared to WT neurons, were still able to generate action potentials in response to noxious heat and capsaicin. Our data indicate that complete loss of DRG neuron excitability is not required for insensitivity to pain and suggest that endogenous opioid and cannabinoid systems are not required for insensitivity to pain in the absence of Nav1.7 channels in this rat Nav1.7 loss-of function model.
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