Many damage-sensing neurons express tetrodotoxin (TTX)-resistant voltage-gated sodium channels. Here we examined the role of the sensory-neuron-specific (SNS) TTX-resistant sodium channel alpha subunit in nociception and pain by constructing sns-null mutant mice. These mice expressed only TTX-sensitive sodium currents on step depolarizations from normal resting potentials, showing that all slow TTX-resistant currents are encoded by the sns gene. Null mutants were viable, fertile and apparently normal, although lowered thresholds of electrical activation of C-fibers and increased current densities of TTX-sensitive channels demonstrated compensatory upregulation of TTX-sensitive currents in sensory neurons. Behavioral studies demonstrated a pronounced analgesia to noxious mechanical stimuli, small deficits in noxious thermoreception and delayed development of inflammatory hyperalgesia. These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects.

ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli.

The tetrodotoxin-resistant sodium channel alpha subunit Nav1.8 is expressed exclusively in primary sensory neurons and is proposed to play an important role in sensitization of nociceptors. Here we compared visceral pain and referred hyperalgesia in Nav1.8-null mice and their wild-type littermates in five tests that differ in the degree to which behavior depends on spontaneous, ongoing firing in sensitized nociceptors. Nav1.8-null mice showed normal nociceptive behavior provoked by acute noxious stimulation of abdominal viscera (intracolonic saline or intraperitoneal acetylcholine). However, Nav1.8-null mutants showed weak pain and no referred hyperalgesia to intracolonic capsaicin, a model in which behavior is sustained by ongoing activity in nociceptors sensitized by the initial application. Nav1.8-null mice also showed blunted pain and hyperalgesia to intracolonic mustard oil, which sensitizes nociceptors but also provokes tissue damage. To distinguish between a possible role for Nav1.8 in ongoing activity per se and ongoing activity after sensitization in the absence of additional stimuli, we tried a visceral model of tonic noxious chemical stimulation, cyclophosphamide cystitis. Cyclophosphamide produces cystitis by gradual accumulation of toxic metabolites in the bladder. In this model, Nav1.8-null mice showed normal responses. There were no differences between null mutants and their normal littermates in tissue damage and inflammation evoked by any of the stimuli tested, suggesting that the behavioral differences are not secondary to impairment of inflammatory responses. We conclude that there is an essential role for Nav1.8 in mediating spontaneous activity in sensitized nociceptors.

The tetrodotoxin‐resistant sodium channel α subunit, Nav1.8, is exclusively expressed in primary sensory neurons and is suggested to play a role in the generation of ectopic action potentials after axonal injury and thereby contribute to neuropathic pain. Here we investigated the involvement of Nav1.8 in ectopic impulse generation in damaged axons by examining spontaneous activity and mechanosensitivity in neuromas formed by section of the saphenous nerve in Nav1.8 null mice and in their wild‐type littermates. We recorded 522 identified units from 24 neuromas in vitro at two time points, 8–11 days (median 10 days) and 19–29 days (median 22 days) post‐operatively. At ≈10 days, neither genotype showed spontaneous activity, but a significantly higher proportion of fibres were mechanosensitive in wild‐type (54 %) compared to Nav1.8 null neuromas (18 %). At ≈22 days, 19 % of fibres recorded in wild‐type neuromas showed spontaneous activity, whereas only one fibre of the 238 (0.4 %) recorded in neuromas taken from null mice showed ongoing activity. In recordings at ≈22 days, a similar proportion of fibres were mechanosensitive in wild‐type and Nav1.8 null neuromas (51 and 46 %, respectively). We conclude that Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons, and may also contribute to the development of ectopic mechanosensitivity.

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