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The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways

Abstract

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 α 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.

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Figure 1: Targeting constructs and sodium channel expression in sns null mutants.
Figure 2: Functional TTX-resistant sodium channel expression in sns null mutants.
Figure 3: Rescue of TTX-resistant channels in null mutants following nuclear injection of a vector encoding the α subunit of SNS.
Figure 4: TTX-sensitive channels are induced in sns null mutant C-fiber-associated sensory neurons.
Figure 5: Normal motor behavior and spinal reflexes in sns null mutants.
Figure 6: The sns null mutant mice show partial analgesia to noxious thermal and mechanical stimulation.
Figure 7: Full inflammatory hyperalgesia is delayed in the sns null mutant.
Figure 8: Systemic lidocaine enhances the analgesic phenotype of sns null mutants.

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Acknowledgements

This work was supported by the MRC (V.S., K.O., B.K., S.M., A.H.D., L.C.S.), the Wellcome Trust (A.A., S.E., J.N.W.) and the Royal Society (N.O.). L.C.S. was supported by a Merck Pharmacology Fellowship. The Centre for Genome Research was supported by the BBSRC. We are grateful to Samantha Ravenall, Madhu Sukumaran, Oro Rufian, Stuart Stevenson, Richard Pugh, Jane Haley, Patrique Delmas and David Brown for technical advice and comments.

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Correspondence to John N. Wood.

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Akopian, A., Souslova, V., England, S. et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 2, 541–548 (1999). https://doi.org/10.1038/9195

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