Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1

Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (Na(V)), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on Na(V)1.1–1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective Na(V) toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all Na(V) subtypes, an increase in the inactivation time constant was observed only at Na(V)1.8, while the slope factor of the conductance-voltage curves was significantly increased for Na(V)1.7 and peak current was significantly increased for Na(V)1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of Na(V)1.8 and the tetrodotoxin-sensitive isoforms Na(V)1.7 and Na(V)1.6, respectively. The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of Na(V) isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.