Ciguatera, the most common form of nonbacterial ichthyosarcotoxism, is caused by consumption of fish that have bioaccumulated the polyether
sodium channel activator
ciguatoxin. The neurological symptoms of
ciguatera include distressing, often persistent sensory disturbances such as paraesthesias and the pathognomonic symptom of cold
allodynia. We show that intracutaneous administration of
ciguatoxin in humans elicits a pronounced axon-reflex flare and replicates cold
allodynia. To identify compounds able to inhibit
ciguatoxin-induced Nav responses, we developed a novel in vitro
ciguatoxin assay using the human
neuroblastoma cell line SH-SY5Y. Pharmacological characterisation of this assay demonstrated a major contribution of Nav1.2 and Nav1.3, but not Nav1.7, to
ciguatoxin-induced Ca2+ responses. Clinically available Nav inhibitors, as well as the Kv7 agonist
flupirtine, inhibited
tetrodotoxin-sensitive
ciguatoxin-evoked responses. To establish their in vivo efficacy, we used a novel animal model of
ciguatoxin-induced cold
allodynia. However, differences in the efficacy of these compounds to reverse
ciguatoxin-induced cold
allodynia did not correlate with their potency to inhibit
ciguatoxin-induced responses in SH-SY5Y cells or at heterologously expressed Nav1.3, Nav1.6, Nav1.7, or Nav1.8, indicating cold
allodynia might be more complex than simple activation of Nav channels. These findings highlight the need for suitable animal models to guide the empiric choice of
analgesics, and suggest that
lamotrigine and
flupirtine could be potentially useful for the treatment of
ciguatera.