title: Analgesic treatment of ciguatoxin-induced cold allodynia.
abstract: 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.
authors.affiliation: Department of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, D-91054 Erlangen, Germany School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Deuis
authors.forename: Marco C
authors.initials: MC
authors.lastname: Inserra
authors.forename: Lindon S
authors.initials: LS
authors.lastname: Collins
authors.forename: Barbara
authors.initials: B
authors.lastname: Namer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cabot
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D002922:Ciguatoxins / Q000302:isolation & purification / Q000633:toxicity*; D003080:Cold Temperature / Q000009:adverse effects*; D004524:Eels; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D002922:Ciguatoxins
keywords: Allodynia; Ciguatoxin; Cold pain; Nociceptor; Peripheral; Sensory neuropathy