Abstract
Cold hypersensitivity is evident in a range of neuropathies and can evoke sensations of paradoxical burning cold pain. Ciguatoxin poisoning is known to induce a pain syndrome caused by consumption of contaminated tropical fish that can persist for months and include pruritus and cold allodynia; at present no suitable treatment is available. This study examined, for the first time, the neural substrates and molecular components of Pacific ciguatoxin‐2‐induced cold hypersensitivity. Electrophysiological recordings of dorsal horn lamina V/VI wide dynamic range neurones were made in non‐sentient rats. Subcutaneous injection of 10 nm ciguatoxin‐2 into the receptive field increased neuronal responses to innocuous and noxious cooling. In addition, neuronal responses to low‐threshold but not noxious punctate mechanical stimuli were also elevated. The resultant cold hypersensitivity was not reversed by 6‐({2‐[2‐fluoro‐6‐(trifluoromethyl)phenoxy]‐2‐methylpropyl}carbamoyl)pyridine‐3‐carboxylic acid, an antagonist of transient receptor potential melastatin 8 (TRPM8). Both mechanical and cold hypersensitivity were completely prevented by co‐injection with the Nav1.8 antagonist A803467, whereas the transient receptor potential ankyrin 1 (TRPA1) antagonist A967079 only prevented hypersensitivity to innocuous cooling and partially prevented hypersensitivity to noxious cooling. In naive rats, neither innocuous nor noxious cold‐evoked neuronal responses were inhibited by antagonists of Nav1.8, TRPA1 or TRPM8 alone. Ciguatoxins may confer cold sensitivity to a subpopulation of cold‐insensitive Nav1.8/TRPA1‐positive primary afferents, which could underlie the cold allodynia reported in ciguatera. These data expand the understanding of central spinal cold sensitivity under normal conditions and the role of these ion channels in this translational rat model of ciguatoxin‐induced hypersensitivity.
Highlights
Cold hypersensitivity can occur after nerve injury and is especially prevalent in patients with chemotherapy-induced neuropathy
Following stable baseline neuronal responses, 10 nM Pacific ciguatoxin (P-CTX)-2 was injected into the receptive field
This study demonstrates, for the first time, that ciguatoxins can induce mechanical hypersensitivity in addition to cold hypersensitivity and that the peripheral site of action of the toxin alters the coding properties of spinal sensory neurones
Summary
Cold hypersensitivity can occur after nerve injury and is especially prevalent in patients with chemotherapy-induced neuropathy. Ciguatera is a common ichthyosarcotoxism characterized initially by gastrointestinal disturbances (vomiting, nausea and diarrhoea) followed by neurological disturbances (paraesthesiae and dysaesthesiae in the extremities, pruritus and cold allodynia). The gastrointestinal effects are typically transient (1–5 days), whereas neurological symptoms can persist for weeks to many months (Lewis, 2006). In vitro electrophysiological studies of the effect of ciguatoxins on tetrodotoxin-sensitive and tetrodotoxinresistant voltage-gated sodium channels reveal a hyperpolarizing voltage shift in activation/inactivation, and an increased rate of recovery from inactivated states, respectively (Strachan et al, 1999; Yamaoka et al, 2009), likely leading to channel activation at resting membrane potentials, ongoing activity in primary sensory afferent fibres, axonal swelling and elevation of intracellular calcium (Molgo et al, 1993; Vetter et al, 2012; Mattei et al, 2014). Ciguatoxins inhibit delayed rectifier and A-type potassium currents in dorsal root ganglia neurones, resulting in further increases in neuronal excitability (Birinyi-Strachan et al, 2005)
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