Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury

Abstract 

Local cold injury often induces hypersensitivity to cold and cold allodynia. Sensitisation of TRPM8 or TRPA1 could be the underlying mechanisms. This was evaluated by psychophysics and axon-reflex-flare induction following topical menthol and cinnamaldehyde application in cold injury patients and healthy subjects. The patients had no signs of neuropathy except cold allodynia. We applied 20% cinnamaldehyde and 40% menthol solutions in the cold-allodynic area of the patients and in a corresponding area in healthy subjects and obtained sensory ratings during application. Thermotesting and Laser Doppler Imaging were performed before and after exposure to the compounds. Menthol did not induce axon-reflex-erythema in patients or in controls. After menthol cold pain threshold was decreased in healthy subjects; however, no further sensitisation was observed in the patients moreover in some patients an amelioration of their cold allodynia was observed. Cinnamaldehyde-induced pain sensation did not differ between patients and controls. Heat pain thresholds following cinnamaldehyde were lowered to a similar extent in patients and controls (43–39.8 and 44–39°C) and also the axon-reflex-flare responses were comparable. No evidence for sensitisation of responses to TRPM8 or TRPA1-stimulation was found in patients with cold injury-induced cold allodynia. The lack of TRPM8 induced axon-reflex indicates that also de-novo expression of TRPM8 on mechano-insensitive C-nociceptors does not underlie cold allodynia in these patients. We conclude from these data that the mechanisms for the induction of cold allodynia in the patients with cold injury are independent of TRPM8 or TRPA1 and differ therefore from neuropathic pain patients.

Keywords: Cold hypersensitivity, Cold allodynia, Cold injury, Menthol, Cinnamaldehyde, Temperature threshold, Axon-reflex-flare, Psychophysics, TRPM8, TRPA1