Thermo- and mechanosensitivity of intact and injured cutaneous afferent neurons and their responsiveness to the transient receptor potential agonist menthol

Introduction and goals: After a nerve lesion, injured afferent neurons can develop ectopic spontaneous activity, thermosensitivity and mechanosensitivity. This ectopic sensitivity may trigger in patients with nerve lesion burning spontaneous pain and mechanical and/or thermal (cold or heat) hyperalgesia and/or allodynia, cold allodynia being a frequent clinical finding. The mechanisms underlying this enhanced sensitivity to innocuous cold stimuli (allodynia) are poorly investigated. The ectopic activity of the injured afferent axons developing at the lesion site could be explained by the fact that the anterograde axonal transport (from the cell bodies to periphery) of sensory transduction molecules for thermal or mechanical stimuli is interrupted leading to accumulation of these molecules at the injury site. Recently it was reported that the transduction molecules for heat stimuli are also present in the membrane of the intact axons. The axonal cold- and mechano-sensitivity has up to date not been systematically investigated. This experimental work on adult rats has two goals: 1. to work out the axonal thermo- and mechano-sensitivity of intact cutaneous afferent neurons; 2. to test, in intact and injured cutaneous afferent nerve fibres, if non-nociceptive (type 1) cold-sensitive C-fibres are sensitive to the transient receptor potential M8 (TRPM8) agonist menthol, whereas the nociceptive (type 2) cold-sensitive C-fibres and the cold-insensitive C-fibres are menthol-insensitive. Additionally it was tested in the intact afferent fibres whether menthol can activate type 1 cold-sensitive neurons when applied to their axons. The thermo- and mechano-sensitivity were investigated on afferent nerve fibres of the sural nerve in anaesthetized Wistar rats with neurophysiological methods in vivo. Results: 1. In 32 experiments, 118 A-fibres and 109 C-fibres physiologically characterized by their responses to cold, heat and/or mechanical stimulation of the skin were tested for their axonal thermo- and mechano-sensitivity. Almost all non-nociceptive (type 1) cold-sensitive C-fibres could be activated by cold stimuli applied to their axons in the nerve. Axonal cold-sensitivity was present in 36% of the nociceptive cold-sensitive afferent fibres and axonal heat-sensitivity in 34% of the heat-sensitive afferent C-fibres. Responses to mechanical stimulation of A-fibres and C-fibres could be elicited from the skin only and not from the axons. 2. In 33 experiments, 77 functionally identified afferent C-fibres (30 intact fibres, 47 injured fibres) and 34 functionally characterized A-fibres (11 intact fibres, 23 injured fibres) were tested for their responses to menthol applied to their receptive fields either in the skin or in the nerve. Almost all (32/34) non-nociceptive (type 1) cold-sensitive C-fibres (20 injured fibres, 12 intact fibres) were activated by menthol and practically all (N=18) nociceptive (type 2) cold-sensitive C-fibres, with one exception, were menthol-insensitive. All heat- and/or mechanosensitive C-fibres tested (intact or injured; N=25) were not excited by menthol. With two exceptions (1 injured type 2 cold-sensitive and 1 injured heat-sensitive fibre), all mechano- or heat-sensitive intact or injured A-fibres were menthol-insensitive. Only one out of 20 type 1 cold-sensitive C-axons tested was activated by menthol. Conclusions: 1. Cold and heat sensitivity of cutaneous afferent neurons is not restricted to the afferent terminals in the skin but can principally extend over the axons in the nerve. Mechanosensitivity is restricted to the afferent endings in the skin. 2. The intact and injured cold-sensitive afferents innervating the rat hindlimb skin are low-threshold and can be activated by menthol, or high-threshold, which are menthol-insensitive. 3. Identification of the mechanism underling the cold allodynia in patients with nerve injury could lead to discovery of new therapeutic tools for treatment.


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