Patel, R; (2015) Electrophysiological characterisation of neuronal components of cold sensitivity. Doctoral thesis , UCL (University College London).

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Abstract

Aberrant cold sensitivity is apparent in several neuropathies of peripheral and central origin, and is poorly treated by currently available drugs. In an attempt to understand the mechanisms of cold evoked hyperalgesia and analgesia, these studies examined the dual pro- and anti-nociceptive roles of TRPM8, a cold temperature gated channel, and the role of calcium channels within cold sensitive pathways through a combination of in vivo electrophysiology, behavioural measures and gene ablation. Blocking TRPM8 with novel antagonists revealed lamina V/VI neuronal responses to innocuous and noxious cold stimulation were conserved in naïve rats. However, under neuropathic conditions inhibition of TRPM8 decreased neuronal responses to innocuous and noxious cold stimuli. This corresponded with an attenuation of behavioural hypersensitivity to innocuous cooling. Remarkably, systemically activating TRPM8 with a novel agonist resulted in identical neuronal and behavioural effects in neuropathic rats. Menthol is known to relieve various pain conditions as well as inducing hyperalgesia. Unlike in human subjects, menthol fails to induce central sensitisation in naïve rats, whereas in neuropathic rats topical menthol exerts some similar effects to the systemically dosed TRPM8 agonist. Gene ablation identifies a role of α2δ-1, an auxiliary calcium channel subunit, in cold and mechanical sensory pathways, likely dependent on impaired trafficking of calcium channels. Furthermore, α2δ-1 knockout mice exhibit a delay in the development of neuropathic like behaviours after injury. In neuropathic rats, systemic and spinal delivery of an activation state dependent Cav2 antagonist suppresses neuronal responses to mechanical stimuli but reveals no change in channel function within cold sensitive pathways. These findings expand the understanding of the neural basis of cold sensitivity and demonstrate TRPM8 is not essential to all forms of cold transduction in naïve rats, and that both inhibiting and activating TRPM8 have similar selective modality related inhibitory effects on cold transduction in neuropathic rats.

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