Amplified Cold Transduction in Native Nociceptors by M-Channel Inhibition

Abstract

Topically applied camphor elicits a sensation of cool, but nothing is known about how it affects cold temperature sensing. We found that camphor sensitizes a subpopulation of menthol-sensitive native cutaneous nociceptors in the mouse to cold, but desensitizes and partially blocks heterologously expressed TRPM8 (transient receptor potential cation channel subfamily M member 8). In contrast, camphor reduces potassium outward currents in cultured sensory neurons and, in cold nociceptors, the cold-sensitizing effects of camphor and menthol are additive. Using a membrane potential dye-basedscreeningassayandheterologouslyexpressedpotassiumchannels,wefoundthattheeffectsofcamphoraremediatedbyinhibitionofK v 7.2/3 channelssubtypesthatgeneratetheM-currentinneurons.Inlinewiththisfinding,thespecificM-currentblockerXE991reproducedthecold-sensitizing effect of camphor in nociceptors. However, the M-channel blocking effects of XE991 and camphor are not sufficient to initiate cold transduction but require a cold-activated inward current generated by TRPM8. The cold-sensitizing effects of XE991 and camphor are largest in high-threshold cold nociceptors. Low-threshold corneal cold thermoreceptors that express high levels of TRPM8 and lack potassium channels are not affected by camphor. We also found that menthol-like camphor-potently inhibits K v 7.2/3 channels. The apparent functional synergism arising from TRPM8 activation and M-current block can improve the effectiveness of topical coolants and cooling lotions, and may also enhance TRPM8-mediated analgesia.

KCNQ Potassium Channels Modulate Sensitivity of Skin Down-hair (D-hair) Mechanoreceptors

“…Indeed, KCNQ2 and -3 were previously reported to be expressed by both small and large diameter DRG neurons (10). M-current was found in bradykinin- (25,57) and capsaicin-(10) sensitive nociceptive neurons, in mas-related G-protein-coupled receptor member D (MrgD)-(58) and protease-activated receptor 2 (PAR-2)-(24) positive nociceptors, as well as in transient receptor potential cation channel subfamily M member 8 (TRPM8)-expressing cold nociceptors (29). Both KCNQ2 (26,28,29) and KCNQ5 (27) were postulated to be the predominant KCNQ subunit in these nociceptive neurons.…”

Переживание Боли При Различных Акцентуациях Свойств Темперамента

“…В настоящее время выяснены ноцицепторы и семейство сенсорных трансдукто-ров в них, принадлежащих к Transient Receptor Potential Family, в частности TRPA 1 [21,29,31], обеспечивающих возникновение холодовой боли.…”

A pharmacological and transcriptomic approach to exploring novel pain targets

“…In other studies, menthol has been found to inhibit nicotinic acetylcholine receptors 68 , inactivate voltage-gated calcium currents 69 , inhibit voltage-gated potassium channels 18 , and activate and/or desensitise TRPA1, another TRP channel 70 , demonstrating the varied targets of this compound and the difficulty of using menthol to assess TRPM8 activity.…”

“…However, as with A-fibres, additional subclasses of C-fibre neurons exist, categorised by sensitivity to a diverse array of stimuli. Some of these C-fibre subclasses are sensitive to a single stimulus type (exclusively responsive to innocuous or noxious heat, cold, or mechanical stimuli [13][14][15][16] ), while others are polymodal nociceptors responding to multiple stimuli 6,17,18 . Select C-fibres groups are also activated by noxious chemical stimuli and inflammatory mediators 19 such as capsaicin 20 and substance P 21 , serving as chemo-sensitive nociceptors.…”

“…The channel is essential for the detection of environmental cold, with a series of potassium channels contributing to threshold adjustment and amplification of TRPM8-dependent cold transduction 18,61,62 . TRPM8 knockout mice show drastically reduced responses to innocuous cold [63][64][65] .…”