Abstract
BackgroundPain is the vital sense preventing tissue damage by harmful noxious stimuli. The capsaicin receptor TRPV1 is activated by noxious temperatures, however, acute heat pain is only marginally affected in mice after TRPV1 knockout but completely eliminated in mice lacking TRPV1 positive fibers. Exploring contribution of candidate signal transduction mechanisms to heat pain in humans needs translational models.MethodsWe used focused, non-damaging, short near-infrared laser heat stimuli (wavelength 1470/1475 nm) to study the involvement of TRPV1-expressing nerve fibers in the encoding of heat pain intensity. Human psychophysics (both sexes) were compared to calcium transients in native rat DRG neurons and heterologously expressing HEK293 cells.ResultsHeating of dermal and epidermal nerve fibers in humans with laser stimuli of ≥ 2.5 mJ (≥ 25 ms, 100 mW) induced pain that increased linearly as a function of stimulus intensity in double logarithmic space across two orders of magnitude and was completely abolished by desensitization using topical capsaicin. In DRG neurons and TRPV1-expressing HEK cells, heat sensitivity was restricted to capsaicin sensitive cells. Strength duration curves (2–10 ms range) and thresholds (DRGs 0.56 mJ, HEK cells 0.52 mJ) were nearly identical. Tachyphylaxis upon repetitive stimulation occurred in HEK cells (54%), DRGs (59%), and humans (25%).ConclusionTRPV1-expressing nociceptors encode transient non-damaging heat pain in humans, thermal gating of TRPV1 is similar in HEK cells and DRG neurons, and TRPV1 tachyphylaxis is an important modulator of heat pain sensitivity. These findings suggest that TRPV1 expressed in dermal and epidermal populations of nociceptors serves as first line defense against heat injury.
Highlights
Sensation of pain is maybe the most important sense quoad vitam since it protects against injury and tissue damage by harmful stimuli
We investigated intensity coding of the same adequate stimulus at different system levels, facilitating translation of peripheral encoding of noxious heat pain from cellular
This study has shown that short diode laser heat stimuli (λ = 1470–1475 nm) induce a rapid temperature rise peaking at around 280 μm tissue depth in human skin, followed by exponential decay with time constants of about τ = 0.3 s
Summary
Sensation of pain is maybe the most important sense quoad vitam since it protects against injury and tissue damage by harmful stimuli. Infrared lasers have been used in a few studies on animal behaviour [1, 8, 39, 63], electrophysiology [14, 56, 58], dorsal root ganglion (DRG) neurons [19, 40] and heterologously expressed TRPV1 [27, 64]. Wavelengths of these lasers, range between 980 and 10,600 nm [19, 59], spot sizes between 0.1 and 10 mm [27, 41] and pulse durations between 3 and 400 ms [19, 53], making comparisons across studies difficult. Exploring contribution of candidate signal transduction mechanisms to heat pain in humans needs translational models
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