Abstract
We propose a new mechanism of sensory modulation through cutaneous dopaminergic signalling. We hypothesize that dopaminergic signalling contributes to differential cutaneous sensitivity in darker versus lighter pigmented humans and mouse strains. We show that thermal and mechanical cutaneous sensitivity is pigmentation dependent. Meta-analyses in humans and mice, along with our own mouse behavioural studies, reveal higher thermal sensitivity in pigmented skin relative to less-pigmented or albino skin. We show that dopamine from melanocytes activates the D1-like dopamine receptor on primary sensory neurons. Dopaminergic activation increases expression of the heat-sensitive TRPV1 ion channel and reduces expression of the mechanically-sensitive Piezo2 channel; thermal threshold is lower and mechanical threshold is higher in pigmented skin.
Highlights
Pigmentation in human skin can affect thermoregulation and photoprotection from ultraviolet (UV) radiation[1]
Animal studies demonstrate that functional knockouts of genes for the α-melanocyte-stimulating hormone (MSH) receptor (MC1R) and the tyrosinase-related protein 1 (TYRP1) produce lower basal heat sensitivity; these two genes are predominantly expressed in melanocytes[19,20,21]
Melanocytes convert tyrosine to L-dopa by tyrosinase; L-dopa is converted to dopamine by DOPA decarboxylase
Summary
Pigmentation in human skin can affect thermoregulation and photoprotection from ultraviolet (UV) radiation[1]. Animal studies demonstrate that functional knockouts of genes for the α-MSH receptor (MC1R) and the tyrosinase-related protein 1 (TYRP1) produce lower basal heat sensitivity; these two genes are predominantly expressed in melanocytes[19,20,21]. Skin melanocytes form tight contacts with cutaneous nerves[22] and secrete the catecholamine precursor L-dopa[23], which is synthesized during melanogenesis by tyrosinase[15, 16]. These studies suggest that skin melanocytes peripherally regulate sensation. Our meta-analysis in humans and mice reveals greater heat sensitivity in mice and in humans with darker skin. The heat sensitivity mechanism in humans and in mice involves pigmentation-dependent dopaminergic signalling from skin melanocytes which modulate gene expressions of the heat-sensitive TRPV1 channel and the mechano-sensitive Piezo[2] channel in primary sensory neurons via D1-like receptors
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