Abstract
UV-irradiation is a well-known translational pain model inducing local inflammation and primary hyperalgesia. The mediators and receptor proteins specifically contributing to mechanical or heat hyperalgesia are still unclear. Therefore, we irradiated buttock skin of humans (n = 16) with 5-fold MED of UV-C and assessed the time course of hyperalgesia and axon reflex erythema. In parallel, we took skin biopsies at 3, 6 and 24 h after UVC irradiation and assessed gene expression levels (RT-PCR ) of neurotrophins (e.g. NGF, BDNF, GDNF), ion channels (e.g. NaV1.7, TRPV1), inflammatory mediators (e.g. CCL-2, CCL-3) and enzymes (e.g. PGES, COX2). Hyperalgesia to mechanical impact (12 m/s) and heat (48°C) stimuli was significant at 6 h (p<0.05 and p<0.01) and 24 h (p<0.005 and p<0.01) after irradiation. Axon reflex erythema upon mechanical and thermal stimuli was significantly increased 3 h after irradiation and particularly strong at 6 h. A significant modulation of 9 genes was found post UV-C irradiation, including NGF (3, 6, 24 h), TrkA (6, 24 h), artemin, bradykinin-1 receptor, COX-2, CCL-2 and CCL-3 (3 and 6 h each). A significant down-regulation was observed for TRPV1 and iNOS (6, 24 h). Individual one-to-one correlation analysis of hyperalgesia and gene expression revealed that changes of Nav1.7 (SCN9A) mRNA levels at 6 and 24 h correlated to the intensity of mechanical hyperalgesia recorded at 24 h post UV-irradiation (Pearson r: 0.57, p<0.04 and r: 0.82, p<0.001). Expression of COX-2 and mPGES at 6 h correlated to the intensity of heat-induced erythema 24 h post UV (r: 0.57, p<0.05 for COX-2 and r: 0.83, p<0.001 for PGES). The individual correlation analyses of functional readouts (erythema and pain response) with local expression changes provided evidence for a potential role of Nav1.7 in mechanical hyperalgesia.
Highlights
The UV-irradiation has extensively been used as a translational model for inflammatory pain and hyperalgesia including studies in rodents [1,2,3,4], pigs [5] and human volunteers [6,7,8,9,10]
A lasting pigmentation as regularly reported after 3-fold minimum erythema dose (MED) UV-B irradiation was not observed upon UV-C exposure
A modulated gene expression pattern was found in the irradiated skin for e.g. bradykinin receptor 1, chemokine ligand CCL-2, Table 1
Summary
The UV-irradiation has extensively been used as a translational model for inflammatory pain and hyperalgesia including studies in rodents [1,2,3,4], pigs [5] and human volunteers [6,7,8,9,10]. Some of these can be accounted for the inflammatory UV-induced responses, such as erythema (i.e. CGRP) or heat hyperalgesia The latter can be explained by acute sensitization of nociceptors by various mediators (e.g. PGE2, bradykinin) and sensitization of heat-sensing ion channels (e.g. TRPV1). The mediators contributing to this phenomenon are largely unknown as acute application of e.g. PGE2, bradykinin or CGRP does not provoke mechanical hyperalgesia in human skin. There is recent evidence for a role of mechanical sensitization of heat insensitive (CM) fibers after UV-irradiation to strong mechanical stimuli [3]. This finding indicates that altered encoding properties of nociceptors could explain mechanical hyperalgesia. The contributing receptor proteins or axonal ion channels involved in mechanical hyperalgesia are still unclear
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