Ultraviolet-B-induced mechanical hyperalgesia: A role for peripheral sensitisation

Abstract

Ultraviolet (UV) induced cutaneous inflammation is emerging as a model of pain with a novel sensory phenotype. A UVB dose of 1000mJ/cm2 produces a highly significant thermal and mechanical hypersensitivity. Here we examined the properties and mechanisms of such hyperalgesia in rats. Significantly, the mechanical hyperalgesia (with approximately 60% change in withdrawal thresholds) was restricted to the lesion site with no changes in mechanical threshold in adjacent non-irradiated skin (i.e. no secondary hypersensitivity), suggesting a peripheral mechanism. Consistent with this, we found that primary mechanical hypersensitivity showed no significant changes after intrathecal treatment with 10microg of the NMDA-receptor antagonist MK-801. Using an in vitro skin-nerve preparation, in the presence and absence of UVB-inflammation, suprathreshold responses to skin displacement stimuli of 6-768microm of 103 peripheral nociceptors were recorded. At the peak of UVB-induced hyperalgesia we observed that mechanical response properties of Adelta-nociceptors recorded from UVB-inflamed skin (n=19) were significantly diminished, by approximately 50%, compared to those recorded from naïve skin (n=13). The mechanical response properties of heat-sensitive C-nociceptors were unchanged while their heat responses were significantly increased, by approximately 75%, in UVB-inflamed (n=26) compared to naïve skin (n=12). Heat-insensitive C-nociceptors, however, demonstrated significantly enhanced (by approximately 60%) response properties to mechanical stimulation in UVB-inflamed (n=21) compared to naïve skin (n=12). Notably alteration in mechanical responses of Adelta- and heat-insensitive C-nociceptors were particular to stronger stimuli. Spontaneous activity was not induced by this dose of UVB. We conclude that UVB-induced mechanical hyperalgesia may be explained by a net shift in peripheral nociceptor response properties.

Corneal Sensory Nerve Activity in an Experimental Model of UV Keratitis

“…A difference in mechanical threshold between mechanoand polymodal nociceptors after UV radiation has been reported in the rat's skin, 37,38 although no significant change in spontaneous firing of nociceptors was observed following UV exposure. 39 In the present experiments, we also observed differences in mechanical threshold between mechano-and polymodal corneal nociceptors and sensitization to mechanical stimulation after UV radiation, proportional to the intensity of exposure. Sensitization was evidenced by the decrease in mechanical threshold and the increase in the percentage of spontaneous activity incidence among mechanonociceptors.…”

“…41 Furthermore, the higher incidence of ongoing firing and augmented responsiveness of polymodal nociceptors, combined with the reduced threshold of mechanonociceptors, also explains the presence of mechanical and chemical hyperalgesia observed 24 hours after UV exposure. 39,42 There is ample evidence of epithelial damage by UV radiation, with the generation of reactive oxygen species and oxidative stress 43,44 that are detrimental to corneal epithelial cells and may lead ultimately to apoptosis. Proinflammatory molecules, such as interleukins, cytokines, matrix metalloproteinases, nuclear factor-jB, or nitric oxide, are locally released in the cornea 12,45-50 accompanied by a significant elevation of interleukins and TNF-a concentrations in tears.…”

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

“…In general, it has been remarkably difficult to convincingly demonstrate nociceptor sensitization to mechanical stimuli in a variety of inflammatory models as conflicting results have been published (Andrew and Greenspan, 1999;Lewin and Moshourab, 2004;Milenkovic et al, 2008;Lennertz et al, 2012), Indeed, initial studies failed to detect prominent mechanical sensitization of nociceptors after acute or long term NGF exposure Obreja et al, 2011b). The UV-B sunburn model is an interesting system to study peripheral mechanisms of mechanical hyperalgesia, as there is convincing evidence that central mechanisms do not play a prominent role in this model (Bishop et al, 2009(Bishop et al, , 2010.…”

“…rates to supra-threshold mechanical stimulation (Bishop et al, 2010). However, although some fiber types like C-fiber mechanonociceptors lacking noxious heat sensitivity (C-Ms) showed increased suprathreshold responses to intense mechanical stimulation, other fiber types like A-δ mechanonociceptors displayed reduced responses (Bishop et al, 2010).…”

“…However, although some fiber types like C-fiber mechanonociceptors lacking noxious heat sensitivity (C-Ms) showed increased suprathreshold responses to intense mechanical stimulation, other fiber types like A-δ mechanonociceptors displayed reduced responses (Bishop et al, 2010). The complex changes in coding properties of different nociceptor sub-classes in the UV-B model raises the possibility that mechanical hyperalgesia may be signaled to the spinal circuits by altered patterns of afferent activation dispersed across two or more nociceptor classes.…”