Mechanical sensitization, increased axonal excitability, and spontaneous activity in C-nociceptors after ultraviolet B irradiation in pig skin

Abstract

Ultraviolet B (UVB) irradiation induces hyperalgesia in human and animal pain models. We investigated mechanical sensitization, increase in axonal excitability, and spontaneous activity in different C-nociceptor classes after UVB in pig skin. We focused on units with receptive fields covering both irradiated and nonirradiated skin allowing intraindividual comparisons. Thirty-five pigs were irradiated in a chessboard pattern, and extracellular single-fibre recordings were obtained 10 to 28 hours later (152 fibers). Units from the contralateral hind limb served as a control (n = 112). Irradiated and nonirradiated parts of the same innervation territory were compared in 36 neurons; low threshold C-touch fibers (n = 10) and sympathetic efferents (n = 2) were unchanged, but lower mechanical thresholds and higher discharge frequency at threshold were found in mechanosensitive nociceptors (n = 12). Half of them could be activated with nonnoxious brush stimuli in the sunburn. Four of 12 mechanoinsensitive nociceptors were found sensitized to mechanical stimulation in the irradiated part of the receptive field. Activity-dependent slowing of conduction was reduced in the irradiated and in the nonirradiated skin as compared with the control leg, whereas increased ability to follow high stimulation frequencies was restricted to the sunburn (108.5 ± 37 Hz UVB vs 6.3 ± 1 Hz control). Spontaneous activity was more frequent in the sunburn (72/152 vs 31/112). Mechanical sensitization of primary nociceptors and higher maximum after frequency are suggested to contribute to primary hyperalgesia, whereas the spontaneous activity of silent nociceptors might offer a mechanistic link contributing to ongoing pain and facilitated induction of spinal sensitization.

Modulation of activity-dependent excitability changes in subclasses of primary afferent nociceptors

“…Interestingly, in some neuropathy patients, pain is accompanied with an axon reflex erythema 385,217,572,132 , indicating that activity in mechano-insensitive "silent" nociceptor (CMi) nociceptors may play a relevant role under neuropathic pain conditions 455,385,448,478,458 . Furthermore, activity of these neurons is particularly susceptible to sensitization processes 371,374,399,462,558,216,407,449,454 , leading to ongoing activity and tonic nociceptive firing 358,559,477,268 . Accordingly, such recruitment of previously silent fibers has been found…”

“…Interestingly, UV-B irradiation also sensitizes human skin by the release of inflammatory mediators 556,109,140,22 , which also have been shown to not only upregulate TTX-r currents 29,80,266,182,178,181,180,536,135 , but also to suppress outward potassium currents 364,146 . Accordingly, in analogy to high doses of NGF, an increase of the SEP may be caused by UV-B mediated inflammation, which in turn may cause phenotype changes, as well as spontaneous activity of nociceptors 559,496 . However, ectopic firing and spontaneous nociceptive discharge after UV-B inflammation alone has never been reported in human volunteers 432 .…”