Background & Aims

Inflammatory states are commonly associated with hyperalgesia (enhanced pain to noxious stimuli) and allodynia (pain induced by innocuous stimulation).1,2 Acute UV-B-induced inflammation is known to reduce mechanical and thermal thresholds.3 Single nerve fibre recordings from pig skin further revealed facilitated discharges to high frequency electrical rectangular stimulation in the UV-B burn.4 Slowly depolarising electrical sinusoidal stimuli have been shown to differentially activate C-nociceptor classes both, in pigs and humans.5,6 We intended to record the activity of peripheral C-fibre subclasses to sinusoidal electrical stimuli after UV-B induced inflammation in pig skin. We were particularly interested in identifying changed excitation patterns of nociceptors and C-LTMR’s (touch fibres) to slow depolarizing electrical stimulation.

Methods

Domestic pigs (Sus scrofa) were submitted and maintained under general anaesthesia using 18mg/Kg Pentobarbital sodium followed by a constant rate infusion (CRI) of 12±1mg/kg/h, respectively. Medial hind limb skin spots of 1cm² located within the innervation territory of Nervus saphenous were irradiated with UV-B of 3-fold minimum erythemal doses (MED, 0.33 J/cm²). After four hours, single nerve fibre recordings were performed from the saphenous nerve using the teased fibre technique.7 C-fibre sub-classes were functionally characterized by means of mechanical and thermal responsiveness as well as their activity dependent slowing (ADS).8,9 Excitability parameters to 1 and 4 Hz electrical sinusoidal stimulation were assessed within the UV-B exposed skin sites, in addition to CO2-Laser heat stimuli and mechanical threshold assessments (Semmes-Weinstein mono-filaments). Data were compared to the responses of C-fibre units previously recorded from non-irradiated control skin.

Results

6 C-LTMR, 5 C-HT, 4 C–VHT and 7 C–Mi (“silent” nociceptors) were recorded from UV-B irradiated skin. There was no significant change in mechanical thresholds for C-HT and C-VHT. The electrical threshold to rectangular stimulus increased for C-LTMR but not for the C-nociceptors tested after UV-B induced inflammation. Conduction velocity in C-LTMR was increased. Inside the UV-B inflamed area, 1 Hz sinusoidal pulses induced fewer APs in C-LTMR, while mechanical insensitive “silent” C-nociceptors, which are virtually unresponsive to 1 Hz sinusoids under control conditions, tended to have reduced activation thresholds and higher AP discharge.

Conclusions

A single 1 Hz sinusoidal pulse evokes a burst of action potentials6 that is particularly seen in C-LTMR fibres and C-HT nociceptors. Preliminary results indicate reduced firing of touch fibres for transcutaneously delivered sine wave 1 Hz pulses in UV-B irradiated skin. “Polymodal” nociceptors were not affected, whereas in “silent” nociceptors the number of action potentials showed an increase when compared to non-irradiated skin. Ongoing experiments are performed to confirm this result. Inflammation-induced depolarization might contribute to axonal de-sensitization of C-touch fibres while sensitizing “silent” nociceptors after UV-B. The results might suggest a role for sensitized “silent” nociceptors to hyperalgesia under inflammatory conditions potentially linked to reduced “pleasant touch”, both of which may be relevant for chronic inflammatory pain conditions in patients.

References

1. Banik RK, Kozaki Y, Sato J, et al. B2 receptor-mediated enhanced bradykinin sensitivity of rat cutaneous C-fiber nociceptors during persistent inflammation. J Neurophysiol 2001; 86: 2727–2735.
2. Harrison GI, Young AR, McMahon SB. Ultraviolet Radiation-Induced Inflammation as a Model for Cutaneous Hyperalgesia. J Invest Dermatol 2004; 122: 183–189.
3. Bishop T, Ballard A, Holmes H, et al. Ultraviolet-B induced inflammation of human skin: Characterisation and comparison with traditional models of hyperlagesia. Eur J Pain 2009; 13: 524–532.
4. Werland F, De Col R, Hirth M, et al. Mechanical sensitization, increased axonal excitability, and spontaneous activity in C-nociceptors after ultraviolet B irradiation in pig skin. Pain 2021; 162: 2002–2013.
5. Jonas R, Namer B, Stockinger L, et al. Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain. Ann Neurol 2018; 83: 945–957.
6. Rukwied R, Thomas C, Obreja O, et al. Slow depolarizing stimuli differentially activate mechanosensitive and silent C-nociceptors in human and pig skin. Pain; Publish Ah. Epub ahead of print 2020. DOI: 10.1097/j.pain.0000000000001912.
7. Campbell JN, Meyer RA, LaMotte RH. Sensitization of myelinated nociceptive afferents that innervate monkey hand. J Neurophysiol 1979; 42: 1669–1679.
8. Hirth M, Rukwied R, Gromann A, et al. Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density. Pain 2013; 154: 2500–2511.
9. Obreja O, Ringkamp M, Namer B, et al. Patterns of activity-dependent conduction velocity changes differentiate classes of unmyelinated mechano-insensitive afferents including cold nociceptors, in pig and in human. Pain 2010; 148: 59–69.

Presenting Author

Sabrina da Silva Soares

Poster Authors

Sabrina da Silva Soares

PhD student

Heidelberg University

Lead Author

E-mail

Topics

  • Assessment and Diagnosis