Lack of relationship between epidermal denervation by capsaicin and incisional pain behaviours: A laser scanning confocal microscopy study in rats

Abstract

Background Spontaneous pain after surgical incision is a significant problem for most post‐operative patients. Pain management that relies on opioids is hindered by numerous side effects, fuelling interest in non‐opioid alternatives and multimodal approaches. Subcutaneous capsaicin infiltration has shown potential for reducing post‐operative pain, but there are unanswered questions about safety and possible side effects. In adult rats, we characterized the analgesic effects of pre‐operative capsaicin infiltration into the skin prior to plantar incision and assessed wound healing and epidermal innervation. Methods The surgical site on the plantar surface of the rat hind paw was infiltrated with 1% capsaicin or vehicle 30 min or 1 week prior to surgical incision. Spontaneous and evoked pain behaviours were assessed. Digital images of incised hind paws were used to quantify the surface area of the wound after suture removal. Epidermal nerve fibre quantification was performed on peri‐incisional tissue biopsies. Results Intraplantar administration of capsaicin 30 min before surgical incision attenuated spontaneous pain behaviours, heat hyperalgesia, epidermal innervation, but it did not alter the rate of wound healing. Incisional pain hypersensitivity returned to baseline 2 weeks post‐incision, at a time when no recovery of epidermal innervation is observed. Conclusions Subcutaneous infiltration of capsaicin prior to surgical incision attenuated incision‐induced pain behaviours and reduced epidermal innervation around the incision site. The long‐lasting epidermal denervation by capsaicin had no impact in the rate of wound healing and recovery from pain behaviours. Significance Pre‐operative capsaicin infiltration attenuated spontaneous pain‐like behaviour and prevented the development of heat hyperalgesia following plantar skin incision. While capsaicin caused long‐lasting and widespread loss of epidermal and dermal nerve fibres, there was no measurable impact on the rate of wound healing. Pre‐ or intra‐operative infiltration of capsaicin into surgical sites could act as a safe prophylactic for post‐operative pain and reduce the need for opioids during recovery.

Capsaicin pretreatment alleviates postoperative pain and reduces primary sensory neuron Ca2+ activity

“…Previously, we showed that both 1% (200 µl) and 0.05% (200 µl) capsaicin intraplantar injection alleviated spontaneous and thermal pain but not mechanical pain, and did not impact wound healing in a rat postoperative pain model (Kang et al, 2010;Uhelski et al, 2020). In the present study, 50 µl of 0.05% capsaicin intraplantar injection alleviated spontaneous, mechanical, and thermal pain in a mouse postoperative pain model.…”

“…Our previous research indicated that intraplantar capsaicin pretreatment before incision alleviates spontaneous and thermal pain due to degeneration of CGRP and IB4/PGP9.5 positive nociceptive nerve fibers in the skin of rats (Kang et al, 2010). In addition, in our experiment with intraplantar capsaicin pretreatment, degeneration of TRPV1-positive primary sensory nerve fibers caused by the capsaicin alleviated spontaneous and thermal pain after plantar incision (Uhelski et al, 2020). Nerve growth factor (Thalakoti, #100) expression level in glabrous skin but not in L4-L6 dorsal root ganglia (DRG) was increased, and increased mRNA levels of insulin-like growth factor-2 (IGF-2) were found using total mRNA sequencing in a rat postoperative pain model (Banik et al, 2005;Tran et al, 2020).…”

In VivoCalcium Imaging Visualizes Incision-Induced Primary Afferent Sensitization and Its Amelioration by Capsaicin Pretreatment

“…Previous studies have shown that both 1% (200 ml) and 0.05% (200 ml) capsaicin intraplantar injection alleviated spontaneous and thermal pain but not mechanical pain, and did not impact wound healing in a rat incisional pain model (Kang et al, 2010;Tran et al, 2020;Uhelski et al, 2020). The present study used a mouse model plantar incision (Banik et al, 2006;Banik and Brennan, 2009).…”

“…Upon initial application, capsaicin evokes pain and hyperalgesia because of the opening of non-selective cation channels located on small diameter neurons expressing TRPV1 receptors. Capsaicin reduced visual analog scores (VAS) in humans and pain-related behaviors in animal models of incisional pain (Hamalainen et al, 2009;Hartrick et al, 2011;Uhelski et al, 2020).The intraplantar capsaicin pretreatment before incision alleviates spontaneous and thermal pain because of degeneration of CGRP and IB4/PGP9.5 positive nociceptive nerve fibers in the skin of rats (Kang et al, 2010). The genomewide transcriptional profiling of dorsal root ganglia (DRG) tissues in a rat model of incisional pain, identified changes in gene expression in the DRG at 1 d after plantar incision, a time point at which pain behaviors were most prominent.…”

Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain

“…[20][21][22][23][24][25] Additionally, our lab and others have reported that intra-plantar infiltration of capsaicin attenuates spontaneous pain behaviors and heat hyperalgesia. 26,27 This phenomenon provides a unique opportunity to identify neural transcriptomes that are specifically induced during incisional pain. For example, incision-induced gene regulatory changes that are sensitive to capsaicin pretreatment are likely involved in the development of pain after incision, whereas those which are insensitive to capsaicin pretreatment are likely involved in processes unrelated to pain.…”