The Preemptive Analgesic Effect of Capsaicin Involves Attenuations of Epidermal Keratinocytes Proliferation and Expression of Pro-Inflammatory Mediators After Plantar Incision in Rats

Purpose: Subcutaneous infiltration of capsaicin, which initially activates transient receptor potential vanilloid 1 (TRPV1) receptors, can subsequently desensitize TRPV1-expressing nociceptors and induce analgesia in different pain models. Yet, whether the modula-tion of keratinocytes may also contribute to the analgesic action of capsaicin treatment remains unclear. In a rat model of postoperative pain, we tested the hypothesis that subcutaneous injection of capsaicin inhibited the proliferation of epidermal keratinocytes and their expression of pronociceptive inflammatory mediators after plantar incision.Methods: The plantar incision model was carried out in the current study. Behavioral tests were used to evaluate postoperative pain -related behaviors in rats. Immunohistochemistry was used to investigate epidermal keratinocytes proliferation and expression of pro -inflammatory mediators in keratinocytes in rats.Results: Behaviorally, plantar incision induced robust postoperative pain hypersensitivity. However, subcutaneous pretreatment of capsaicin (1%) but not the vehicle, prevented the development of postoperative pain. There was an increased proliferation of keratinocytes and the expressions of interleukin-113 (IL-113) and tumour necrosis factor-alpha (TNF-alpha) in keratinocytes at 3 d and 7 d after plantar incision. However, these changes were also significantly attenuated by capsaicin pretreatment.Conclusion: Our findings suggest that capsaicin pretreatment may inhibit incision-induced keratinocytes proliferation and reduce their expression of pronociceptive inflammatory mediators under postoperative pain conditions, which represents a peripheral non -neuronal mechanism of capsaicin-induced analgesia.