Persistent proliferation of keratinocytes and prolonged expression of pronociceptive inflammatory mediators might be associated with the postoperative pain in KK mice

Abstract

Epidermal keratinocytes play a vital role in restoration of the intact skin barrier during wound healing. The negative effect of hyperglycemia may prolong the wound healing process. Epidermal keratinocytes have been demonstrated to modulate and directly initiate nociceptive responses in rat models of fractures and chemotherapy-induced neuropathic pain. However, it is unclear whether epidermal keratinocytes are involved in the development and maintenance of incisional pain in nondiabetic or diabetic animals. In the current study, using behavioral tests and immunohistochemistry, we investigated the differential keratinocytes proliferation and expression of pronociceptive inflammatory mediators in keratinocytes in C57BL/6J mice and diabetic KK mice. Our data showed that plantar incision induced postoperative pain hypersensitivity in both C57BL/6J mice and KK mice, while the duration of postoperative pain hypersensitivity in KK mice was longer than that in C57BL/6J mice. Moreover, plantar incision induced the keratinocytes proliferation and expression of IL-1β and TNF-α in keratinocytes in both C57BL/6J mice and KK mice. Interestingly, compared to C57BL/6J mice, the slower and more persistent proliferation of keratinocytes and expression of IL-1β and TNF-α in keratinocytes were observed in KK mice. Together, our study suggested that plantar incision may induce the differential keratinocytes proliferation and expression of IL-1β and TNF-α in kertinocytes in diabetic and nondiabetic animals, which might be associated with the development and maintenance differences in diabetic and nondiabetic postoperative pain.

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

“…In the vehicle-treated group, plantar incision-induced pain behaviors were similar to that observed in our previous study. 13 Strikingly, 1% capsaicin pretreatment prevented the expression of postoperative pain after plantar incision, indicating that capsaicin induced a preemptive analgesic effect. These findings are in line with previous results.…”

“…Our previous study showed that postoperative pain was associated with a significant increase in PCNA in the epidermis around the plantar incision site. 13 Capsaicin was reported to display anti-proliferative activity, such as inhibiting the proliferation of human small-cell lung cancer and breast cancer. 22 , 23 Capsaicin was shown to reduce the activation of epidermal cell proliferation around the incision site in the hairy skin of rats, 24 but it did not impact wound healing.…”

“…Our previous studies showed that keratinocytes around the plantar incision secrete several pro-inflammatory factors including TNFα and IL-1β. 13 Capsaicin showed anti-inflammatory effects in a variety of models. 25–27 Here, the secretion of pro-inflammatory factors by keratinocytes around the incision area was significantly reduced in capsaicin-treated rats, as compared with that in vehicle control, especially at 3 d after plantar incision.…”

“… 12 Our previous study demonstrated that keratinocytes are also involved in the maintenance of postoperative pain by proliferation and secreting pronociceptive inflammatory factors such as interleukin-1β (IL-1β) and tumour necrosis factor-alpha (TNF-α). 13 Capsaicin is a chili pepper extract and a member of the vanilloid family. Subcutaneous infiltration of capsaicin, which initially strongly activates transient receptor potential vanilloid 1 (TRPV1) receptors, can later induce an analgesic effect in different pain models.…”

Emerging roles of keratinocytes in nociceptive transduction and regulation

“…In addition to CRPS, a proliferation of KCs and an increased release of IL-1β, IL-6, and TNFα were observed in a murine incisional model for postsurgical pain (Clark et al, 2007;Guo et al, 2020). These changes were more persistent in diabetic mice, in associations with a prolonged postoperative pain hypersensitivity (Guo et al, 2020).…”