Abstract
Postoperative pain (POP) of various durations is a common complication of surgical procedures. POP is caused by nerve damage and inflammatory responses that are difficult to treat. The neuroinflammation-glia-steroid network is known to be important in POP. It has been reported that the Gelsemium alkaloid koumine possesses analgesic, anti-inflammatory and neurosteroid modulating activities. This study was undertaken to test the analgesic effects of koumine against POP and explore the underlying pharmacologic mechanisms. Our results showed that microglia and astroglia were activated in the spinal dorsal horn post-incision, along with an increase of proinflammatory cytokines (interleukin 1β, interleukin 6, and tumor necrosis factor α). Both subcutaneous and intrathecal (i.t.) koumine treatment after incision significantly prevented mechanical allodynia and thermal hyperalgesia, inhibited microglial and astroglial activation, and suppressed expression of proinflammatory cytokines. Moreover, the analgesic effects of koumine were antagonized by i.t. administration of translocator protein (18 kDa) (TSPO) antagonist PK11195 and GABAA receptor antagonist bicuculline. Together, koumine prevented mechanical allodynia and thermal hyperalgesia caused by POP. The pharmacologic mechanism of koumine-mediated analgesia might involve inhibition of spinal neuroinflammation and activation of TSPO. These data suggested that koumine might be a potential pharmacotherapy for the management of POP.
Highlights
Postoperative pain (POP) of varying duration is extremely common after surgery
We found that plantar incision significantly decreased the withdrawal threshold to thermal stimulation and mechanical stimulation and the development of thermal hyperalgesia and mechanical allodynia peaked on postoperative day 1 and decreased gradually until approaching baseline on day 6–7 (Fig. 1 A and B)
thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) measured in the hind paw ipsilateral to surgery demonstrated that repeated koumine treatment at a dose range between 0.28 to 7.0 mg/kg attenuated the intensity of persistent POP in a dose-dependent manner
Summary
Postoperative pain (POP) of varying duration is extremely common after surgery. Long-lasting, life-changing painful sequelae caused by surgical injury have been long recognized as a major clinical problem[1]. Primary hyperalgesia from surgical incisions and other manipulations invariably causes some measure of nerve damage and inflammatory response that, in some cases, lead to the development of lasting forms of secondary hyperalgesia, such as neuropathic pain. This longer duration pain results from “central sensitization” in the spinal cord (SC) and brain (i.e. neuropathy) following peripheral injury. Experimental animal models (mostly in rodents), such as plantar incision, that mimic the transition from primary hyperalgesia to secondary hyperalgesia and neuropathy are important for studying the underlying causes of POP and evaluating novel therapies[4,5,6] In these models, a surgical incision through the skin and muscles of the foot (or back) lead to 3–5 days of acute post-incisional pain, which is manifest in different severities of secondary hyperalgesia. In order to elucidate the relationship between the analgesic effects of koumine on POP and the neuroinflammation-glia-steroid network in the SC, we performed an analysis of the effects of koumine treatment on glial activation and proinflammatory cytokines expression in the lumbar SC over a time course corresponding to the development and progression of POP-induced pain symptoms
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