Background The paucity of objective and reliable measurements of pain-like behaviors has impeded the translatability of mouse models of postsurgical pain. The advanced dynamic weight-bearing (DWB) system enables evaluation of spontaneous pain-like behaviors in pain models. This study investigated the suitability and efficiency of the DWB system for assessing spontaneous pain-like behaviors and analgesic therapies in murine models of postsurgical pain. Methods Male adult C57BL/6JJcl mice were subjected to multiple surgical pain models with distinct levels of invasiveness, including a superficial incisional pain model involving only hind paw skin incision, deep incisional pain model that also involved incision and elevation of the underlying hind paw muscles, and orthopedic pain model involving tibial bone fracture and fixation with a pin (fracture and pinning [F/P] model). Spontaneous pain-like behaviors post-surgery were evaluated using weight distribution, pawprint area of the operated paw in the DWB system, and guarding pain score. Mechanical hypersensitivity was assessed using the von Frey test. The therapeutic effects of analgesics (diclofenac and buprenorphine for the deep incision model and diclofenac for the F/P model) were evaluated using the DWB system and von Frey test. Results The von Frey test demonstrated contradictory results between superficial and deep incisional pain models. The DWB system captured weight distribution changes in the operated hind paw, in accordance with the invasiveness and time course of wound healing in these surgical pain models. The reduction in weight-bearing on the operated paw correlated with guarding score, degree of paw swelling, and local expression of inflammatory mediators. DWB enabled accurate evaluation of the pharmacological effects of analgesics for detecting attenuation of surgery-induced weight-bearing changes in these models. Conclusion The DWB system serves as an objective and reliable method for quantifying pain-like behaviors and evaluating the therapeutic effects of analgesics in mouse models of postsurgical pain models.

Purpose The involvement of hypoxic response mechanisms in local functional impairments in surgical wounds is unclear. In the present study, we characterized tissue hypoxia in surgical wounds and investigated the role of pharmacological ischemic conditioning (PIC) using roxadustat, an oral prolyl hydroxylase domain enzyme inhibitor, in postoperative local functional impairments in a murine model of deep hind paw incision. Methods Male BALB/cAJcl mice aged 9–13 weeks were used in all experiments. Plantar skins of mice that underwent surgical incision were subjected to immunohistochemistry to localise tissue hypoxia. Pain-like behaviours and sudomotor function were compared between mice treated with 6-week perioperative PIC and control mice. The effects of PIC were examined in vitro by immunocytochemistry using sympathetically differentiated PC12 cells and in vivo by immunohistochemistry using plantar skins collected on postoperative day 21. Results Prominent tissue hypoxia was detected within axons in the nerve bundles underneath surgical wounds. Six-week perioperative PIC using roxadustat failed to ease spontaneous pain-like behaviors; however, it mitigated local sudomotor impairment postoperatively. Upregulation of sympathetic innervation to the eccrine glands was observed in the PIC-treated skins collected on postoperative day 21, in accordance with the in vitro study wherein roxadustat promoted neurite growth of sympathetically differentiated PC12 cells. Conclusion This study suggests that tissue hypoxia is involved in the pathogenesis of local sudomotor dysfunction associated with surgical trauma. Targeting the hypoxic response mechanisms with PIC may be of therapeutic potential in postsurgical local sympathetic impairments that can be present in complex regional pain syndrome.

BackgroundPatients undergoing total knee arthroplasty (TKA) surgery are at high risk of chronic postsurgical pain (CPSP). Accumulating evidence suggests an active role of neuroinflammation in chronic pain. However, its role in the progression to CPSP following TKA surgery remains unanswered. Here, we examined the associations between preoperative neuroinflammatory states and pre‐ and postsurgical chronic pain in TKA surgery.MethodsThe data of 42 patients undergoing elective TKA surgery for chronic knee arthralgia at our hospital were analyzed in this prospective study. Patients completed the following questionnaires: brief pain inventory (BPI), hospital anxiety and depression scale, painDETECT, and pain catastrophizing scale (PCS). Cerebrospinal fluid (CSF) samples were collected preoperatively and concentrations of IL‐6, IL‐8, TNF, fractalkine, and CSF‐1 were measured by electrochemiluminescence multiplex immunoassay. CPSP severity was ascertained, using the BPI, 6 months postsurgery.ResultsWhile no significant correlation was observed between the preoperative CSF mediator levels and preoperative pain profiles, the preoperative fractalkine level in the CSF showed a significant correlation with CPSP severity (Spearman's rho = −0.525; p = .002). Furthermore, multivariate linear regression analysis revealed that the preoperative PCS score (standardized β coefficient [β]: .11; 95% confidence interval [CI]: 0.06–0.16; p < .001) and CSF fractalkine level (β: −.62; 95% CI: −1.10 to −0.15; p = .012) were independent predictors of CPSP severity 6 months after TKA surgery.ConclusionsWe identified the CSF fractalkine level as a potential predictor for CPSP severity following TKA surgery. In addition, our study provided novel insights into the potential role of neuroinflammatory mediators in the pathogenesis of CPSP.