McCoy Eric S, Ryan Dan F, Park Sang Kyoon, Zylka Mark J
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Pain. 2025 Jul 15. doi: 10.1097/j.pain.0000000000003720.
Neurokinin-1 (substance P) receptor (NK1R) antagonists failed to effectively treat pain in humans despite having antinociceptive properties in animals. Here, we sought to evaluate the efficacy of NK1R antagonist CP-99994 at reducing facial grimacing in white-coated CD-1 mice after laparotomy surgery when compared to the analgesics carprofen and buprenorphine. To enable this investigation, we developed a machine learning algorithm to automatically score facial grimacing in white-coated mice using the PainFace software platform. This algorithm detects 5 facial action units of the mouse grimace scale (MGS; orbitals, nose, ears, whiskers, cheeks) and assigns a facial grimace score (0-10) for each video frame analyzed. Carprofen and buprenorphine significantly reduced mean MGS scores and percentage of high grimace (MGS scores ≥5) frames for up to 4 hours postsurgery across multiple doses. In contrast, CP-99994 showed limited efficacy, with only the highest 30 mg/kg dose reducing grimacing at 2 hours. Likewise, principal component analysis of grimace data over time indicated that carprofen and buprenorphine were effective at reducing facial grimacing, whereas CP-99994 was not. However, both buprenorphine and CP-99994 reduced mechanical allodynia at the incision site. These findings reveal a dissociation between the effects of CP-99994 on a spontaneous pain measure (grimacing) and an evoked nociceptive response, whereas a known analgesic reduced both measures. Our study suggests that using facial grimacing to assess spontaneous pain alongside traditional nociceptive assays may better predict analgesic potential and possibly reduce risk of translational failures when selecting drug candidates for clinical advancement.
尽管神经激肽-1（P物质）受体（NK1R）拮抗剂在动物中具有抗伤害感受特性，但在人类中未能有效治疗疼痛。在此，我们试图评估与镇痛药卡洛芬和丁丙诺啡相比，NK1R拮抗剂CP-99994在剖腹手术后减轻白色被毛CD-1小鼠面部 grimacing 的疗效。为了进行这项研究，我们开发了一种机器学习算法，使用PainFace软件平台自动对白色被毛小鼠的面部 grimacing 进行评分。该算法检测小鼠 grimace 量表（MGS；眼眶、鼻子、耳朵、胡须、脸颊）的5个面部动作单元，并为每个分析的视频帧分配一个面部 grimace 评分（0-10）。卡洛芬和丁丙诺啡在多个剂量下均能在术后长达4小时显著降低平均MGS评分和高 grimace（MGS评分≥5）帧的百分比。相比之下，CP-99994疗效有限，只有最高30mg/kg剂量在2小时时能减轻 grimacing。同样，随着时间对 grimace 数据进行主成分分析表明，卡洛芬和丁丙诺啡在减轻面部 grimacing 方面有效，而CP-99994则无效。然而，丁丙诺啡和CP-99994均能减轻切口部位的机械性异常性疼痛。这些发现揭示了CP-99994对自发疼痛指标（grimacing）和诱发的伤害性反应的影响之间的分离，而一种已知的镇痛药能同时降低这两种指标。我们的研究表明，在选择临床推进的候选药物时，使用面部 grimacing 与传统的伤害性检测一起评估自发疼痛，可能更好地预测镇痛潜力，并可能降低转化失败的风险。
