Department of Pharmacology, Faculty of Medicine, University of Granada, Granada 18016, Spain; Institute of Neuroscience, Biomedical Research Center, University of Granada, Armilla, Granada 18100, Spain; Biosanitary Research Institute ibs.GRANADA, Granada 18012, Spain.
Laboratori de Química Farmacèutica, Facultat de Farmàcia i Ciències de lÁlimentació Universitat de Barcelona, Barcelona 08028, Spain.
Biomed Pharmacother. 2024 Nov;180:117459. doi: 10.1016/j.biopha.2024.117459. Epub 2024 Sep 20.
Postoperative pain management is challenging. We used mice with a transverse laparotomy to study tactile allodynia measured by the von Frey test, pain at rest measured by facial pain expressions detected by an artificial intelligence algorithm, and movement-induced pain measured by reductions in exploratory activity. The standard analgesics morphine and ibuprofen induced distinct patterns of outcome-dependent effects. Whereas morphine was more effective in reversing pain at rest compared to tactile allodynia, it was unable to alter movement-induced pain. Ibuprofen showed comparable effects across the three outcomes. Administered together, the compounds induced synergistic effects in the three aspects of postoperative pain, mirroring the known advantages of multimodal analgesia used in clinical practice. We explored the impact of neuroimmune interactions using a neutrophil depletion strategy. This reversed pain at rest and movement-induced pain, but did not alter cutaneous sensitivity. Non-peptidergic (IB4+) and peptidergic (CGRP+) nociceptors are segregated neuronal populations in the mouse. We tested the effects of gefapixant, an antitussive drug targeting non-peptidergic nociceptors through P2X3 antagonism, and olcegepant, an antimigraine drug acting as a CGRP antagonist. Both compounds reversed tactile allodynia, while only gefapixant reversed pain at rest, and none of them reversed movement-induced pain. In conclusion, tactile allodynia, pain at rest, and movement-induced pain after surgery have different pharmacological profiles, and none of the three aspects of postoperative pain can predict the effects of a given intervention on the other two. Combining these measures provides a more realistic view of postoperative pain and has the potential to benefit analgesic development.
术后疼痛管理具有挑战性。我们使用进行了横切口腹部手术的小鼠，通过 von Frey 测试研究触觉过敏（触诱发痛），通过人工智能算法检测面部疼痛表情来研究静息痛，通过减少探索活动来研究运动诱发痛。标准镇痛药吗啡和布洛芬诱导出不同的结果相关效应模式。与吗啡相比，吗啡在逆转静息痛方面更有效，但不能改变运动诱发痛。布洛芬在这三种结果上表现出相当的效果。联合使用这两种化合物在术后疼痛的三个方面诱导出协同作用，反映了临床实践中多模式镇痛的已知优势。我们使用中性粒细胞耗竭策略来探索神经免疫相互作用的影响。这逆转了静息痛和运动诱发痛，但没有改变皮肤敏感性。非肽（IB4+）和肽（CGRP+）伤害感受器是小鼠中分离的神经元群体。我们测试了 gefapixant（一种通过 P2X3 拮抗作用靶向非肽伤害感受器的镇咳药）和 olcegepant（一种作为 CGRP 拮抗剂的偏头痛药物）的作用。这两种化合物都逆转了触觉过敏，而只有 gefapixant 逆转了静息痛，并且它们都没有逆转运动诱发痛。总之，术后的触觉过敏、静息痛和运动诱发痛具有不同的药理学特征，并且这三种术后疼痛的任何一个方面都不能预测特定干预措施对其他两个方面的效果。结合这些措施可以更真实地了解术后疼痛，并有可能有益于镇痛药物的开发。
