Departments of Orthopaedic Surgery (C.Y., M.S.H., S.J., M.A.O., A.J.D., K.Y.C., J.Y., J.P., R.J.L., W.K.H., and E.L.H.) and Cell and Molecular Biology (S.R.S.), Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Simpson Querrey Institute, Northwestern University, Chicago, Illinois.
J Bone Joint Surg Am. 2021 Jun 2;103(11):984-991. doi: 10.2106/JBJS.20.00573.
After spinal surgery and other orthopaedic procedures, most patients receive opioids for pain, leading to potential complications such as pseudarthrosis and opioid abuse associated with long-term use. As an alternative, the endocannabinoid system has been shown to have antinociceptive activity, while contributing to bone homeostasis via the CB1 and CB2 cannabinoid receptors. This study evaluates the impact of the cannabinoid receptor agonist WIN55,212-2 (WIN55) on osteogenic differentiation in vitro as well as bone regeneration and spinal fusion in a preclinical rat model.
Primary rat bone marrow stromal cells were cultured in standard or osteogenic media and exposed to vehicle alone or WIN55. Runx2 and Alkaline phosphatase (Alpl) were quantified via qPCR (quantitative real-time polymerase chain reaction), followed by assessment of ALP activity and matrix mineralization. For in vivo evaluation, 45 female Sprague Dawley rats (n = 15 per group) underwent L4-L5 posterolateral spinal fusion with bilateral placement of collagen scaffolds preloaded with low-dose rhBMP-2 (recombinant human bone morphogenetic protein-2; 0.5 μg/implant). Postoperatively, rats received the vehicle alone or 0.5 or 2.5 mg/kg WIN55 via daily intraperitoneal injections for 5 days. Bone regeneration and spinal fusion were assessed using radiography, manual palpation-based fusion scoring, microcomputed tomography imaging, and histology.
mRNA expression levels of Runx2 and Alp were similar among cells treated with vehicle alone and WIN55. Likewise, exposure to WIN55 did not inhibit ALP activity or bone matrix mineralization. In this animal model, no significant differences were found among groups with regard to mean fusion score, fusion rate, or new bone volume.
WIN55 showed no adverse impact on osteogenic differentiation, bone regeneration, and spinal fusion. This supports that cannabinoid receptor agonists should be further investigated as a potential alternative approach for postoperative analgesia following spinal fusion and other orthopaedic procedures requiring bone-healing.
The identification of alternative treatments for postoperative pain following orthopaedic surgical procedures is crucial in combating the ongoing opioid abuse crisis. The endocannabinoid system may represent a viable alternative target for addressing orthopaedic postoperative pain.
脊柱手术后和其他矫形手术后，大多数患者会接受阿片类药物来缓解疼痛，这可能导致假关节和长期使用阿片类药物相关的滥用等潜在并发症。作为替代方法，内源性大麻素系统已显示出具有镇痛活性，同时通过 CB1 和 CB2 大麻素受体有助于骨稳态。本研究评估了大麻素受体激动剂 WIN55,212-2（WIN55）对体外成骨分化以及临床前大鼠模型中骨再生和脊柱融合的影响。
原代大鼠骨髓基质细胞在标准或成骨培养基中培养，并单独接触载体或 WIN55。通过 qPCR（实时定量聚合酶链反应）定量 Runx2 和碱性磷酸酶（Alpl），然后评估 ALP 活性和基质矿化。对于体内评估，45 只雌性 Sprague Dawley 大鼠（每组 15 只）接受 L4-L5 后路脊柱融合术，双侧放置预先加载低剂量 rhBMP-2（重组人骨形态发生蛋白-2；0.5 μg/植入物）的胶原支架。手术后，大鼠每天腹膜内注射单独的载体或 0.5 或 2.5 mg/kg WIN55，共 5 天。使用 X 射线、基于手动触诊的融合评分、微计算机断层扫描成像和组织学评估骨再生和脊柱融合。
单独用载体处理和 WIN55 处理的细胞中 Runx2 和 Alp 的 mRNA 表达水平相似。同样，暴露于 WIN55 并未抑制 ALP 活性或骨基质矿化。在该动物模型中，各组之间的平均融合评分、融合率或新骨体积均无显著差异。
WIN55 对成骨分化、骨再生和脊柱融合没有不良影响。这支持大麻素受体激动剂应作为脊柱融合和其他需要骨愈合的骨科手术后术后镇痛的潜在替代方法进一步研究。
确定骨科手术后疼痛的替代治疗方法对于对抗阿片类药物滥用危机至关重要。内源性大麻素系统可能是解决骨科术后疼痛的可行替代靶标。
