de Kock Michaela, Chetty Sean, Sherif Isa Ahmed, Qulu-Appiah Lihle
Division of Medical Physiology, Faculty of Medicine and Health Science, Stellenbosch University, South Africa.
Anaesthesiology and Critical Care, Faculty of Medicine and Health Science, Stellenbosch University, South Africa.
Neurobiol Pain. 2024 Mar 7;16:100152. doi: 10.1016/j.ynpai.2024.100152. eCollection 2024 Jul-Dec.
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect with ineffective preventative and curative treatment. Currently, only Duloxetine has been recommended as effective treatment for CIPN, which has shown individual-dependent, short-term analgesic effects, with limiting adverse effects and poor bioavailability. The neuropeptide, oxytocin, may offer significant analgesic and anxiolytic potential, as it exerts central and peripheral attenuating effects on nociception. However, it is unknown whether the intervention administered in a model of CIPN is an effective therapeutic alternative or adjuvant. The intervention was divided into two phases. Phase 1 aimed to induce CIPN in adult Wistar rats using the chemotherapeutic agent Paclitaxel. Mechanical (electronic von Frey filament) and thermal (acetone evaporation test and Hargreaves test) hypersensitivity testing were used to evaluate changes due to the neuropathic induction. Phase 2 consisted of a 14-day intervention period with saline (o.g.), duloextine (o.g.), or oxytocin (i.n.) administered as treatment. Following the intervention, anxiety-like behaviour was assessed using the elevated plus maze (EPM) and light-dark box protocols. Analysis of peripheral plasma corticosterone, peripheral plasma oxytocin, and hypothalamic oxytocin concentrations were assessed using ELISA assays. The findings showed that we were able to successfully establish a model of chemotherapy-induced peripheral neuropathy during Phase 1, determined by the increase in mechanical and thermal nociceptive responses following Paclitaxel administration. Furthermore, the animals treated with oxytocin displayed a significant improvement in mechanical sensitivity over the intervention phase, indicative of an improvement in nociceptive sensitivity in the presence of neuropathic pain. Animals that received Paclitaxel and treated with oxytocin also displayed significantly greater explorative behaviour during the EPM, indicative of a reduced presence of anxiety-like behaviour. Our results support the hypothesis that intranasally administered oxytocin may augment the analgesic and anxiolytic effects of duloxetine in a chemotherapy induced peripheral neuropathy model in a Wistar rat. Future studies should consider administering the treatments in combination to observe the potential synergistic effects.
化疗引起的周围神经病变（CIPN）是一种剂量限制性副作用，其预防和治疗方法均无效。目前，仅度洛西汀被推荐为治疗CIPN的有效药物，它显示出个体依赖性的短期镇痛效果，副作用有限，但生物利用度较差。神经肽催产素可能具有显著的镇痛和抗焦虑潜力，因为它对伤害感受具有中枢和外周的减轻作用。然而，在CIPN模型中进行的干预是否是一种有效的治疗选择或辅助治疗尚不清楚。该干预分为两个阶段。第一阶段旨在使用化疗药物紫杉醇在成年Wistar大鼠中诱导CIPN。使用机械（电子von Frey细丝）和热（丙酮蒸发试验和哈格里夫斯试验）超敏反应测试来评估神经病变诱导引起的变化。第二阶段包括为期14天的干预期，分别给予生理盐水（经口）、度洛西汀（经口）或催产素（经鼻）作为治疗。干预后，使用高架十字迷宫（EPM）和明暗箱试验评估焦虑样行为。使用酶联免疫吸附测定法评估外周血浆皮质酮、外周血浆催产素和下丘脑催产素浓度。研究结果表明，在第一阶段我们能够成功建立化疗诱导的周围神经病变模型，这通过紫杉醇给药后机械和热伤害性反应的增加来确定。此外，在干预期内，接受催产素治疗的动物在机械敏感性方面有显著改善，表明在存在神经性疼痛的情况下伤害感受敏感性有所改善。接受紫杉醇并接受催产素治疗的动物在EPM中也表现出明显更强的探索行为，表明焦虑样行为减少。我们的结果支持这样的假设，即经鼻给予催产素可能增强度洛西汀在Wistar大鼠化疗诱导的周围神经病变模型中的镇痛和抗焦虑作用。未来的研究应考虑联合使用这些治疗方法以观察潜在的协同效应。
