Griffiths Lisa A, Duggett Natalie A, Pitcher Ann L, Flatters Sarah J L
Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK.
Pain Res Manag. 2018 Jun 3;2018:8217613. doi: 10.1155/2018/8217613. eCollection 2018.
Paclitaxel-induced neuropathic pain is a major dose-limiting side effect of paclitaxel therapy. This study characterises a variety of rat behavioural responses induced by intermittent administration of clinically formulated paclitaxel. 2 mg/kg paclitaxel or equivalent vehicle was administered intraperitoneally on days 0, 2, 4, and 6 to adult male Sprague-Dawley rats. Evoked pain-like behaviours were assessed with von Frey filaments, acetone, or radiant heat application to plantar hind paws to ascertain mechanical, cold, or heat sensitivity, respectively. Motor coordination was evaluated using an accelerating RotaRod apparatus. Ongoing pain-like behaviour was assessed via spontaneous burrowing and nocturnal wheel running. Mechanical and cold hypersensitivity developed after a delayed onset, peaked approximately on day 28, and persisted for several months. Heat sensitivity and motor coordination were unaltered in paclitaxel-treated rats. Spontaneous burrowing behaviour and nocturnal wheel running were significantly impaired on day 28, but not on day 7, indicating ongoing pain-like behaviour, rather than acute drug toxicity. This study comprehensively characterises a rat model of paclitaxel-induced peripheral neuropathy, providing the first evidence for ongoing pain-like behaviour, which occurs in parallel with maximal mechanical/cold hypersensitivity. We hope that this new data improve the face validity of rat models to better reflect patient-reported pain symptoms, aiding translation of new treatments to the clinic.
紫杉醇诱导的神经性疼痛是紫杉醇治疗的主要剂量限制性副作用。本研究描述了间歇性给予临床配方紫杉醇所诱发的多种大鼠行为反应。于第0、2、4和6天对成年雄性斯普拉格-道利大鼠腹腔注射2mg/kg紫杉醇或等量赋形剂。分别用von Frey细丝、丙酮或对后足底施加辐射热来评估诱发的疼痛样行为，以确定机械性、冷或热敏感性。使用加速转棒仪评估运动协调性。通过自发打洞和夜间轮转跑步评估持续性疼痛样行为。机械性和冷超敏反应在延迟发作后出现，大约在第28天达到峰值，并持续数月。紫杉醇治疗的大鼠热敏感性和运动协调性未改变。自发打洞行为和夜间轮转跑步在第28天显著受损，但在第7天未受损，表明存在持续性疼痛样行为，而非急性药物毒性。本研究全面描述了紫杉醇诱导的周围神经病变大鼠模型，为与最大机械性/冷超敏反应同时出现的持续性疼痛样行为提供了首个证据。我们希望这些新数据能提高大鼠模型的表面效度，以更好地反映患者报告的疼痛症状，有助于将新治疗方法转化至临床。
