Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache.
Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache.
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DOI：
10.1177/0333102416681571
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Levy D
中科院分区：
文献类型：
--
作者：
Bree D;Levy D
创伤后头痛（PTH）是轻度创伤性脑损伤或脑震荡后最常见、最令人衰弱和最难控制的症状之一。然而，PTH的潜在机制仍然难以捉摸，部分原因是缺乏临床相关的动物模型。在这里，我们第一次在大鼠脑震荡模型中表征了头痛和疼痛相关行为，该模型由轻度闭合性脑损伤（mCHI）诱发-与PTH相关的军事和民用相关创伤的主要类型-并测试了对当前和新型头痛疗法的反应。成年雄性大鼠采用失重法诱发脑震荡。头痛和疼痛相关行为的表征包括使用von Frey单丝评估皮肤触觉疼痛敏感性，以及使用条件性位置偏好或厌恶（CPP/CPA）范式评估持续疼痛。通过将大鼠暴露于低剂量的三硝酸甘油酯（GTN）来测试对头痛/偏头痛触发物的敏感性。治疗包括舒马曲坦的急性全身给药和小鼠抗CGRP单克隆抗体的慢性全身给药。脑震荡大鼠头部的触觉疼痛过敏，解决了两个星期后，受伤，并改善与舒马曲坦或抗CGRP单克隆抗体治疗。在mCHI后7天，舒马曲坦也产生CPP，但在假手术动物中不产生。在脑震荡诱发的头部超敏反应消退后，GTN的给药产生了一种新的和明显的头部疼痛超敏反应，这种超敏反应被舒马曲坦或抗CGRP抗体治疗以及CGRP依赖性CPA抑制。GTN对假手术动物无影响。脑震荡导致头痛和疼痛相关行为的发展，特别是对GTN的持续增强反应，其通过CGRP依赖性机制介导。用抗CGRP抗体治疗可能是治疗PTH的有用方法。
Posttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a mild traumatic brain injury, or concussion. However, the mechanisms underlying PTH remain elusive, in part due to the lack of a clinically relevant animal model. Here, we characterized for the first time, headache and pain-related behaviours in a rat model of concussion evoked by a mild closed head injury (mCHI) – the major type of military and civilian related trauma associated with PTH – and tested responses to current and novel headache therapies. Concussion was induced in adult male rats using a weight-drop device. Characterization of headache and pain related behaviours included assessment of cutaneous tactile pain sensitivity, using von Frey monofilaments, and ongoing pain using the conditioned place preference or aversion (CPP/CPA) paradigms. Sensitivity to headache/migraine triggers was tested by exposing rats to low-dose glyceryl trinitrate (GTN). Treatments included acute systemic administration of sumatriptan and chronic systemic administration of a mouse anti-CGRP monoclonal antibody. Concussed rats developed cephalic tactile pain hypersensitivity that was resolved by two weeks post-injury and was ameliorated by treatment with sumatriptan or anti-CGRP monoclonal antibody. Sumatriptan also produced CPP seven days post mCHI, but not in sham animals. Following the resolution of the concussion-evoked cephalic hypersensitivity, administration of GTN produced a renewed and pronounced cephalic pain hypersensitivity that was inhibited by sumatriptan or anti-CGRP antibody treatment as well as a CGRP-dependent CPA. GTN had no effect in sham animals. Concussion leads to the development of headache and pain-related behaviours, in particular sustained enhanced responses to GTN, that are mediated through a CGRP-dependent mechanism. Treatment with anti-CGRP antibodies may be a useful approach to treat PTH.
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