Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ.
Ann Neurol. 2013 Aug;74(2):257-65. doi: 10.1002/ana.23922. Epub 2013 Sep 10.
Preclinical evaluation of headache by behavioral assessment of reward from pain relief.
Inflammatory mediators (IMs) or control solution were applied to the rat dura mater to elicit a presumed state of cephalic pain. Hind paw incision was used in separate groups of animals to model noncephalic postsurgical pain. Drugs were given systemically or microinjected within the rostral ventromedial medulla (RVM), nucleus accumbens (NAc), or rostral anterior cingulate cortex (rACC). Peripheral nerve block was produced at the level of the popliteal fossa, and behavior was assessed using evoked sensory stimuli or conditioned place preference (CPP). Immunohistochemistry and brain microdialysis measurements were performed.
Dural IMs produced long-lasting generalized cutaneous allodynia. RVM lidocaine produced CPP, increased NAc c-Fos, and dopamine release selectively in rats receiving dural IMs; CPP was blocked by intra-NAc α-flupenthixol, a dopaminergic antagonist. Intravenous α-calcitonin gene-related peptide (αCGRP)(8-37) produced CPP and elicited NAc dopamine release selectively in rats treated with dural IMs. Prior lesion of the rACC or treatment with systemic sumatriptan or αCGRP(8-37) abolished RVM lidocaine-induced CPP in IM-treated rats. Sumatriptan treatment blocked NAc dopamine release in IM-treated rats receiving RVM lidocaine. Systemic sumatriptan did not alter pain relief-induced CPP in rats with incisional injury.
Cephalic pain was unmasked in rats by assessment of motivated behavior to seek relief. Relief of pain activates the dopaminergic reward pathway to elicit negative reinforcement of behavior. Medications clinically effective for migraine headache selectively elicit relief of ongoing cephalic, but not postsurgical, noncephalic pain. These studies provide a platform for exploring migraine pathophysiology and for the discovery of new headache therapies.
通过疼痛缓解的行为评估来对头痛进行临床前评估。
将炎症介质（IMs）或对照溶液应用于大鼠硬脑膜，以引发头部疼痛的假定状态。在单独的动物组中，进行后爪切口以模拟非头部手术后疼痛。药物通过全身给予或在延髓腹内侧（RVM）、伏隔核（NAc）或额前扣带皮层（rACC）内微注射给予。在腘窝水平进行外周神经阻滞，并使用诱发感觉刺激或条件性位置偏好（CPP）评估行为。进行免疫组织化学和脑微透析测量。
硬脑膜 IMs 产生持久的全身性皮肤痛觉过敏。RVM 利多卡因产生 CPP，增加 NAc c-Fos，并选择性地释放多巴胺，仅在接受硬脑膜 IMs 的大鼠中；CPP 被 NAc 内的α-氟哌啶醇阻断，一种多巴胺拮抗剂。静脉内 α-降钙素基因相关肽（αCGRP）（8-37）选择性地在接受硬脑膜 IMs 治疗的大鼠中产生 CPP 并引起 NAc 多巴胺释放。rACC 前病变或全身性舒马曲坦或 αCGRP（8-37）治疗消除了 IM 治疗大鼠中 RVM 利多卡因诱导的 CPP。舒马曲坦治疗阻断了接受 RVM 利多卡因治疗的 IM 治疗大鼠的 NAc 多巴胺释放。全身性舒马曲坦不会改变接受手术损伤的大鼠中疼痛缓解诱导的 CPP。
通过寻求缓解疼痛的动机行为评估来揭示大鼠的头部疼痛。疼痛缓解激活多巴胺奖励途径，引起行为的负性强化。对偏头痛头痛有效的药物选择性地缓解持续的头部疼痛，但不缓解非头部的手术后疼痛。这些研究为探索偏头痛病理生理学和发现新的头痛治疗方法提供了一个平台。
