Edelmayer Rebecca M, Vanderah Todd W, Majuta Lisa, Zhang En-Tan, Fioravanti Beatriz, De Felice Milena, Chichorro Juliana G, Ossipov Michael H, King Tamara, Lai Josephine, Kori Shashi H, Nelsen Andrew C, Cannon Keri E, Heinricher Mary M, Porreca Frank
Department of Pharmacology, University of Arizona, Tucson, USA.
Ann Neurol. 2009 Feb;65(2):184-93. doi: 10.1002/ana.21537.
To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia.
Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized.
IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene-related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM.
Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders.
建立并验证一种由硬脑膜炎症引发的皮肤异常性疼痛模型，用于研究与头痛相关的疼痛。探索头部和头部以外部位异常性疼痛的神经机制。
通过先前植入的套管将炎性介质（IM）应用于未麻醉大鼠的硬脑膜，并对其面部和后爪的感觉阈值进行表征。
IM引发了强烈的面部和后爪异常性疼痛，在3小时内达到峰值。这些效应类似于偏头痛或其他原发性头痛患者中出现的皮肤异常性疼痛，并可被临床上用于治疗偏头痛的药物所逆转，包括舒马曲坦、萘普生和降钙素基因相关肽拮抗剂。与临床观察一致，神经激肽-1拮抗剂对异常性疼痛没有影响。在确定面部和后爪异常性疼痛是头痛相关异常性疼痛的有用动物模型后，我们接下来表明，阻断延髓头端腹内侧（RVM）的疼痛易化过程会干扰其表达。布比卡因、破坏假定的疼痛易化神经元或阻断胆囊收缩素受体可预防或显著减轻IM诱导的异常性疼痛。电生理研究证实，IM后疼痛易化的RVM“开”细胞被激活，RVM“关”细胞被短暂抑制。
与硬脑膜刺激相关的面部和后爪异常性疼痛是包括偏头痛在内的原发性头痛相关疼痛的有用模型，并且可以从机制上用于开发治疗头痛疼痛的新策略。数据还表明，RVM下行易化的激活是颅部和颅外皮肤异常性疼痛表达所必需的，并且与头痛障碍相关的异常性疼痛的脑干发生器一致。
