EFFECTS OF NEUROKININ-1 RECEPTOR AGONISM AND ANTAGONISM IN THE ROSTRAL VENTROMEDIAL MEDULLA OF RATS WITH ACUTE OR PERSISTENT INFLAMMATORY NOCICEPTION
EFFECTS OF NEUROKININ-1 RECEPTOR AGONISM AND ANTAGONISM IN THE ROSTRAL VENTROMEDIAL MEDULLA OF RATS WITH ACUTE OR PERSISTENT INFLAMMATORY NOCICEPTION
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DOI：
10.1016/j.neuroscience.2009.10.064
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发表时间：
2010-02-03
期刊：
影响因子：
3.3
通讯作者：
Hammond, D. L.
中科院分区：
文献类型：
--
作者：
Hamity, M. V.;White, S. R.;Hammond, D. L.
延髓头端腹内侧区（RVM）是调节伤害感受的球脊髓通路的中枢中继，含有高浓度的P物质（Sub P）和神经激肽-1（NK 1）受体。然而，对RVM中Sub P的功能知之甚少。本研究描述了在无损伤的情况下RVM中Sub P的作用，然后使用两种NK 1受体拮抗剂L-733，060和L-703，606来探测内源性释放的Sub P在免疫或神经源性持续炎性伤害感受的发展和维持中的作用。在未损伤大鼠中，在RVM中微量注射Sub P产生短暂的热抗伤害感受，其通过用L-733，060或L-703，606预处理而减弱。它没有改变阈值撤回触觉刺激与冯弗雷细丝。单独微量注射拮抗剂不改变缩爪潜伏期（PWL）或阈值，表明在没有损伤的情况下，Sub P在RVM中不紧张性释放。然而，在RVM中微量注射任一拮抗剂足以在足底（ipl）注射完全弗氏佐剂（CFA）后4小时、4天或2周逆转热痛觉过敏。RVM中NK 1受体的拮抗作用不能阻止或逆转CFA诱导的触觉超敏反应，但确实减弱了辣椒素产生的触觉超敏反应。NK 1受体拮抗剂不能阻止芥子油（MO）引起的热痛觉过敏、触觉超敏反应或自发痛行为的发生。结果表明，亚P在RVM中具有双峰作用，并且在炎性损伤后，它可以在痛觉过敏和触觉超敏反应的发展和维持中发挥关键作用。然而，其作用高度依赖于刺激方式和损伤类型，这可能是NK 1受体拮抗剂在临床试验中疗效差的另一个基础。(C)2010年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The rostral ventromedial medulla (RVM), a central relay in the bulbospinal pathways that modulate nociception, contains high concentrations of substance P (Sub P) and neurokinin-1 (NK1) receptors. However, the function of Sub P in the RVM is poorly understood. This study characterized the actions of Sub P in the RVM in the absence of injury and then used two NK1 receptor antagonists, L-733,060 and L-703, 606, to probe the role of endogenously released Sub P in the development and maintenance of persistent inflammatory nociception of immune or neurogenic origin. In uninjured rats, microinjection of Sub P in the RVM produced a transient thermal antinociception that was attenuated by pretreatment with L-733,060 or L-703,606. It did not alter threshold to withdrawal from tactile stimulation with von Frey filaments. Microinjection of the antagonists alone did not alter paw withdrawal latency (PWL) or threshold suggesting that Sub P is not tonically released in the RVM in the absence of injury. However, microinjection of either antagonist in the RVM was sufficient to reverse heat hyperalgesia 4 h, 4 days or 2 weeks after intraplantar (ipl) injection of complete Freund's adjuvant (CFA). Antagonism of NK1 receptors in the RVM did not prevent or reverse tactile hypersensitivity induced by CFA, but did attenuate that produced by capsaicin. NK1 receptor antagonism did not prevent the development of thermal hyperalgesia, tactile hypersensitivity or spontaneous pain behaviors induced by mustard oil (MO). The results suggest that Sub P has bimodal actions in the RVM and that following inflammatory injury, it can play a critical role as a pronociceptive agent in the development and maintenance of hyperalgesia and tactile hypersensitivity. However, its actions are highly dependent on the stimulus modality and the type of injury, and this may be an additional basis for the poor efficacy of NK1 receptor antagonists in clinical trials. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.