TRPV1 Expressing Sensory Afferents in Postoperative Pain

TRPV1 在术后疼痛中表达感觉传入

• 批准号: 7142465
• 负责人: TIMOTHY JOHN BRENNAN
• 金额: $ 21.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142465
• 关键词: acidity /alkalinity; behavior test; capsaicin; dorsal horn; electrophysiology; excitatory aminoacid; genetically modified animals; hyperalgesia; immunocytochemistry; laboratory mouse; laboratory rat; membrane channels; nerve growth factors; neural information processing; neurons; neurophysiology; neuropsychology; nociceptors; postoperative state; protein structure function; protein tyrosine kinase; stimulus /response; thermoreception

DESCRIPTION (provided by applicant): Postoperative, incisional pain is a unique but common form of acute pain. Since effective postoperative analgesia reduces morbidity following surgery, new treatments continue to be investigated. The proposal is dedicated toward defining peripheral mechanisms of incisional pain. Our working hypothesis is that TRPV1 containing nociceptors that have ongoing activity as a consequence of incision signal nonevoked, guarding pain behavior and that this ongoing activity is due to NGF-induced sensitization of TRPV1 to heat and acid pH. In vivo primary afferent and dorsal horn cell recordings, in vitro primary afferent recordings, transgenic mice, immunohistochemistry, and behavioral studies will be used in concert to examine the mechanisms that contribute to activation and sensitization of nociceptors by incision. Our working hypothesis is that 1) guarding pain behaviors and spontaneous acitivity in nociceptors and dorsal horn neurons will be exacerbated and reduced by warming and cooling the hindpaw, respectively. 2) Capsaicin treatment will cause loss of CGRP and IB4 (C-fibers) staining but not N52 (A-fibers) staining. Capsaicin treatment will reduce heat hyperalgesia and guarding behaviors but not mechanical hyperalgesia. Certain doses may differentiate guarding and heat hyperalgesia. 3) Heat, pH and NGF responses but not mechanical responses will be decreased by capsaicin in the incised glabrous skin nerve preparation. 4) C-fibers from incised congenic TRPV1 KO mice will have decreased response to heat, pH and NGF compared to incised C57BI6 mice. Few spontaneously active afferents and dorsal horn neurons will be present in vivo from incised rats after destruction of TRPV1 containing fibers. 5) NGF will be increased in incised skin but TRPV1 and Trk A receptors will be unchanged after incision indicating NGF is contributing to pain by producing acute sensitization of nociceptors. The results of these studies will provide important new insights into the mechanisms that subserve nociceptor activation, nonevoked, guarding pain behavior and heat hyperalgesia as a consequence of incisional injury. A separate pathway, likely an A-fiber mediated pathway, is sufficient to transmit the enhanced mechanical responses.

描述（由申请人提供）：术后，切开疼痛是急性疼痛的独特但常见的形式。由于有效的术后镇痛可降低手术后的发病率，因此继续研究新的治疗方法。该提议致力于定义切口疼痛的外围机制。我们的工作假设是，含有因切口信号而持续活性的伤害感受器的TRPV1，避免了疼痛行为，并且这种持续的活动是由于NGF诱导的TRPV1对热和酸性pH的敏感性。体内原发性传入和背角细胞记录，体外原发性传入记录，转基因小鼠，免疫组织化学和行为研究将在协同过程中使用，以检查有助于通过切割来激活和敏感的机制。我们的工作假设是，1）分别通过变暖和冷却后爪，使伤害感受器和背喇叭神经元的疼痛行为和自发的尊重会加剧和减少。 2）辣椒素治疗将导致CGRP和IB4（C纤维）染色的损失，而不是N52（A纤维）染色。辣椒素治疗将减少热痛觉过敏和保护行为，而不是机械性痛觉过敏。某些剂量可能会区分守卫和加热痛觉过敏。 3）在切开的无毛皮肤神经制备中，辣椒素会减少热量，pH和NGF反应，但不会通过辣椒素减少。 4）与切开的C57BI6小鼠相比，来自切开的TRPV1 KO小鼠的C纤维对热，pH和NGF的反应降低。破坏了含有纤维的TRPV1后，很少有自发活性传入和背角神经元在体内存在于体内。 5）在切开的皮肤中，NGF将增加，但是在切口表明NGF通过产生伤害感受器的急性敏化来导致疼痛后，TRPV1和TRK A受体将保持不变。这些研究的结果将为您提供对伤害感受器激活的机制提供重要的新见解，这是无反应的，由于切开损伤而避免疼痛行为和热痛觉过敏。单独的途径可能是A纤维介导的途径，足以传递增强的机械响应。