TRPV1 Expressing Sensory Afferents in Postoperative Pain

TRPV1 在术后疼痛中表达感觉传入

基本信息

批准号：
7254228
负责人：
TIMOTHY JOHN BRENNAN
金额：
$ 30.79万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/7254228
关键词：
Absence of pain sensation Acids Acute Acute Pain Adverse effects Affect Analgesics Award Behavior Behavioral C Fiber CALCA gene Calcitonin Gene-Related Peptide Capsaicin Data Development Dose Excitatory Amino Acid Receptors Excitatory Amino Acids Exhibits Fiber Fibers, A Functional disorder Gene Deletion Goals Heating Hyperalgesia Imines Immunohistochemistry In Vitro Infiltration Injury JSTX spider toxin Knock-out Liquid substance Long-Term Potentiation Measures Mechanics Mediating Medicine Modeling Morbidity - disease rate Mus N-Methylaspartate Nerve Nerve Fibers Nerve Growth Factor 1 Nerve Growth Factor Pathway Nerve Growth Factors Neurons Nociception Nociceptors Operative Surgical Procedures Pain Pain Research Pain management Painless Pathway interactions Patients Pattern Perioperative Peripheral Phosphate Buffer Physiology Posterior Horn Cells Postoperative Pain Postoperative Period Preparation Process Protein Tyrosine Kinase Protons Quinoxalines Rattus Research Personnel Response to stimulus physiology S100A12 gene Saline Sensory Signal Transduction Skin Skin Temperature Spinal Ganglia Staining method Stains Stimulus Sulfonamides Surgical incisions TRPV1 gene Temperature Transgenic Mice Translating Work afferent nerve alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate central sensitization congenic day dorsal horn human S100A12 protein in vivo insight nerve supply neurophysiology novel receptive field receptor response vanilloid receptor subtype 1

项目摘要

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）：术后切口疼痛是一种独特但常见的急性疼痛形式。由于有效的术后镇痛可降低手术后的发病率，因此不断研究新的治疗方法。该提案致力于定义切口疼痛的外周机制。我们的工作假设是，含有伤害感受器的 TRPV1 由于切口信号未诱发而具有持续的活动，保护疼痛行为，并且这种持续的活动是由于 NGF 诱导的 TRPV1 对热和酸 pH 的敏感性。体内初级传入细胞和背角细胞记录、体外初级传入细胞记录、转基因小鼠、免疫组织化学和行为研究将共同用于检查通过切口激活和敏化伤害感受器的机制。我们的工作假设是：1）伤害感受器和背角神经元的保护疼痛行为和自发活动将分别通过加热和冷却后爪而加剧和减少。 2) 辣椒素处理会导致 CGRP 和 IB4（C 纤维）染色丧失，但不会导致 N52（A 纤维）染色丧失。辣椒素治疗会减少热痛觉过敏和防护行为，但不会减少机械痛觉过敏。某些剂量可以区分警觉痛觉过敏和热痛觉过敏。 3) 切开的无毛皮肤神经制剂中的辣椒素会降低热、pH 和 NGF 反应，但不会降低机械反应。 4) 与切开的 C57BI6 小鼠相比，切开的同源 TRPV1 KO 小鼠的 C 纤维对热、pH 和 NGF 的反应会降低。在含有 TRPV1 的纤维被破坏后，被切开的大鼠体内几乎不会出现自发活动的传入神经元和背角神经元。 5) 切口皮肤中的 NGF 会增加，但切口后 TRPV1 和 Trk A 受体将保持不变，表明 NGF 通过产生伤害感受器的急性敏化而导致疼痛。这些研究的结果将为促进伤害感受器激活、非诱发、保护疼痛行为和切口损伤导致的热痛觉过敏的机制提供重要的新见解。单独的通路（可能是 A 纤维介导的通路）足以传递增强的机械响应。