Nociception from Deep Muscle Incision

深层肌肉切口造成的伤害

基本信息

批准号：
8324874
负责人：
TIMOTHY JOHN BRENNAN
金额：
$ 33.81万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-01 至 2014-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In order to decrease morbidity after surgery, it is critical that pain treatment strategies that have greater efficacy and are devoid of serious side effects be developed for postoperative patients. The long-term goal of this proposal is to understand how factors that activate and sensitize pain transmitting neurons can be effectively targeted for the improved treatment of pain in patients undergoing surgery. The overall objective of this proposal is to demonstrate powerful activation of nociceptive pathways by deep muscle incision and sensitization of nociceptive pathways to ischemic pain mediators and to muscle contraction by incision. The central hypothesis is that incisions that include deep muscle tissue produce much greater activation of the nociceptive system than incisions of skin only. The rationale that underlies the proposed research is that it will be possible to understand the mechanisms and origin of pain at rest and pain with activities in patients after surgery. To accomplish the overall objective, the following specific aims are proposed: 1. Demonstrate unique pain-related behaviors are produced by deep muscle incision. The working hypothesis, supported by preliminary studies, is that deep muscle incision will cause guarding pain and will reduce activities requiring muscle contraction. Skin incision will not affect these behaviors. 2. Demonstrate activation and sensitization of primary afferent nociceptors by deep muscle incision but not by skin incision. Based on previous studies, skin incision does not produce sustained activation of nociceptors. We hypothesize that nociceptors from the hindpaw of rats with deep muscle incision will have ongoing activity and will be sensitized to muscle contractions. 3. Demonstrate greater excitability of incised muscle compared to unincised muscle in a rat hindpaw in vitro muscle- nerve preparation. We hypothesize deep tissue incision will sensitize nociceptors and this will be evident in vitro. We will record nociceptors in vitro and examine excitation of nociceptors by heat, mechanical stimuli, and acid as well as muscle contraction. The effect of ASIC and TRPV1 receptor blockade on excitation by acid will be tested. 4. Demonstrate DRG innervating incised muscle have increased responses to acid and increased mRNA expression for ASICs and TRPV1 compared to DRG innervating unincised muscle. We hypothesize that 1) the percentage of DRG expressing ASIC and TRPV1 currents and/or the amplitude of the ASIC- and TRPV1-like currents will be greater in incised muscle, and 2) mRNA expression for ASICs and TRPV1 will be greater in incised muscle. 5. Demonstrate greater excitability of incised muscle compared to unincised muscle in a mouse in vitro muscle nerve preparation. We hypothesize murine muscle nociceptors will be sensitized by incision. This aim will provide the basis for future studies that will incorporate KO mice for key receptors and mediators of nociceptor activation and sensitization by muscle incision. It is expected that strong activation and sensitization of nociceptive pathways by incision of deep muscle tissues will be demonstrated. The proposed research is significant because it will demonstrate that after incision, sensitization of nociceptors to chemical stimuli and muscle contractions occurs. From this research, ischemic pain mechanisms and therapeutic targets like TRPV1 and ASICs can be advanced. PUBLIC HEALTH RELEVANCE: Pain from surgery on muscle tissue will be studied. From this research, new mechanisms and treatments will become available so that pain at rest and with movement will be reduced, perioperative morbidity will decline, and health care costs will decrease.

描述（由申请人提供）：为了降低手术后的发病率，为术后患者开发更有效且没有严重副作用的疼痛治疗策略至关重要。该提案的长期目标是了解如何有效地靶向激活和敏化疼痛传递神经元的因子，以改善接受手术的患者的疼痛治疗。该提案的总体目标是证明深层肌肉切口对伤害性通路的强大激活以及伤害性通路对缺血性疼痛介质和切口肌肉收缩的敏感性。中心假设是，包含深层肌肉组织的切口比仅皮肤切口对伤害感受系统产生更大的激活。这项研究的基本原理是，将有可能了解患者术后休息时疼痛和活动时疼痛的机制和根源。为了实现总体目标，提出以下具体目标： 1. 展示深层肌肉切口产生独特的疼痛相关行为。得到初步研究支持的工作假设是，深层肌肉切口会引起守护痛，并减少需要肌肉收缩的活动。皮肤切口不会影响这些行为。 2. 证明深层肌肉切口而非皮肤切口对初级传入伤害感受器的激活和敏化。根据之前的研究，皮肤切口不会产生伤害感受器的持续激活。我们假设，深部肌肉切口的大鼠后爪的伤害感受器将持续活动，并对肌肉收缩敏感。 3. 在大鼠后爪体外肌肉神经制剂中，显示出与未切割的肌肉相比，切割的肌肉具有更高的兴奋性。我们假设深层组织切口会使伤害感受器敏感，这在体外会很明显。我们将在体外记录伤害感受器，并检查热、机械刺激、酸以及肌肉收缩对伤害感受器的兴奋。将测试 ASIC 和 TRPV1 受体阻断对酸激发的影响。 4. 证明与 DRG 神经支配未切开的肌肉相比，DRG 支配切开的肌肉对酸的反应增加，并且 ASIC 和 TRPV1 的 mRNA 表达增加。我们假设 1) 表达 ASIC 和 TRPV1 电流的 DRG 的百分比和/或 ASIC 和 TRPV1 样电流的幅度在切开的肌肉中会更大，2) ASIC 和 TRPV1 的 mRNA 表达在切开的肌肉中会更大。 5. 在小鼠体外肌肉神经制剂中，与未切割的肌肉相比，显示切割的肌肉具有更高的兴奋性。我们假设小鼠肌肉伤害感受器会因切口而敏感。这一目标将为未来的研究奠定基础，这些研究将通过肌肉切口将 KO 小鼠纳入伤害感受器激活和敏化的关键受体和介质中。预计将证明通过切开深层肌肉组织对伤害性通路的强烈激活和敏化。拟议的研究意义重大，因为它将证明切开后，伤害感受器对化学刺激和肌肉收缩敏感。通过这项研究，可以推进缺血性疼痛机制和 TRPV1 和 ASIC 等治疗靶点。公共卫生相关性：将研究肌肉组织手术引起的疼痛。从这项研究中，将出现新的机制和治疗方法，从而减少休息和运动时的疼痛，围手术期发病率下降，医疗费用也会降低。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Simultaneous disruption of mouse ASIC1a, ASIC2 and ASIC3 genes enhances cutaneous mechanosensitivity.

同时破坏小鼠 ASIC1a、ASIC2 和 ASIC3 基因可增强皮肤机械敏感性。

DOI：
发表时间：
2012
期刊：
影响因子：
3.7
作者：
Kang, Sinyoung;Jang, Jun Ho;Price, Margaret P;Gautam, Mamta;Benson, Christopher J;Gong, Huiyu;Welsh, Michael J;Brennan, Timothy J
通讯作者：
Brennan, Timothy J

Increased sensitivity of group III and group IV afferents from incised muscle in vitro.

体外切割肌肉的 III 组和 IV 组传入神经的敏感性增加。