Postoperative pain of moderate to severe intensity is experienced by 20-30% of patients despite advances in surgical techniques and perioperative analgesic strategies. Furthermore, unrelieved postoperative pain is a common cause for unplanned hospital admission and contributes to suboptimal functional outcomes. The development of analgesics possessing novel mechanisms of action would have significant value in addressing these problems. Acute inflammation is characteristic of surgical wounds. Few analgesic therapies are directed specifically at reducing the intensity of the inflammatory process itself. The complement system is one component of the acute inflammatory process which is activated by surgical incisions. Two of the so-called split products of complement system activation, C3a and C5a;have prominent roles in supporting inflammation in many disease states. In wounds these molecules stimulate the production of additional algogenic inflammatory mediators, and act as chemoattractants to enhance leukocytic infiltration. The principal goal of this project is to determine how the complement system functions within incisional wounds to support nociceptive sensitization and inflammation. In the first specific aim the use of selective C3a and C5a receptor antagonists, null mutant mice single fiber nerve recordings, dorsal root ganglion neuron patch clamp electrophysiology and other approaches to determine if and where these fragments act to support nociception. In the second specific aim we will delineate alterations in primary afferent and spinal cord gene expression related to the role of complement in nociception. In the third aim we examine the roles C3a/C5a have in supporting incisional edema, cytokine production and leukocytic infiltration, and define the roles of cytokines whose production is supported by complement. The main benefit in terms of public health is to move us towards the point of conducting clinical trials examining the efficacy of complement receptor antagonists as analgesics. A number of complement activity modifying compounds are in late stage clinical trials, and translational projects arising from this work are likely.
The main benefit in terms of public health is to move us towards the point of conducting clinical trials examining the efficacy of complement receptor antagonists as analgesics. A number of complement activity modifying compounds are in late stage clinical trials, and translational projects arising from this work are likely.
|Shutov, Leonid P; Warwick, Charles A; Shi, Xiaoyu et al. (2016) The Complement System Component C5a Produces Thermal Hyperalgesia via Macrophage-to-Nociceptor Signaling That Requires NGF and TRPV1. J Neurosci 36:5055-70|
|Sun, Yuan; Sahbaie, Peyman; Liang, DeYong et al. (2015) DNA Methylation Modulates Nociceptive Sensitization after Incision. PLoS One 10:e0142046|
|Sun, Yuan; Sahbaie, Peyman; Liang, DeYong et al. (2014) Opioids enhance CXCL1 expression and function after incision in mice. J Pain 15:856-66|
|Sun, Yuan; Sahbaie, Peyman; Liang, De-Yong et al. (2013) Epigenetic regulation of spinal CXCR2 signaling in incisional hypersensitivity in mice. Anesthesiology 119:1198-208|
|Sun, Yuan; Li, Xiang-Qi; Sahbaie, Peyman et al. (2012) miR-203 regulates nociceptive sensitization after incision by controlling phospholipase A2 activating protein expression. Anesthesiology 117:626-38|
|Sahbaie, Peyman; Shi, Xiaoyou; Li, Xiangqi et al. (2012) Preprotachykinin-A gene disruption attenuates nociceptive sensitivity after opioid administration and incision by peripheral and spinal mechanisms in mice. J Pain 13:997-1007|
|Sahbaie, Peyman; Li, Xiangqi; Shi, Xiaoyou et al. (2012) Roles of Gr-1+ leukocytes in postincisional nociceptive sensitization and inflammation. Anesthesiology 117:602-12|
|Liang, De-Yong; Li, XiangQi; Shi, Xiaoyu et al. (2012) The complement component C5a receptor mediates pain and inflammation in a postsurgical pain model. Pain 153:366-72|
|Li, Wen-Wu; Guo, Tian-Zhi; Liang, De-yong et al. (2012) Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat fracture model of complex regional pain syndrome. Anesthesiology 116:882-95|
|Jang, Jun H; Liang, Deyong; Kido, Kanta et al. (2011) Increased local concentration of complement C5a contributes to incisional pain in mice. J Neuroinflammation 8:80|
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