Preprotachykinin-A Gene Disruption Attenuates Nociceptive Sensitivity After Opioid Administration and Incision by Peripheral and Spinal Mechanisms in Mice

JOURNAL OF PAIN

卷:13

Article

Sahbaie, Peyman^1,2  Shi, Xiaoyou^1,2  Li, Xiangqi^1,2  Liang, Deyong^1,2  Guo, Tian-Zhi^3,4  Qiao, Yanli²  Yeomans, David C.²  Kingery, Wade S.^3,4  Clark, J. David^1,2 

[1] VAPAHCS, Anesthesiol Serv 112 A, Palo Alto, CA 94304 USA

[2] Stanford Univ, Dept Anesthesia, Sch Med, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Orthoped Surg, Sch Med, Stanford, CA 94305 USA

[4] VAPAHCS, Phys Med & Rehabil Serv 117, Palo Alto, CA 94304 USA

关键词: Cytokines;    NGF;    substance P;    opioid-induced hyperalgesia;    skin incision;   

DOI  :  10.1016/j.jpain.2012.07.009

来源: Elsevier

【 摘 要 】

The preprotachykinin A gene (ppt-A) codes for Substance P (SP), supports nociceptive sensitization, and modulates inflammatory responses after incision. Repeated opioid use produces paradoxical pain sensitization termed opioid-induced hyperalgesia (OIH) which can exacerbate pain after incision. Here the contribution of SP to peri-incisional nociceptive sensitization and nociceptive mediator production after opioid treatment was examined utilizing ppt-A knockout (-/-) mice and the neurokinin (NK1) receptor antagonist LY303870. Less mechanical allodynia was observed in ppt-A(-/-) mice compared to wild types (wt) after morphine treatment both before and after incision. Moreover, LY303870 administered with morphine reduced incisional hyperalgesia in wt mice. Incision after saline or escalating morphine treatment upregulated skin IL-1 beta, IL-6, G-CSF and MIP-1 alpha levels in ppt-A(-/-) and wt mice similarly. However, chronic morphine treatment greatly exacerbated increases in skin nerve growth factor levels after incision, an effect entirely dependent upon intact SP signaling. Additionally, SP dependent upregulation of prodynorphin, NMDA1 and NK1 receptor expression in spinal cord was seen after morphine treatment and incision. A similar pattern was seen for 5-HT3 receptor expression in tissue from dorsal root ganglia. Therefore, SP may work at both central and peripheral sites to enhance nociceptive sensitization after morphine treatment and incision. Perspective: These studies show that SP signaling modulates enhanced nerve growth factor production and changes in neuronal gene expression seen after incision in mice previously exposed to morphine. (C) 2012 by the American Pain Society

【 授权许可】

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