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Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision

Sahbaie, Peymana,b,*; Shi, Xiaoyoua,b; Guo, Tian-Zhic,d; Qiao, Yanlia; Yeomans, David C.a; Kingery, Wade S.c,d; Clark, David J.a,b

doi: 10.1016/j.pain.2009.06.037

ABSTRACT Substance P (SP) signaling facilitates nociceptive sensitization in various inflammatory and chronic pain models and we postulated that SP signaling might also contribute to the development of post-incisional hyperalgesia. These studies used mice with a deletion of the pre-protachykinin A gene (ppt-A−/−) which codes for SP to determine the role of SP signaling in post-incisional pain and in the increased cytokine and nerve growth factor (NGF) expression observed in the incised skin. SP deficient ppt-A−/− mice displayed reduced mechanical allodynia and heat hyperalgesia compared to the wild-type (wt) mice at all post-incision time points, despite similar baseline values (p < 0.001). Furthermore, the NK-1 receptor antagonist LY303870 attenuated mechanical allodynia produced by incision in the wt mice (p < 0.001). Incision also up-regulated IL-6, TNF-α and KC levels but not IL-1β after 2 h in the wt mice skin. However, ppt-A−/− mice had more skin NGF levels 2 h post-incision. Subcutaneous hind paw SP injection produced acute and transient elevations of IL-1β, IL-6, and KC but modest elevations in TNF-α levels in the wt mice. Systemic LY303870 reversed the SP-induced elevations of these cytokines. Hind paw injection of IL-6 and NGF dose dependently produced less mechanical allodynia in the ppt-A−/− compared to wt mice. Additionally, SP produced mechanical allodynia in a dose-dependent fashion in wt mice. Therefore, SP supports nociceptive sensitization after hind paw incision and potentially participates directly in modulating the intensity of inflammatory response in peri-incisional tissue.

aDepartment of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA

bAnesthesiology Service (112-A), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

cDepartment of Orthopedic Surgery, Stanford University School of Medicine, Stanford, CA, USA

dPhysical Medicine and Rehabilitation Service (117), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

*Corresponding author. Address: Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue (112-A), Palo Alto, CA, USA. Tel.: +1 650 493 5000x65413; fax: +1 650 852 3423.


Received November 22, 2008; Received in revised form June 25, 2009; Accepted June 30, 2009.

© 2009 Lippincott Williams & Wilkins, Inc.
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