Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision.
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-alpha and KC levels but not IL-1beta after 2h in the wt mice skin. However, ppt-A(-/-) mice had more skin NGF levels 2h post-incision. Subcutaneous hind paw SP injection produced acute and transient elevations of IL-1beta, IL-6, and KC but modest elevations in TNF-alpha 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.
Sahbaie
Peyman
P
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Anesthesiology Service (112-A), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, CA, USA Physical Medicine and Rehabilitation Service (117), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
Shi
Xiaoyou
X
Guo
Tian-Zhi
TZ
Qiao
Yanli
Y
Yeomans
David C
DC
Kingery
Wade S
WS
Clark
David J
DJ
D000704:Analysis of Variance; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010149:Postoperative Pain / Q000378:metabolism* / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013373:Substance P / Q000378:metabolism*; D015320:Tachykinins / Q000172:deficiency; D013997:Time Factors
C096759:1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane; D016207:Cytokines; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011498:Protein Precursors; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; D020932:Nerve Growth Factor