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

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-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.

• Authors: Peyman Sahbaie, Xiaoyou Shi, Tian-Zhi Guo, Yanli Qiao, David C Yeomans, Wade S Kingery, David J Clark
• Journal: Pain (Pain) Vol. 145 Issue 3 Pg. 341-349 (Oct 2009) ISSN: 1872-6623 [Electronic] United States
• PMID: 19660865 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane
• Cytokines
• Indoles
• Neurokinin-1 Receptor Antagonists
• Piperidines
• Protein Precursors
• Tachykinins
• preprotachykinin
• Substance P
• Nerve Growth Factor

Topics

• Analysis of Variance
• Animals
• Cytokines (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects, genetics)
• Hyperalgesia (drug therapy, physiopathology)
• Indoles (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nerve Growth Factor (metabolism)
• Neurokinin-1 Receptor Antagonists
• Pain Measurement (methods)
• Pain Threshold (drug effects, physiology)
• Pain, Postoperative (metabolism, physiopathology)
• Piperidines (pharmacology)
• Protein Precursors (deficiency)
• Signal Transduction (drug effects, genetics, physiology)
• Substance P (metabolism)
• Tachykinins (deficiency)
• Time Factors