title: Preprotachykinin-A gene disruption attenuates nociceptive sensitivity after opioid administration and incision by peripheral and spinal mechanisms in mice.
abstract: 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-1β, IL-6, G-CSF and MIP-1α 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA. psahbaie@stanford.edu
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.forename: Xiaoyou
authors.initials: X
authors.lastname: Shi
authors.forename: Xiangqi
authors.initials: X
authors.lastname: Li
authors.forename: Deyong
authors.initials: D
authors.lastname: Liang
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Guo
authors.forename: Yanli
authors.initials: Y
authors.lastname: Qiao
authors.forename: David C
authors.initials: DC
authors.lastname: Yeomans
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.forename: J
authors.initials: J
authors.lastname: David Clark
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D054405:Chemokine CCL3 / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D010146:Pain / Q000235:genetics* / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*; D015320:Tachykinins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C096759:1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane; D000701:Analgesics, Opioid; D054405:Chemokine CCL3; D007211:Indoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011498:Protein Precursors; D015320:Tachykinins; C044206:preprotachykinin; D016179:Granulocyte Colony-Stimulating Factor; D009020:Morphine