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.
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.
Key words
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Article info
Publication history
Accepted:
July 20,
2012
Received in revised form:
June 30,
2012
Received:
January 13,
2012
Footnotes
This work was supported by NIH grants DA021332 and GM079126. The authors do not have financial or other relationships that might lead to a conflict of interest.
Identification
Copyright
© 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.
