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Preprotachykinin-A Gene Disruption Attenuates Nociceptive Sensitivity After Opioid Administration and Incision by Peripheral and Spinal Mechanisms in Mice

  • Peyman Sahbaie
    Correspondence
    Address reprint requests to Peyman Sahbaie, MD, Veterans Administration Palo Alto Health Care System (VAPAHCS), 3801 Miranda Ave, 112-A, Palo Alto, CA 94304.
    Affiliations
    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
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  • Xiaoyou Shi
    Affiliations
    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
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  • Xiangqi Li
    Affiliations
    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
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  • Deyong Liang
    Affiliations
    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
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  • Tian-Zhi Guo
    Affiliations
    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
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  • Yanli Qiao
    Affiliations
    Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA
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  • David C. Yeomans
    Affiliations
    Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA
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  • Wade S. Kingery
    Affiliations
    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
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  • J. David Clark
    Affiliations
    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
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      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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