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 up-regulated 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 NGF levels after incision, an effect entirely dependent upon intact SP signaling. Additionally, SP dependent up-regulation 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.

Liquid chromatography-electrospray linear ion trap mass spectrometry analysis of targeted neuropeptides in Tac1−/− mouse spinal cords reveals significant lower concentration of opioid peptides

“…SP induced Ca 2+ mobilization is highly correlated with NK1 receptor activation, induction and internalization in the dorsal horn [Sahbaie et al, 2012]. The Ca 2+ influx and NK1 internalization induces an increase of the expression of δ and µ-opioid receptors but not κ-opioid receptor [Aimone andYaksh 1989, Yaksh 1988].…”

Opioids Enhance CXCL1 Expression and Function After Incision in Mice

“…Mice received subcutaneous morphine (Sigma Chemical, St. Louis, MO) injections twice per day on an ascending schedule: day 1, 10 mg/kg; day 2, 20 mg/kg; day 3, 30 mg/kg and day 4, 40 mg/kg in 50 μl to 100 μl volumes as described previously 37 . Saline vehicle injections in control animals followed the same twice daily schedule.…”

“…Incision and nociceptive testing procedures began approximately 18 hours after the final dose of morphine or saline. This morphine administration protocol has been used extensively by the lab in studying opioid tolerance, dependence and hyperalgesia 22, 23, 37 .…”

“…For example, Chapman et al showed that chronic pain patients receiving prolonged opioid therapy showed more intense acute postoperative pain compared with chronic pain patients without histories of opioid pharmacotherapy 7 . Moreover, several groups have studied the interaction of chronic opioid administration and surgical incision in rodent models generally concluding that perioperative opioid exposure worsens thermal, punctate and pressure-related nociceptive sensitization 3, 21, 22, 37 . Our group reported that chronic morphine treatment prior to incision leads to excess production of wound area cytokines thus providing one potential mechanism whereby preoperative opioid exposure worsens postoperative pain 22 .…”

“…The modification of histone proteins, DNA methylation and microRNA regulation are well-known mechanisms of epigenetic regulation that influence gene expression. Since our previous studies demonstrated that epigenetic mechanisms play a crucial role in opioid-induced hyperalgesia 23 , and chronic opioid exposure leads to the enhanced local expression of chemokines after incision 22, 37 , we hypothesized that the epigenetic regulation of CXCL1 and its cognate CXCR2 receptor near incisional wounds may lead to the enhanced activity of this pain-related signaling pathway. The current study, therefore, was designed to investigate the role of CXCL1/CXCR2 signaling in opioid-enhanced incisional sensitization.…”