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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    643—Visceral Pain

    Tuesday, November 12, 2013, 1:00 pm - 5:00 pm

    643.24: Perioperative morphine administration prolongs post-operative pain: a role for TLR4 and inflammasome signaling

    Location: Halls B-H

    ">*E. L. GALER1, P. M. GRACE1, K. A. STRAND1, K. CORRIGAN1, D. BERKELHAMMER1, B. SKARDA1, K. C. RICE2, S. F. MAIER1, L. R. WATKINS1;
    1Psychology and Neurosci., Univ. of Colorado At Boulder, Boulder, CO; 2Chem. Biol., Natl. Inst. on Drug Abuse and Natl. Inst. on Alcohol Abuse and Alcoholism, Rockville, MD

    Abstract Body: Moderate to severe post-operative pain after surgery ranges from 25-76%. Opioids activate glia via Toll Like Receptor 4 (TLR4) initiating proinflammatory cytokine and chemokine release that have anti-analgesic effects against the classical opioid receptor mediated analgesia. Since opioids are front-line analgesics for pain of diverse etiology, it is of clinical interest to define if perioperative morphine exacerbates post-operative pain and mechanisms by which this may occur. We hypothesized that giving perioperative morphine to male Sprague-Dawley rats would prolong post-operative pain in a TLR4-inflammasome-dependent fashion. As morphine is not given clinically in the absence of pain, a glia-independent forepaw chronic pain (~4 wk) was induced in rats by injecting acidic saline (pH 4, 100 μL) twice at a 5 day interval in the right tricep, as this foreleg pain does not confound hindpaw testing. Morphine (5 mg/kg, n=6) or saline (n=6) was given sc for 2 wk, beginning 2 wk after the 1st acidic saline dose to simulate clinical treatment of ongoing forepaw pain. The day after the last morphine dose, laparotomy was conducted to model exploratory abdominal surgery. Von Frey testing of the hindpaws occurred at baseline, pre-surgery, and post-surgery at days 3, 7, 10, 14, and weekly thereafter. While hindpaw allodynia due to surgery resolved by 2 wk in rats receiving prior forepaw pain + saline, hindpaw allodynia persisted for 6 wk in rats whose forepaw pain was treated with morphine prior to surgery (P< 0.001). The above study was repeated, adding intrathecal osmotic mini-pumps to deliver the non-opioid TLR4 antagonist, (+)-naloxone (60 μg/h, n=6), or saline (n=6) for the last 9 days of morphine dosing. (+)-Naloxone abolished the morphine-potentiated post-operative pain, suggesting that TLR4 signaling during morphine exposure mediates the allodynia observed long after morphine cessation. To test if morphine would also amplify post-operative pain when given in the early post-trauma period, sc morphine (5 mg/kg, n=12) began 18 hr after laparotomy and continued for 1 wk. While surgical allodynia resolved by 2 wk in saline treated rats, allodynia persisted for 4 wk after surgery in rats given morphine (P<0.05). Post-surgery morphine increased gene expression of IL-1β (P<0.01), TNF-α (P<0.05), biglycan (P<0.001), MMP2 (P<0.01), P2X7 (P<0.05), caspase-1 (P<0.05), and decreased that of miR-223 (P<0.05), at 2 wk post surgery, suggesting a potential role for the inflammasome. These data suggest that morphine and the products of laparotomy may interact, resulting in paradoxical enhancement of post-operative pain.

    Lay Language Summary: Our findings show that morphine, a
    common painkiller, paradoxically prolongs pain when humanely prescribed to
    alleviate suffering after abdominal surgery in rats. Explaining this
    counter-intuitive result, we show that morphine exacerbates excitatory immune/glial
    signaling in spinal cord, overriding the pain-relieving actions of morphine.
    Importantly, we prevented prolonged
    pain after surgery by blocking morphine-induced immune/glial signaling.
    Narcotic opioids, like morphine, are the gold-standard painkillers for moderate
    to severe pain, like that related to surgery. Despite opioid treatment, up to
    76% of patients still experience moderate to severe pain after surgery. Our
    laboratory has shown that morphine not only acts on the electrical wiring of
    the body, the nerves, to relieve pain, but also activates immune/glial cells in
    the spinal cord. Once activated, the immune/glial cells release “pain signals”
    to the surrounding nerves. These cellular actions raise the possibility that
    opioids might not simply fail to relieve pain, but are contributing to the
    problem.
    Another research group previously found that morphine pre-treatment prolonged
    pain after surgery in rats, but mechanisms were not investigated, in contrast
    to our current study. While these findings have not yet been reported in human
    pain populations, a review of the literature indicates that this is a failure
    to explicitly test for the phenomenon, rather than an absence of the phenomenon
    per se. Opioid treatment could well be an unexpected, unappreciated, but
    critical, contributor to chronic pain in humans. Therefore, clinical studies
    are desperately needed
    to explore this alarming possibility, given the pervasive and virtually
    exclusive use of these drugs for early post-trauma pain control.
    In Study 1, we administered morphine to rats prior to surgery, modeling
    pre-surgical pain. After two weeks of pre-surgery pain, all rats received
    morphine for 5 days to “treat the pre-existing pain”. Rats either continued
    morphine treatment or were treated with saline for 9 days. All rats then
    received exploratory abdominal surgery to test if prior exposure to morphine
    influenced post-surgical pain, as anticipated. The rats that had received
    saline 9 days before surgery recovered normally, with pain resolving within 2
    weeks. In contrast, the pain did not resolve until 6 weeks after surgery for
    rats that had received morphine 9 days before surgery. Importantly, blocking
    morphine-induced immune/glial signaling with an inhibitor completely
    abolished prolonged pain, with rats being pain-free within 2 weeks of surgery.
    In Study 2, we treated acute pain after surgery with morphine, modeling
    post-surgical pain management. Exploratory abdominal surgery was conducted on
    rats followed by 7 days of morphine or saline. Rats receiving morphine took 4
    weeks to recover from surgical pain compared to saline treated rats that
    recovered normally after 2 weeks.
    Our research suggests that morphine, and likely other opioid painkillers,
    contribute to the high rate of enduring pain after surgery. The enhanced
    post-surgical pain is likely due to an immune/glial interaction between morphine and surgery, but can be prevented by avoiding
    morphine administration immediately preceding or following surgery, or
    (preferably) by blocking the immune/glial signaling of morphine at the innate
    immune receptor_Toll-Like Receptor 4_with the selective, non-opioid inhibitor,
    (+)-naloxone tested in Study 1. The efficacy of (+)-naloxone is exciting given that it is moving toward clinical trials.
    Our studies provide evidence for the role of morphine in prolonging
    post-surgical pain, and have been correlated with changes in gene expression
    along Toll-Like Receptor 4 and associated immune pathways in the spinal cord.
    Future work will determine how morphine and exploratory abdominal surgery
    activates these pathways, resulting in release of “pain signals”. This research
    may lead to a better understanding of factors that contribute to post-surgical
    pain and methods for prevention of post-surgical pain becoming chronic.