Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation
PainSci summary of Grace 2016?This page is one of thousands in the PainScience.com bibliography. It is not a general article: it is focused on a single scientific paper, and it may provide only just enough context for the summary to make sense. Links to other papers and more general information are provided at the bottom of the page, as often as possible. ★★★☆☆?3-star ratings are for typical studies with no more (or less) than the usual common problems. Ratings are a highly subjective opinion, and subject to revision at any time. If you think this paper has been incorrectly rated, please let me know.
This rat study demonstrated that opioids can actually cause chronic pain rather than treating it. In rats, anyway. Obviously replication in human studies is needed.
original abstract†Abstracts here may not perfectly match originals, for a variety of technical and practical reasons. Some abstacts are truncated for my purposes here, if they are particularly long-winded and unhelpful. I occasionally add clarifying notes. And I make some minor corrections.
Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.
related content
- “A comprehensive review of opioid-induced hyperalgesia,” Marion Lee, Sanford M Silverman, Hans Hansen, Vikram B Patel, and Laxmaiah Manchikanti, Pain Physician, 2011.
- “Who Benefits from Chronic Opioid Therapy? Rethinking the Question of Opioid Misuse Risk,” Elizabeth Huber, Richard C Robinson, Carl E Noe, and Olivia Van Ness, Healthcare (Basel), 2016.
These four articles on PainScience.com cite Grace 2016 as a source:
- Trigger Points & Myofascial Pain Syndrome — A guide to the unfinished science of muscle pain, with reviews of every theory and self-treatment and therapy option
- Frozen Shoulder Guide — An extremely detailed & readable guide to one of the strangest of all common musculoskeletal problems, for both patients and pros
- Opioids for Chronic Aches & Pains — The nuclear option: “Hillbilly heroin” (Oxycontin), codeine and other opioids for musculoskeletal problems like neck and back pain
- A Rational Guide to Fibromyalgia — The science of the mysterious disease of pain, exhaustion, and mental fog
This page is part of the PainScience BIBLIOGRAPHY, which contains plain language summaries of thousands of scientific papers & others sources. It’s like a highly specialized blog. A few highlights:
- Effectiveness of customised foot orthoses for Achilles tendinopathy: a randomised controlled trial. Munteanu 2015 Br J Sports Med.
- A Bayesian model-averaged meta-analysis of the power pose effect with informed and default priors: the case of felt power. Gronau 2017 Comprehensive Results in Social Psychology.
- The neck and headaches. Bogduk 2014 Neurol Clin.
- Agreement of self-reported items and clinically assessed nerve root involvement (or sciatica) in a primary care setting. Konstantinou 2012 Eur Spine J.
- Effect of NSAIDs on Recovery From Acute Skeletal Muscle Injury: A Systematic Review and Meta-analysis. Morelli 2017 Am J Sports Med.