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Papers of the Week

Papers: 29 Jun 2019 - 5 Jul 2019

Animal Studies, Pharmacology/Drug Development

2019 Sep

J Pharmacol Exp Ther



Experimental colitis enhances the rate of antinociceptive tolerance to morphine via peripheral opioid receptors.


Komla E, Stevens DL, Zheng Y, Zhang Y, Dewey WL, Akbarali HI
J Pharmacol Exp Ther. 2019 Sep; 370(3):504-513.
PMID: 31248978.


Opioids are highly effective analgesics, however their therapeutic use is limited by adverse effects that include respiratory depression, dependence, and tolerance. Inflammation has been implicated as a significant driver for the development of tolerance to opioids. Recent studies show that chronic morphine in mice results in gut microbial dysbiosis and inflammation in the colon. In the present study we examined whether colonic inflammation results in tolerance to the antinociceptive effects of morphine. Colonic inflammation was induced in mice by intrarectal administration of 2,4,6-trinitro-benzene sulfonic acid (TNBS). The development of antinociceptive tolerance was determined by warm-water tail-immersion assay in mice implanted with 25 mg, 50 mg or 75 mg morphine pellet. Colonic inflammation significantly enhanced the rate at which tolerance developed in each cohort of chronic morphine treated mice. At the lowest dose of morphine pellet (25 mg), antinociceptive tolerance only developed in the presence of colonic inflammation; whereas, in 50 mg and 75 mg pelleted mice, tolerance developed faster in the inflamed animals than the non-inflamed mice. The enhanced antinociceptive tolerance was attenuated with daily administration of peripheral opioid receptor antagonist, 6β-N-heterocyclic substituted naltrexamine derivative (NAP), irrespective of colonic inflammation. Collectively, these findings show that the rate of tolerance to morphine antinociception is exaggerated in the presence of colonic inflammation and tolerance is prevented by a peripheral mu-opioid receptor antagonist. These studies suggest a peripheral component to the development of antinociceptive tolerance to opioids. Furthermore, peripherally selective opioid antagonists may be useful adjuncts in opioid based pain management. SIGNIFICANCE STATEMENT: Our study supports the notion that inflammation influences the development of antinociceptive tolerance to chronic morphine exposure. We found that as the dose of morphine increased in the presence of colonic inflammation, the more tolerant the mice became to the antinociceptive effects of morphine. We also found that treatment with a peripheral opioid receptor antagonist prevented morphine antinociceptive tolerance. By increasing opioid intake during an inflammatory state would result in decreased analgesia and enhanced analgesic tolerance, which puts patients with inflammatory bowel diseases, inflammatory joint diseases, and sickle cell anemia at risk for a heavy opioid use.