The Effect of Colonic Inflammation on Morphine Induced Antinociceptive Tolerance

Abstract

Opioids are one of the most widely prescribed classes of drugs for the treatment of moderate to severe pain. Opioids are prescribed for abdominal pain, a major symptom associated with Crohn's Disease. Recent studies have reported that continued opioid use in patients with Crohn's Disease is associated with increased mortality rate, duration and severity of disease, as well as infection. However, it is not clear if this association is causal. We have previously demonstrated that chronic use of morphine, in addition to the development of antinociceptive tolerance, also causes the disruption of the intestinal barrier function resulting in bacterial translocation from the gut lumen into the peritoneal organs, thus inducing an inflammatory response in the colon. Therefore, we tested if inflammation in the colon, as in Crohn's disease, affects the rate of antinociceptive tolerance development to morphine. To test this hypothesis, we induced colonic inflammation in Swiss Webster male mice using 2,4,6‐trinitro‐benzene sulfonic acid (TNBS) or vehicle intrarectally and then surgically implanted 25 mg, 50 mg (2 × 25 mg), or 75 mg slow release morphine pellets or placebo pellets subcutaneously on the dorsum. Tail immersion assay was performed on day 3, 4, and 5 post treatment and colons were extracted from the animals to measure mRNA expression of Interleukin 1 beta (IL‐1β) and tumor necrosis factor alpha (TNF‐α) by real‐time polymerase chain reaction (RT‐PCR). A morphine (10 mg/kg) challenge was used to test for the development of antinociceptive tolerance at various times in morphine pelleted with (n= 7) or without TNBS (n= 5). In TNBS + morphine pelleted mice, tolerance developed by day 5 in 25 mg morphine pelleted mice, by day 4 in 50 mg (2 × 25 mg) morphine pelleted mice, and as early as day 2 in 75 mg morphine pelleted mice. In the absence of TNBS‐induced inflammation, tolerance to morphine did not develop to either 25 mg or 50 mg morphine pellets up to day 5, and at day 4 in 75 mg morphine pellets. Furthermore, IL‐1β production was significantly increased in the morphine and placebo pelleted treated animals with TNBS from day 1 compared to the vehicle treated groups. In summary, chronic morphine administration in the presence of colonic inflammation leads to an increased rate and extent of antinociceptive tolerance development.Support or Funding InformationAgency: NIDA Agency Number: 5R01DA036975‐04This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.