Reversal of the Development of Antinociceptive Effects to Chronic Morphine in Mice by Fecal Microbiota Transplantation (FMT)

Abstract

Morphine remains one of the most frequently prescribed drugs for the treatment of moderate to severe pain, including pain due to cancer or surgery. However, the long‐term use of this excellent pain reliever in man is limited by side‐effects that include analgesic tolerance, dependence and constipation. We have previously shown that depletion of gut bacteria by oral vancomycin results in the loss of antinociceptive tolerance, decreases epithelial permeability and reduces colonic inflammation by chronic morphine. The aim of this study was to investigate the effect of colonizing the gut with non‐opioid commensal microbiome on reversal of morphine‐induced antinociceptive tolerance. Gut bacteria were collected from 5 day placebo and morphine pelleted mice from fecal pellets designated as donor mice groups (PP‐FMT and MP‐FMT). The microbiome was then orally gavaged (1×109 cells/dose) daily for 5 days to placebo (PP) and morphine (MP) pelleted (75 mg pellet, 5 days) recipient mice groups, and the presence of antinociceptive tolerance was determined by morphine challenge (10 mg/kg, s.c.) in the tail immersion and hot plate tests. Daily gavage of the microbiome from morphine pelleted mice to the morphine‐pelleted recipient mice (MP+MP‐FMT) resulted in antinociceptive tolerance to morphine challenge. However, gavage of the microbiome from placebo pelleted donor mice to the morphine pelleted recipient mice (PP+MP‐FMT), prevented the development of antinociceptive tolerance. We further investigated whether an exogenous microbiome could reverse chronic morphine induced antinociceptive tolerance development. In these studies, oral gavage of gut microbiome was commenced after development of tolerance to morphine. Similar to the induction of tolerance, oral gavage of placebo microbiome to morphine tolerant mice (MP+PP‐FMT) reversed antinociceptive tolerance. In order to determine if transplantation of the gut microbiome also prevents the loss of epithelial integrity by chronic morphine treatment, intestinal permeability was measured by oral administration of FITC (Fluorescein isothiocyanate)‐dextran (44 mg/kg, p.o.) in placebo or morphine pelleted mice for 5 days. FITC levels were significantly higher in morphine pelleted mice (MP) treated with the microbiome from morphine donors (MP‐FMT) than placebo pelleted controls (PP, p<0.0001). However, the epithelial integrity was maintained in morphine pelleted mice (MP) treated with the commensal microbiome from placebo donors (PP‐FMT). These studies define a novel microbiome‐gut‐brain interaction in the development of opioid tolerance.Support or Funding InformationNIH R01 DA036975 and NIH T32 DA007027This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.