The effect of gut microbiome on tolerance to morphine mediated antinociception in mice

Abstract

There is growing appreciation for the importance of gastrointestinal microbiota in many physiological and pathophysiological processes. While morphine and other narcotics are the most widely prescribed therapy for moderate to severe pain clinically, they have been noted to alter microbial composition and promote bacterial translocation to other tissues. Here we examined the pharmacodynamic properties of chronic morphine in mice following bacterial depletion with oral gavage of an antibiotic cocktail (ABX). ABX significantly reduced gut bacteria and prevented chronic morphine induced increases in gut permeability, colonic mucosal destruction, and colonic IL-1β expression. In addition, ABX prevented the development of antinociceptive tolerance to chronic morphine in both the tail-immersion and acetic acid stretch assays. Morphine tolerance was also reduced by oral vancomycin that has 0% bioavailability. These findings were recapitulated in primary afferent neurons isolated from dorsal root ganglia (DRG) innervating the lower gastrointestinal tract, wherein in-vivo administration of ABX prevented tolerance to morphine-induced hypoexcitability. Finally, though ABX repeatedly demonstrated an ability to prevent tolerance, we show that it did not alter susceptibility to precipitation of withdrawal by naloxone. Collectively, these finding indicate that the gastrointestinal microbiome is an important modulator of physiological responses induced by chronic morphine administration.

Connexin‐purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation

“…Morphine causes bacterial dysbiosis in the gut lumen and translocation of intestinal bacteria to extraintestinal organs (10, 27, 28). We have recently shown that long‐term morphine exposure via 5 d pellet implantation in mice induces alterations of bacterial composition and compromises GI epithelial tight junction integrity, promoting secondary gut wall inflammation and bacterial translocation (9). To determine the effect of gut bacterial products on activation of enteric glia, ATP currents were measured from glia pretreated with LPS for 16 h. In the enteric glial cell line CRL2690, the peak amplitude of ATP‐induced inward current was 0.94 ± 0.22 pA/pF ( n = 17) in control/untreated glia, 3 ± 1.14 pA/pF ( n = 10) in glia treated with 1 μg/ml LPS, 4.73 ± 1.51 pA/pF ( n = 8) in glia treated with 10 μg/ml LPS, and 7.89 ± 1.38 pA/pF ( n = 10) in glia treated with 100 μg/ml LPS.…”

“…Prolonged exposure to morphine also causes immune dysregulation, thus increasing susceptibility to infection, not only in the GI tract but also systemically, initiating secondary inflammation (8). Recently, we (9) and others (10) have shown that prolonged morphine exposure compromises gut epithelial barrier function, induces bacterial dysbiosis and translocation of bacteria to extraintestinal organs. This effect results in colonic inflammation and disorganization of the epithelial tight junction proteins occludin and zonula occludens‐1 (10).…”

The gut–brain interaction in opioid tolerance

“…The increased risk of infection can arise from bacterial translocation in the colon and lead to sepsis (21) and immune dysregulation that occurs not only in the GI tract but also systemically (22). Recent studies show that chronic opioid use is associated with microbial dysbiosis in man (23, 24)} and mice (25–27). The disruption of gut epithelial barrier by chronic morphine in mice enhances “leakiness” allowing for bacterial translocation in ileum (26) and in colon (27).…”

“…Recent studies show that chronic opioid use is associated with microbial dysbiosis in man (23, 24)} and mice (25–27). The disruption of gut epithelial barrier by chronic morphine in mice enhances “leakiness” allowing for bacterial translocation in ileum (26) and in colon (27). Meng et al (26) reported disruption of the gut epithelial barrier as a result of morphine mediated activation of the toll-like receptors (TLR) on the epithelial cells, allowing for bacterial products to translocate.…”

“…Treatment of mice with oral gavage of an antibiotic cocktail prevented the development of antinociceptive tolerance to chronic morphine in mice (27). Further analysis of individual antibiotics showed that oral vancomycin, which has poor bioavailability (33), was sufficient to prevent tolerance, suggesting that the microbial translocation, specifically Gram – positive bacteria from the gut lumen is intricately involved in this process.…”