The gut-brain interaction in opioid tolerance

Abstract

The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function.

Figure 1

Schema of gut-brain interaction through the dorsal root ganglia neurons. The gut microbiome is altered in the presence of chronic morphine. Bacterial translocation due to disruption of the epithelial barrier results in activation of TLR’s on enteric glia increasing connexin43 and P2X expression. Cytokines (Inflammatory soup) released from glia affect extrinsic sensory afferents whose cell bodies lie within the dorsal root ganglia (DRG) and induce tolerance to opioids.