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Chronic opioids produce tolerance to analgesic but not constipating effects.Chronic opioids can worsen GI diseases.The gut microbial diversity is altered with chronic opioids in man and mice.Changes in the microbiome alter neuronal tolerance in extrinsic sensory afferents.The gastrointestinal microbiome may mediate opioid tolerance to analgesia.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.