Longitudinal and Concurrent Changes in Brain and Gut due to Morphine Self-Administration

Abstract

Opioid agonists are known for their effects on the opioid and dopaminergic systems; however, new research points to complementary changes in the gut underlying maladaptive changes associated with opioid use. The gut–brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders, but the spatiotemporal correspondence between quantitative translational measures of gut and brain health is not clear. In this work, we determined longitudinal and concurrent changes in the brain and gut of rodents trained to self-administer morphine for 14 days. Active lever presses delivered a single infusion of morphine (0.4 mg/kg/infusion). We used MRI and 16s rDNA analysis of faecal matter to identify changes from baseline (naïve, nondrug state) to an acute phase (early in the self-administration process, after 2 days of self-administration) and a chronic phase (late in the self-administration process, after 14 days of self-administration). Animals were scanned in a 7T MRI scanner three times (baseline, acute and chronic), and before scanning, faecal matter was collected from each rat. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum and thalamus. We posit that gut changes precede the effects observed in MRI, with the striatum and thalamus emerging as crucial links mediating communication between the gut and the brain.