Opioid-induced hyperalgesia (OIH) is a complication of pain treatment where opioids paradoxically increase pain sensitivity. Using a mouse model, about 60% of mice developed OIH after three days of morphine, shown by abnormal movement and anxiety-like behaviors. Mice whose gut microbiota were eliminated with antibiotics did not develop hyperalgesia, but those receiving fecal transplants from OIH mice did. S-ketamine, but not R-ketamine, prevented OIH. Gut microbiota analysis revealed increased Enterobacteriaceae in OIH-susceptible mice, which decreased after S-ketamine treatment. The findings suggest S-ketamine alleviates morphine-induced OIH by reducing gut Enterobacteriaceae levels.
In a mouse model of depression induced by lipopolysaccharide, CD38 expression increased in the hippocampus and cortex. Pharmacological inhibition or genetic knockout of CD38 reduced neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, and improved depression-like behaviors. Optogenetic activation of glutamatergic neurons in the hippocampal CA3 region reduced depression susceptibility and lowered CD38 expression. The antidepressant (R)-ketamine suppressed CD38 expression and reversed synaptic defects. Hippocampal CD38 is closely linked to depressive behaviors in this inflammation model, suggesting it as a potential therapeutic target.