A brain-to-small intestine circuit mediates morphine-induced constipation in male mice.

Opioid-induced constipation is one of the most common and persistent side effect of opioid analgesics, yet the underlying neural mechanism(s) remain unclear. Here we show morphine-induced constipation is mediated by a neural circuit from glutamatergic neurons in the paraventricular nucleus of hypothalamus (PVNGlu) to acetylcholinergic neurons in the dorsal motor nucleus of the vagus (DMVAch), and subsequently to the small intestine in mice. Microendoscopic calcium imaging revealed morphine inhibits the PVNGlu→DMVAch→small intestine circuit, and this is accompanied by decreased small intestinal motility. Chemogenetic activation of this circuit, as well as pharmacological inhibition or knockdown of the μ-opioid receptor (MOR) in PVNGlu neurons alleviates morphine-induced constipation. Conversely, artificial inhibition of this circuit mimics morphine-induced constipation in naïve mice. Moreover, we show that morphine suppresses tonic NMDA receptor-mediated currents in DMVAch neurons. These findings reveal a brain-gut circuit underlying opioid-induced constipation and suggest potential therapeutic strategies to mitigate this debilitating side effect.