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

Abstract 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 (PVN Glu ) to acetylcholinergic neurons in the dorsal motor nucleus of the vagus (DMV Ach ), and subsequently to the small intestine in mice. Microendoscopic calcium imaging revealed morphine inhibits the PVN Glu →DMV Ach →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 PVN Glu 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 DMV Ach neurons. These findings reveal a brain-gut circuit underlying opioid-induced constipation and suggest potential therapeutic strategies to mitigate this debilitating side effect.