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

## TL;DR

The study identifies a brain-gut circuit in mice that causes constipation from morphine and suggests ways to potentially treat this side effect.

## Contribution

The discovery of a specific brain-to-intestine neural circuit responsible for morphine-induced constipation in mice.

## Key findings

- Morphine inhibits a PVNGlu→DMVAch→small intestine circuit, reducing intestinal motility.
- Activating or blocking μ-opioid receptors in PVNGlu neurons alleviates morphine-induced constipation.
- Morphine suppresses NMDA receptor activity in DMVAch neurons, contributing to constipation.

## 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 (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.

Neural mechanisms mediating opioid-induced constipation are not fully understood. Here authors find that morphine-induced constipation is mediated by a neural circuit from the paraventricular nucleus of hypothalamus to the dorsal motor nucleus of the vagus, and subsequently to the small intestine in male mice.