Objective：

Postoperative visceral pain and motility dysfunction are severe complications of colon surgery that delay recovery and compromise patient well-being. Here, we identify a distinct neuronal population in the rostral ventromedial medulla (RVM) that bidirectionally modulates intestinal function and pain perception. This finding offers novel mechanistic insights into the "medulla-gut" axis underlying these postoperative disorders.

Method：

Colorectal and small intestinal transit recordings, in vivo chemogenetic manipulation, in vivo electrophysiological recording, open field tests, gait analysis, retrograde trans-synaptic viral tracing, anterograde trans-monosynaptic viral tracing and immunohistochemistry.

Results：

We have reported that GPER is a marker for GABAergic ON cells; furthermore, we found that this population of neurons is extensively activated in the mouse model of colorectal surgery. Then, we observed that chemogenetic activation of GPER-positive neurons induced dual pathophysiological alterations in mice: (1) development of visceral hypersensitivity and (2) prolonged intestinal transit time. Furthermore, anterograde trans-monosynaptic viral tracing shows that RVM^GPER neurons achieve co-regulation of intestinal pain sensitivity and intestinal motility disorders through descending “dual projections” to the superficial laminae of the spinal cord dorsal horn (sensory transmission zone) and the ‌intermediolateral nucleus.

Conclusion：

These findings demonstrate that GPER-positive neurons in the RVM serve as a critical hub for the co-regulation of chronic postsurgical pain and persistent intestinal dysfunction following colon surgery. Specifically, we identify RVM^GPER neurons as a previously unrecognized neuronal population whose activation induces both visceral hypersensitivity and prolonged intestinal transit. Moreover, anterograde trans-monosynaptic viral tracing reveals that these neurons exert dual descending projections to the superficial laminae of the spinal dorsal horn and the anterior horn, thereby providing a mechanistic basis for the simultaneous modulation of sensory and motor components of postoperative gastrointestinal disorders. Our study elucidates a novel "medulla-spinal cord" pathway underlying the "medulla-gut" axis, and identifies GPER as a potential therapeutic target for managing both pain and motility dysfunction after colorectal surgery.