An enteric-DRG pathway for interoception and visceral pain in mice

Sensory afferents are major interoceptive pathways for organ-brain communication. Within the distal colon, dorsal root ganglia (DRGs) afferents regulate key gut physiology. Inflammation causes hypersensitivity of DRG pathways, leading to visceral pain. However, whether enteric neurons contribute to interoception and visceral pain remains unclear. Here, we surveyed the DRG innervation along the gastrointestinal tract in mice and found extensive associations between DRG terminals and enteric neurons. Optogenetic activation of different DRG terminals in the distal colon elicited variable degrees of behavioral responses, but only designated subpopulations induced aversion. Notably, optogenetic activation of colon cholinergic, but not nitrergic, enteric neurons signaled through the DRG-spinal pathway to evoke a non-aversive nociceptive-like reflex. Acetylcholine is part of the enteric-DRG signaling. Remarkably, inflammation shifted the nature of the enteric-DRG pathway from non-aversive to aversive. These findings expand the previous understanding of DRG-mediated visceral sensation, highlighting the contribution of enteric neuron-DRG communication to inflammation-induced visceral pain.