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- Title
Enteric glia promote visceral hypersensitivity during inflammation through intercellular signaling with gut nociceptors.
- Authors
Morales-Soto, Wilmarie; Gonzales, Jacques; Jackson, William F.; Gulbransen, Brian D.
- Abstract
Inflammation in the intestines causes abdominal pain that is challenging to manage. The terminals of sensory neurons innervating the gut are surrounded by glia. Here, using a mouse model of acute colitis, we found that enteric glia contribute to visceral pain by secreting factors that sensitized sensory nerves innervating the gut in response to inflammation. Acute colitis induced a transient increase in the production of proinflammatory cytokines in the intestines of male and female mice. Of these, IL-1β was produced in part by glia and augmented the opening of the intercellular communication hemichannel connexin-43 in glia, which made normally innocuous stimuli painful in female mice. Chemogenetic glial activation paired with calcium imaging in nerve terminals demonstrated that glia sensitized gut-innervating nociceptors only under inflammatory conditions. This inflammatory, glial-driven visceral hypersensitivity involved an increased abundance of the enzyme COX-2 in glia, resulting in greater production and release of prostaglandin E2 that activated EP4 receptors on sensory nerve terminals. Blocking EP4 receptors reduced nociceptor sensitivity in response to glial stimulation in tissue samples from colitis-model mice, and impairing glial connexin-43 reduced visceral hypersensitivity induced by IL-1β in female mice. The findings suggest that therapies targeting enteric glial–neuron signaling might alleviate visceral pain caused by inflammatory disorders. Editor's summary: The pain associated with gut inflammation can be debilitating, chronic, and difficult to manage. Morales-Soto et al. found that local glial cells may be major contributors to this inflammatory pain. Inducing inflammation in the gut in mice provoked enteric glia to secrete prostaglandin E2, which activated receptors on gut-innervating sensory neurons that sensitized the neurons to stimuli that were otherwise not noxious. Activating the glia in the absence of inflammation did not stimulate neurons or produce visceral pain. The findings reveal a cellular and molecular source of pain in the intestines that is specifically inflammation associated and that may be therapeutically targetable. —Leslie K. Ferrarelli
- Subjects
VISCERAL pain; NOCICEPTORS; INFLAMMATORY bowel diseases; NERVE endings; SENSORY receptors; SENSORY neurons
- Publication
Science Signaling, 2023, Vol 16, Issue 812, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.adg1668