Treating abdominal pain caused by intestinal inflammation remains challenging due to the poor understanding of the underlying mechanisms. Pioneering research conducted at Michigan State University (MSU) has shed light on the causative factors contributing to visceral pain, particularly in individuals who have undergone gut inflammation, such as those afflicted by irritable bowel syndrome (IBS). The investigative approach, utilizing mouse models, delineates the pivotal role of glia, a subtype of nervous system cells, in increasing the propensity of adjacent neurons to convey pain signals following an inflammatory event. The study published in the journal Science Signaling suggests that the glia’s role in reducing the activation threshold of neurons could explain the increased sensitivity to pain.
The study aimed to test the hypothesis that enteric glia regulates the sensitivity of nociceptive nerve terminals in the intestine, leading to visceral hypersensitivity. Using glial-specific perturbations, the team assessed the impact of glial signaling on nociceptor sensitivity in both healthy and inflamed contexts. The research emphasizes the critical distinction between nociception (nervous system signals in response to physical stimuli) and pain when translating results from animal studies to human applications.
The study by Morales-Soto et al. unveiled the role of enteric glia in visceral hypersensitivity and the potential for developing therapies that target glia to alleviate or eliminate visceral pain. Focusing on the enteric nervous system, often referred to as the ‘second brain,’ the research revealed that glial cells in the gut, previously underestimated for their perceived lack of electrical activity, are indeed chemically active. Employing advanced tools and techniques, the researchers observed the behavior of glial cells before and after gut inflammation, discovering that inflammation prompts glia to release compounds that alter gut chemistry and sensitize nerve fibers. This process contributes to heightened pain sensitivity.
The research underscores the complexity of treating visceral pain due to an incomplete understanding of causal mechanisms. It highlights that enteric glia sensitizes intestinal nociceptors through intercellular signaling mechanisms triggered by inflammation. While normal glial signaling does not impact nociceptor sensitivity in health, it plays a significant role in sensitizing afferents during inflammation. The underlying mechanisms involve facilitating the effects of proinflammatory cytokines on glial Cx43 hemichannels, an upregulation of glial cyclooxygenase-2(COX-2), and an increase in stimulated glial prostaglandin E2(PGE2) release, which acts on EP4 receptors. These glial mechanisms offer insights into promoting visceral pain at the site of transduction, opening avenues for further exploration.
The study prompts further investigation into gender disparities in visceral pain and the influence of early life adversity, stress, and trauma on pain susceptibility. Gaining a deeper understanding of the role of glia in both scenarios could pave the way for innovative approaches to the treatment of gut pain.
Reference
Morales-Soto W, Gonzales J, Jackson WF, Gulbransen BD. Enteric glia promote visceral hypersensitivity during inflammation through intercellular signaling with gut nociceptors. Sci Signal. 2023 Nov 21;16(812):eadg1668.