Endocannabinoids regulate enteric neuron–glia networks and visceral hypersensitivity following inflammation through a glial‐dependent mechanism

• Published in: Glia 2024-11, Vol.72 (11), p.2095-2114
• Main Authors: Morales‐Soto, Wilmarie, Thomasi, Beatriz, Gulbransen, Brian D.
• Format: Article
• Language: English
• Subjects: Animals; Calcium imaging; Cannabinoid CB1 receptors; Cannabinoid CB2 receptors; Cannabinoids; Cellular communication; Colitis; Colitis - chemically induced; Colitis - metabolism; Colitis - pathology; Digestive system; disorders of gut‐brain interaction; DNA nucleotidylexotransferase; Endocannabinoid system; Endocannabinoids - metabolism; enteric glia; Enteric nervous system; Enteric Nervous System - drug effects; Enteric Nervous System - metabolism; Female; Females; Gastric motility; Gastrointestinal tract; Gender differences; Glial fibrillary acidic protein; Glial plasticity; Hyperalgesia - metabolism; Hypersensitivity; In vivo methods and tests; Inflammation; Inflammation - metabolism; Inflammatory bowel disease; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monoacylglycerol Lipases - metabolism; Motor task performance; Neuroglia - drug effects; Neuroglia - metabolism; Neuronal-glial interactions; Neurons - drug effects; Neurons - metabolism; Neuroplasticity; Pain; Pain perception; Pain sensitivity; Sensitivity analysis; Sex differences; Sexual dimorphism; visceral hypersensitivity; Visceral Pain - metabolism
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.24599

Acute gastrointestinal (GI) inflammation induces neuroplasticity that produces long‐lasting changes in gut motor function and pain. The endocannabinoid system is an attractive target to correct pain and dysmotility, but how inflammation changes endocannabinoid control over cellular communication in enteric neurocircuits is not understood. Enteric glia modulate gut neurons that control motility and pain and express monoacylglycerol lipase (MAGL) which controls endocannabinoid availability. We used a combination of in situ calcium imaging, chemogenetics, and selective drugs to study how endocannabinoid mechanisms affect glial responses and subsequent enteric neuron activity in health and following colitis in Wnt1Cre;GCaMP5g‐tdT;GFAP::hM3Dq mice. Trpv1Cre;GCaMP5gtdT mice were used to study nociceptor sensitivity and Sox10CreERT2;Mgllf/f mice were used to test the role of glial MAGL in visceral pain. The data show that endocannabinoid signaling regulates neuro‐glial signaling in gut neurocircuits in a sexually dimorphic manner. Inhibiting MAGL in healthy samples decreased glial responsiveness but this effect was lost in females following colitis and converted to an excitatory effect in males. Manipulating CB1 and CB2 receptors revealed further sex differences amongst neuro‐glia signaling that were impacted following inflammation. Inflammation increased gut nociceptor sensitivity in both sexes but only females exhibited visceral hypersensitivity in vivo. Blocking MAGL normalized nociceptor responses in vitro and deleting glial Mgll in vivo rescued visceral hypersensitivity in females. These results show that sex and inflammation impact endocannabinoid mechanisms that regulate intercellular enteric glia–neuron communication. Further, targeting glial MAGL could provide therapeutic benefits for visceral nociception in a sex‐dependent manner. Main Points Endocannabinoids regulate intercellular signaling between enteric glia and neurons in a sex‐dependent manner. Inflammation changes cellular responses in the enteric nervous system and the effects of endocannabinoids on intercellular communication. Inflammation increases gut nociceptive nerve terminal sensitivity and inhibiting MAGL dampens nerve fiber responses. Deleting glial Mgll protects females from developing visceral hypersensitivity following inflammation.