| Autor: |
Barton JR; Department of Pharmacology, Physiology, & Cancer Biology., Londregan AK; Department of Pharmacology, Physiology, & Cancer Biology., Alexander TD; Department of Neurosciences., Entezari AA; Department of Pharmacology, Physiology, & Cancer Biology., Bar-Ad S; Department of Pharmacology, Physiology, & Cancer Biology., Cheng L; Department of Neurosciences., Lepore AC; Department of Neurosciences., Snook AE; Department of Pharmacology, Physiology, & Cancer Biology.; Department of Microbiology & Immunology, and.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Covarrubias M; Department of Neurosciences., Waldman SA; Department of Pharmacology, Physiology, & Cancer Biology.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. |
| Abstrakt: |
Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient - but not GUCY2C-deficient - neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes. |
