title: Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation.
abstract: Morphine is one of the most widely used drugs for the treatment of pain. However, side effects, including persistent constipation and antinociceptive tolerance, limit its clinical efficacy. Prolonged morphine treatment results in a "leaky" gut, predisposing to colonic inflammation that is facilitated by microbial dysbiosis and associated bacterial translocation. In this study, we examined the role of enteric glia in mediating this secondary inflammatory response to prolonged treatment with morphine. We found that purinergic P2X receptor activity was significantly enhanced in enteric glia that were isolated from mice with long-term morphine treatment (in vivo) but not upon direct exposure of glia to morphine (in vitro). LPS, a major bacterial product, also increased ATP-induced currents, as well as expression of P2X4, P2X7, IL6, IL-1β mRNA in enteric glia. LPS increased connexin43 (Cx43) expression and enhanced ATP release from enteric glia cells. LPS-induced P2X currents and proinflammatory cytokine mRNA expression were blocked by the Cx43 blockers Gap26 and carbenoxolone. Likewise, colonic inflammation related to prolonged exposure to morphine was significantly attenuated by carbenoxolone (25 mg/kg). Carbenoxolone also prevented gut wall disruption and significantly reduced morphine-induced constipation. These findings imply that enteric glia activation is a significant modulator of morphine-related inflammation and constipation.-Bhave, S., Gade, A., Kang, M., Hauser, K. F., Dewey, W. L., Akbarali, H. I. Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Sukhada
authors.initials: S
authors.lastname: Bhave
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Aravind
authors.initials: A
authors.lastname: Gade
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Minho
authors.initials: M
authors.lastname: Kang
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA hamid.akbarali@vcuhealth.org.
authors.forename: Hamid I
authors.initials: HI
authors.lastname: Akbarali
mesh_terms: D000255:Adenosine Triphosphate; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D018031:Connexin 43 / Q000378:metabolism*; D003248:Constipation / Q000139:chemically induced*; D055724:Electrophysiological Phenomena; D005786:Gene Expression Regulation; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009457:Neuroglia / Q000502:physiology*; D012333:RNA, Messenger; D058469:Receptors, Purinergic P2X / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D018031:Connexin 43; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D058469:Receptors, Purinergic P2X; D009020:Morphine; D000255:Adenosine Triphosphate
keywords: ATP; electrophysiology; inflammation; lipopolysaccharide