Ligand-induced trafficking of G protein-coupled receptors and their interaction with associated proteins are key steps regulating receptor-mediated signal transduction and cellular responsiveness. ? opioid receptor (?OR) mediates the analgesic effects of opiates, potent drugs used for pain control, and their side effects, including opioid bowel syndrome (profound constipation and abdominal pain), and tolerance. We previously showed that a) ?OR endocytoses in enteric neurons in response to endogenously opioids and to most opiates, but not to morphine, b) chronic ?OR activation confers morphine the ability to trigger ?OR endocytosis and induces over expression and translocation of dynamin, an intracellular protein that is important for receptor internalization, c) the magnitude of ?OR endocytosis induced by high efficacy opiates does not change in a condition of opioid tolerance, d) activation of ?OR with an internalizing agonist stimulates mitogen-activated protein kinase (MAPK) phosphorylation in cultured myenteric neurons. This application will test the hypothesis that prolonged ?OR activation induces alterations in the intracellular machinery that regulates agonist-induced ?OR trafficking and post-receptor signaling in enteric neurons, which are possible mechanisms underlying the development of tolerance.
Specific Aim 1 will establish which intracellular proteins regulate ?OR trafficking following acute and chronic activation in vitro using neuronal transfection of native cells expressing ?OR and correlate their expression with receptor endocytosis and state of gut tolerance in vivo.
Specific Aim 2 will determine the effects of acute and chronic ?OR stimulation on MAPK activation in enteric neurons, the effects of MAPK inhibitors on agonist- induced ?OR desensitization and internalization, and whether chronic opiate treatment resulting in a state of tolerance in the gut induces sustained MAPK activation in intact segments of the ileum. These studies will provide a better knowledge of opiate-induced adaptations in enteric neurons naturally expressing ?OR, which will increase our understanding of opioid bowel syndrome, a condition affecting patients receiving chronic opiates for pain, and tolerance, which hamper the use of these drugs.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DIG-C (03))
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Serrano, Jose
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Anselmi, L; Huynh, J; Duraffourd, C et al. (2015) Activation of ? opioid receptors modulates inflammation in acute experimental colitis. Neurogastroenterol Motil 27:509-23
Duraffourd, Celine; Kumala, Erica; Anselmi, Laura et al. (2014) Opioid-induced mitogen-activated protein kinase signaling in rat enteric neurons following chronic morphine treatment. PLoS One 9:e110230
Anselmi, Laura; Jaramillo, Ingrid; Palacios, Michelle et al. (2013) Ligand-induced ? opioid receptor internalization in enteric neurons following chronic treatment with the opiate fentanyl. J Neurosci Res 91:854-60
Anselmi, Laura; Huynh, Jennifer; Vegezzi, Gaia et al. (2013) Effects of methylnaltrexone on guinea pig gastrointestinal motility. Naunyn Schmiedebergs Arch Pharmacol 386:279-86
Sternini, Catia (2013) In search of a role for carbonation: is this a good or bad taste? Gastroenterology 145:500-3
Saccani, Francesca; Anselmi, Laura; Jaramillo, Ingrid et al. (2012) Protective role of ? opioid receptor activation in intestinal inflammation induced by mesenteric ischemia/reperfusion in mice. J Neurosci Res 90:2146-53
Patierno, Simona; Anselmi, Laura; Jaramillo, Ingrid et al. (2011) Morphine induces ? opioid receptor endocytosis in guinea pig enteric neurons following prolonged receptor activation. Gastroenterology 140:618-26
Anselmi, Laura; Stella Jr, Salvatore L; Brecha, Nicholas C et al. (2009) Galanin inhibition of voltage-dependent Ca(2+) influx in rat cultured myenteric neurons is mediated by galanin receptor 1. J Neurosci Res 87:1107-14
Rozengurt, Enrique; Sternini, Catia (2007) Taste receptor signaling in the mammalian gut. Curr Opin Pharmacol 7:557-62
Bradesi, Sylvie; Kokkotou, Efi; Simeonidis, Simos et al. (2006) The role of neurokinin 1 receptors in the maintenance of visceral hyperalgesia induced by repeated stress in rats. Gastroenterology 130:1729-42

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