Ligand-induced trafficking of G protein-coupled receptors (GPCRs) and their interaction with associated proteins are key steps regulating receptor-mediated signal transduction and cellular responsiveness, u opioid receptor (?OR) mediates the effects of opiates, potent drugs used for pain control, including analgesia, opioid bowel syndrome (constipation and abdominal pain), and tolerance. We showed that a) ?OR endocytoses in enteric neurons in response to endogenously released opioids and to opiates, except 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) N-Methyl-D-Aspartate receptors (NMDA-Rs) are likely to be involved in the ?OR-mediated impairment of gastrointestinal transit induced by prolonged ?OR activation. This application will test the hypotheses that: 1) prolonged exposure to ?OR ligands induces changes in the intracellular machinery regulating ?OR trafficking in enteric neurons and cellular signaling located downstream of the receptor, and 2) NMDA-R activation mediates the development of ileus/constipation induced by chronic ?OR activation.
Specific Aim 1 will establish which intracellular proteins regulate ?OR trafficking following acute and chronic activation.
Specific Aim 2 will test whether agonist-activation of ?OR stimulates MAP kinase cascade in enteric neurons through a mechanism requiring receptor internalization and whether sustained ?OR endocytosis following chronic ?OR activation is associated with persistent MAP kinase activity.
Specific Aim 3 will test the role of NMDA-Rs in mediating the effects of chronic opiate treatment in gastrointestinal motility and at the receptor level. Relevance: A better knowledge of how enteric neurons respond and react to chronic opiate drugs will advance our understanding of opioid bowel syndrome, a condition affecting patients receiving chronic opiates for pain, and may facilitate the development of novel therapeutic approaches that reduce the side effects but preserving the efficacy of these drugs.
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