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Pathway Description
Trimebutine Opioid Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2023-08-28
Last Updated: 2023-11-27
Trimebutine is a spasmolytic agent that regulates intestinal and colonic motility and relieves abdominal pain. It has a dual function that stimulates or inhibits spontaneous contractions depending on the concentration and prior contractile activity. Trimebutine is also an antagonist of muscarinic acetylcholine receptors, further inhibiting the contraction of intestine smooth muscles.
Trimebutine is taken orally and travels to the myenteric plexus, which is a plexus of neurons that is located between the longitudinal and circular muscle layers of the intestine. Here it activates the mu-opioid receptors which is coupled with G-protein receptors. Binding of Trimebutine stimulates the exchange of GTP for GDP on the G-protein complex. The G-protein system inhibits adenylate cyclase which prevents ATP from being synthesized into cAMP which causes a decrease in intracellular cAMP. The activated G-proteins also close N-type voltage-operated calcium channels which prevents calcium from entering the neuron, and it opens calcium-dependent inwardly rectifying potassium channels which causes sodium to leave the neuron. This results in hyperpolarization and reduced neuronal excitability. Subsequently this prevents acetylcholine and other excitatory neurons from being released into the synapse. The low concentration of acetylcholine means it cannot activate muscarinic acetylcholine (M2 and M3) receptors located on the circular muscles of the instestine. Muscarinic acetylcholine receptors M3 are coupled to the Gq signaling cascade. The activation of this leads to the acitvation of phospholipase C, which converts Phosphatidylinositol (3,4,5)-trisphosphate to inositol (3,4,5)-trisphosphate (IP3) and diacylglycerol (DAG). IP3 activates IP3 receptors on the sarcoplasmic reticulum leading to the release of stored calcium into the cytosol. DAG activates protein kinase C (PKC). One of the downstream effects of PKC include activation of calcium channels on the membrane, leading to influx of calcium ions into the cytosol. Both IP3 and DAG increase cytosolic levels of calcium which then binds to calmodulin to create a calcium-calmodulin complex. Muscle contraction and relaxation are controlled by the enzymes myosin kinase and myosin phosphatase. Myosin kinase phosphorylates myosin light chain, leading to interaction between actin and myosin, producing muscle contraction. The calcium-calmodulin activates myosin kinase, leading to increased phosphorylation of myosin light chain and more muscle contraction. With acetylcholine in low concentrations, myosin light chain kinase is activated less which means contraction of the muscle occurs less often. Nitric oxide is synthesized in the epithelial cells as well as many other places near the intestine. It is lipid soluble so it can enter the myocyte and activate guanalyl cyclase which catalyzes GTP into cGMP. CGMP activates Myosin light chain phosphatase which dephosphorylates the phosphorylated myosin light chain, preventing interaction with actin, producing muscle relaxation. This keeps the myocyte relaxed for longer and slows the cyclic muscle contractions caused by action potential in the cyclic myocytes of the intestine. This keeps the substances in the intestine for longer, allowing the intestine to absorb more water from the substances.This also suppresses the gastrocolic reflex.
References
Trimebutine Opioid Pathway References
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Pubmed: 16710414
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