Mu Opioid Receptor Agonism Molecular AOPWiki 2017-06-08T12:02:02 2017-06-08T12:02:02 Release of G Proteins Cellular AOPWiki 2017-06-08T12:03:09 2017-06-08T12:04:58 Inhibition of Ca Channels Cellular AOPWiki 2017-06-23T06:50:26 2017-06-23T06:50:26 Inhibition of neurotransmitter release Cellular AOPWiki 2017-06-23T06:52:15 2023-06-27T17:42:52 Analgesia Individual AOPWiki 2017-06-08T12:08:20 2017-06-08T12:08:20 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308b93bd0> AOPWiki 2017-06-08T12:09:04 2017-06-08T12:09:04 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308bc5b08> AOPWiki 2017-06-23T06:53:18 2017-06-23T06:53:18 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308c23618> AOPWiki 2017-06-23T06:53:30 2017-06-23T06:53:30 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308c8bd30> AOPWiki 2017-06-23T06:53:42 2017-06-23T06:53:42 Mu Opioid Receptor Agonism to Analgesia via Ca Channel Evgeniia Kazymova <p>Timothy E H Allen, University of Cambridge, teha2@cam.ac.uk</p> BY-SA 1.0 <p>Agonism of the opioid receptors leads to the release of G proteins mimicking the body&rsquo;s natural analgesic pathways (which are activated by endorphins). The released G Proteins move to effectors in the cell to initiate their function. For the G&beta;&gamma;, one of these is the Ca2+ ion channel. The inhibition of Ca ion channels prevents the flow of Ca2+ ions into neurons, a key step in the release of neurotransmitters which carry the signal across the synapse to another neuron. A reduction in the ability of neurons to transmit signals between one another causes an analgesic effect in the individual. Mu opioid receptors are found in peripheral sensory nerves explaining their analgesic activity.</p> <p>This putative&nbsp;AOP has been constructed using literature knowledge to provide qualitative information to link&nbsp;<em>in silico</em>&nbsp;predictions to adverse outcomes.</p> adjacent Not Specified High adjacent Not Specified High adjacent Not Specified High non-adjacent Not Specified High <p>Below direct quotes from literature sources provide evidence for each KE and KER.</p> <p><strong>Mu opioid receptor&nbsp;</strong><strong>agonism</strong><strong>&nbsp;leading to release of G proteins</strong></p> <p>&ldquo;When the [G protein coupled] receptor is occupied, the a subunit is uncoupled and forms a complex which interacts with cellular systems to produce and effect&rdquo; LA Chahl 1996</p> <p>&ldquo;Once the [opioid] receptor is activated, it releases a portion of the G protein, which diffuses within the membrane until it reaches its target&rdquo; AM Trescot 2008</p> <p>&ldquo;Following activation by an agonist&hellip;the G&alpha; and G&beta;&gamma; subunits dissociate from one another and subsequently act on various intracellular effector pathways&rdquo; R Al-Hasani 2011</p> <p>&ldquo;The activation of the three (&mu;, &delta;, &kappa;) opioid receptors leads to Gi/o protein activation&rdquo; K Ikeda 2002</p> <p><strong>Release of G proteins leading to inhibition of N-type Ca ion channel&nbsp;</strong></p> <p>&ldquo;Opioids inhibit N-type Ca2+ channels and thus inhibit neurotransmitter release&rdquo; LA Chahl 1996</p> <p>&ldquo;transient overexpression of G&beta;&gamma; in sympathetic neurons mimics and occludes the voltage-dependent Ca2+ channel modulation produced by noradrenaline&rdquo; SR Ikeda 1996</p> <p>&ldquo;Opioid receptors located on the presynaptic terminals of the nociceptive C-fibers and A delta fibers, when activated by an opioid agonist, will indirectly inhibit&hellip;voltage-dependent calcium channels&hellip;blocking the release of pain neurotransmitters&hellip;resulting in analgesia&rdquo; AM Trescot 2008</p> <p><strong>Inhibition of N-type Ca ion channel leading to inhibition of neurotransmitter release</strong></p> <p>&ldquo;The Ca2+ dependence of neurotransmitter release is a fundamental property of chemical synapses&rdquo; DA Rusakov 2006</p> <p>&ldquo;Recent work has established that different geometric arrangements of calcium channels are found at different presynaptic terminals, leading to a wide spread of calcium signals for triggering neurotransmitter release&rdquo; GJ Augustine 2001</p> <p>&ldquo;The intracellular calcium concentration has important roles in the triggering of neurotransmitter release&rdquo; E Neher 2008</p> <p>&ldquo;In the nerve terminal, it is well established that the most prominent [action of Ca2+] triggering of neurotransmitter release achieves its unique properties by activating a relatively low-affinity Ca2+ sensor&rdquo; E Neher 2008</p> <p><strong>Inhibition of neurotransmitter release leading to analgesia</strong></p> <p>&ldquo;There appears to be two mechanisms by which the transmission of pain sensations are depressed; hyperpolarization of interneurons within the dorsal cord and depressing the release of the neurotransmitters associated with pain transmission&rdquo; J Lipp 1991</p> <p>&ldquo;The opioid drugs produce analgesia by actions at several levels of the nervous system, in particular, inhibition of neurotransmitter release&nbsp; from the primary afferent terminals in the spinal cord&rdquo; LA Chahl 1996</p> <p><strong>Neuronal Location</strong></p> <p>&ldquo;the functionally exclusive localization of opioid receptors to primary afferent (but not sympathetic) neurons&rdquo; C Stein 2013</p> <p>&ldquo;Opiate receptors are manufactured by primary sensory neurons (dorsal root ganglion or DRG cells) and transported centrally&rdquo; RE Coggeshall 1997</p> <p>&ldquo;Opiate receptors have also been demonstrated peripherally in fine cutaneous nerves by light microscopic techniques&rdquo; RE Coggeshall 1997</p> <p>Al-Hasani R., Bruchas M.R. (<strong>2011</strong>)&nbsp;<em>Anesthesiology.</em>&nbsp;115, 1363.</p> <p>Augustine&nbsp;G.J. (<strong>2001</strong>)&nbsp;<em>Curr. Opin. Neurobiol.&nbsp;</em>11, 320.</p> <p>Chahl L.A. (<strong>1996</strong>)&nbsp;<em>Aust. Prescr.</em>&nbsp;19, 63.</p> <p>Coggeshall R.E. (<strong>1997</strong>)&nbsp;<em>Brain Res.</em>&nbsp;764, 126.</p> <p>Ikeda S. R. (<strong>1996</strong>)&nbsp;<em>Nature&nbsp;</em>380, 255.</p> <p>Ikeda K. (<strong>2002</strong>)&nbsp;<em>Neurosci. Res.</em>&nbsp;44, 121.</p> <p>Lipp J. (<strong>1991</strong>)&nbsp;<em>Clin Neuropharmacol.</em>&nbsp;14, 131.</p> <p>Neher E., Sakaba&nbsp;T. (<strong>2008</strong>)&nbsp; Neuron 59, 453.​</p> <p>Rusakov D. A. (<strong>2006</strong>)&nbsp;<em>Neurosci.</em>&nbsp;12, 317.</p> <p>Stein C. (<strong>2012</strong>)&nbsp;<em>Madame Curie Bioscience Database (online)</em></p> <p>Trescot A.M., Datta S., Lee M., Hansen H. (<strong>2008</strong>)&nbsp;<em>Pain Phys.</em>&nbsp;11, S133.</p> AOPWiki 2017-06-23T06:33:09 2023-09-25T16:26:57