View source for Mu Opioid Receptor

== Mu Opioid Receptor==
<StructureSection load='4n6h' size='340' side='right' caption='Chimera of human Delta Opioid 7TM Receptor and E. coli cytochrome B562 in complex with oleate, tartrate, naltrindole, oleate derivative and Na+ ion (PDB code [[4n6h]])' scene=''>
Opioid receptors are G-protein coupled receptors (GPCR), which bind endogenous opioid peptide neurotransmitters (such as enkephalins and endorphins) and exogenous synthetic opiate drugs (such as morphine, codeine, and heroin) as ligands to hinder pain-signaling in the brain, peripheral nerves, and digestive tract.  μ-opioid receptors are one of the four major classes of opioid receptors, which also includes δ-opioid receptors, κ-opioid receptors, and nociceptin opioid receptors.  The '''μ-opioid receptor''' MOR-1 is expressed by the gene OPRM1 in vertebrates. <ref name="past">DOI: 10.1124/pr.112.007138</ref> MOR-1 has important implications as a target for pain relievers as well as a treatment for drug abuse. 

See also [[Transmembrane (cell surface) receptors]]

== Structural highlights ==

The molecular structure of MOR-1 was better understood after its cloning in 1993. According to the American Society for Pharmacology and Experimental Therapeutics, the amino acid sequence of MOR-1 is 60-70% homologous to the other classes of opioid receptors. The difference between MOR-1 and the other opioid receptor proteins lies in its extracellular N-terminus, intracellular C-terminus, and second and third extracellular loops. The μ-opioid receptor is a<scene name='77/778329/7tm/1'> 7-multispanning integral membrane protein</scene> found in dorsal root ganglion cells and peripheral nerve cells in humans, with its binding site exposed to the extracellular surface. The transmembrane domain of MOR-1 will dimerize at TM5 and TM6 to form oligomers. <ref name="past"/> The active site of the receptor, where opioid molecules bind, is between TM3, TM5, TM6, and TM7. <ref name="sero">DOI: 10.1016/j.str.2011.08.003</ref>

== Function ==

MOR-1 is a G-protein coupled receptor (GPCRs), which binds extracellular signaling molecules including exogenous opiate drugs (such as morphine, codeine, and heroin) and endogenous opioid peptide neurotransmitters (such as enkephalins, endorphins, and dynorphins) as ligands to hinder pain-signaling.  Endogenous opioids play a role in naturally reducing sensations of pain felt by the body.  However, they do not evoke as powerful a physiological response as exogenous opioids. <ref name="past"/>

In the presence of a signaling molecule, an active G protein will have GTP bound, to promote an intracellular signaling cascade.  After the G protein has transduced the signal, it exchanges GTP for GDP and becomes inactive until another signaling molecule binds to the GPCR.  

In the case of the μ-opioid receptor, the binding of an opioid signaling molecule induces a <scene name='78/786661/Mor_on_off/2'>conformational change</scene> in the receptor that activates an inhibitory G-protein (Gαi/o).  This results in the dissociation of the G-protein complex.  The Gα subunit then inhibits adenylyl cyclase.  The Gβγ subunit acts to inhibit Ca2+ channels while activing K+ channels.  While much has been learned about μ-opioid receptors since their discovery in 1973, there is still much that is unknown about their structure and <scene name='78/786661/Mor_on_off/4'>activation mechanism</scene>.  Thus, further research into this area is needed. <ref name="sero"/>
== Disease ==

μ-opioid receptors are the only opioid receptors that are linked with physical dependence to opioids.  A study by Matthes et al. found that mice lacking μ-opioid receptors showed no physical response or dependence after being injected with morphine. They also did not observe these effects when δ-opioid receptors and κ-opioid receptors were present in the mice injected with morphine.  These results suggest that only μ-opioid receptors are involved in physical response and dependence secondary to opioids. <ref>DOI: 10.1038/383819a0</ref>

== Relevance ==

According to the National Institute on Drug Abuse, 115 Americans die every day as a result of opioid overdose. Furthermore, the opioid crisis our country faces has two million Americans directly in its grips. <ref name= "Article 1" >National Institute on Drug Abuse. “Opioid Overdose Crisis.” NIDA, 6 Mar. 2018, www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis. </ref>. The opioid drug class includes the controlled substances morphine, fentanyl, codeine, hydrocodone, and oxycodone as well as the illegal substance, heroin.  The aforementioned drugs act at opioid receptors in the brain and provide pain relief in addition to a sense of euphoria and sedation. Exogenous opioids that result in physical dependence act specifically at μ-opioid receptors (MOR). <ref>DOI: 10.1016/j.aat.2010.12.008</ref> To wage a successful war against opioids in the United States, we must fully understand the science behind opioid addiction. 

The biochemistry of opioid addiction points to the ventral tegmental area (VTA) of the brain, the reward center.  In this area, there are a high concentration of μ-opioid receptors on the surfaces of neurons.  When exogenous opioid agonists are present, they bind to the active site of the μ-opioid receptor.  This sends a signal along the axon of the neuron to activate dopaminergic neurons.  Upon activation of dopaminergic neurons, dopamine is released into the synapse and binds to post-synaptic receptors.  The binding of dopamine results in feelings of euphoria.  Exogenous opioids produce larger amounts of dopamine than endogenous opioids.  When exogenous opioids are abused, the behavior of abusing them is reinforced by the feelings of pleasure from dopamine.  Overtime, an addicted person develops a tolerance and more opioids are needed in order to release the same amount of dopamine as the first use. <ref name= "Article 2" > Contet, Candice, et al. “Mu Opioid Receptor: a Gateway to Drug Addiction.” Current Opinion in Neurobiology, 19 May 2004, pp. 370–378., doi:10.1016/s0959-4388(04)00072-8. </ref>.

</StructureSection>
== References ==
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