Μ-opioid receptor



The μ-opioid receptors (MOR) are a class of is_associated_with::opioid receptors with high affinity for is_associated_with::enkephalins and is_associated_with::beta-endorphin but low affinity for is_associated_with::dynorphins. They are also referred to as μ opioid is_associated_with::peptide (MOP) receptors. The prototypical μ receptor is_associated_with::agonist is is_associated_with::morphine, the primary psychoactive alkaloid in is_associated_with::opium. In fact, μ (mu) refers to morphine.

Types
Three variants of the μ opioid receptor are well-characterized, though reverse-transcriptase PCR has identified up to 10 total splice variants in humans.

Location
They can exist either presynaptically or postsynaptically depending upon cell types.

The μ-receptors exist mostly presynaptically in the is_associated_with::periaqueductal gray region, and in the superficial dorsal horn of the is_associated_with::spinal cord (specifically the is_associated_with::substantia gelatinosa of Rolando). Other areas where μ-receptors have been located include the external plexiform layer of the is_associated_with::olfactory bulb, the is_associated_with::nucleus accumbens, in several layers of the is_associated_with::cerebral cortex and in some of the nuclei of the is_associated_with::amygdala, as well as the nucleus of the solitary tract.

μ receptors are also found in the intestinal tract. Activation of these receptors inhibits peristaltic action which causes constipation, a major side effect of μ agonists.

Activation
MOR can mediate acute changes in neuronal excitability via "disinhibition" of presynaptic release of GABA (see works from and ). Activation of the MOR leads to different effects on dendritic spines depending upon the agonist, and may be an example of is_associated_with::functional selectivity at the μ receptor. The physiological and pathological roles of these two distinct mechanisms remain to be clarified. Perhaps, both might be involved in opioid addiction and opioid-induced deficits in cognition.

Activation of the μ receptor by an agonist such as is_associated_with::morphine causes is_associated_with::analgesia, is_associated_with::sedation, slightly reduced is_associated_with::blood pressure, is_associated_with::itching, is_associated_with::nausea, is_associated_with::euphoria, is_associated_with::decreased respiration, is_associated_with::miosis (constricted pupils) and decreased bowel motility often leading to is_associated_with::constipation. Some of these effects, such as analgesia, sedation, euphoria and decreased respiration, tend to lessen with continued use as tolerance develops. Miosis and reduced bowel motility tend to persist; little tolerance develops to these effects.

The canonical MOR1 isoform is responsible for morphine-induced analgesia whereas the alternatively spliced MOR1D isoform (through heterodimerization with the is_associated_with::gastrin-releasing peptide receptor) is required for morphine-induced itching.

Deactivation
As with other is_associated_with::G protein-coupled receptors, signalling by the mu opioid receptor is terminated through several different mechanisms, which are upregulated with chronic use, leading to rapid is_associated_with::tachyphylaxis. The most important regulatory proteins for the mu opioid receptor are the β-arrestins is_associated_with::Arrestin beta 1 and is_associated_with::Arrestin beta 2,  and the RGS proteins is_associated_with::RGS4, RGS9-2, is_associated_with::RGS14 and RGSZ2.

Long-term or high dose use of opioids may also lead to additional mechanisms of tolerance becoming involved. This includes downregulation of mu opioid receptor gene expression, so the number of receptors presented on the cell surface is actually reduced, as opposed to the more short-term desensitisation induced by β-arrestins or RGS proteins. Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect and so reduce the effects of opioid drugs by altering downstream pathways, regardless of mu opioid receptor activation.

Tolerance and overdoses
Opioid overdoses kill through is_associated_with::apnea and fatal hypoxia, often caused by combination with is_associated_with::ethanol, is_associated_with::benzodiazepines or is_associated_with::barbiturates. Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses. However tolerance to respiratory depression is lost just as quickly during withdrawal. Many overdoses occur in people who misuse their medication after being in withdrawal long enough to lose the tolerance to respiratory depression. Less commonly, massive overdoses have been known to cause is_associated_with::circulatory collapse.

Opioid overdoses can be rapidly reversed through the use of opioid antagonists, is_associated_with::naloxone being the most widely used example.