μ-opioid receptor

The μ-opioid receptors (MOR) are a class of

The structure of the inactive μ-opioid receptor has been determined with the antagonists β-FNA^[6] and alvimopan.^[7] Many structures of the active state are also available, with agonists including DAMGO,^[8] β-endorphin,^[9] fentanyl and morphine.^[10] The structure with the agonist BU72 has the highest resolution,^[11] but contains unexplained features that may be experimental artifacts.^[12][13] This large body of evidence has enabled structure-based design of a new class of opioids with functional selectivity.^[14]

Splice variants

Three variants of the μ-opioid receptor are well characterized, though reverse transcription polymerase chain reaction has identified up to 10 total splice variants in humans.^[15][16][17]

Location

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

The μ-opioid receptors exist mostly

Some MORs are also found in the intestinal tract. Activation of these receptors inhibits peristaltic action which causes constipation, a major side effect of μ agonists.[21]

Activation

MOR can mediate acute changes in neuronal excitability via suppression of presynaptic release of

The canonical MOR1 isoform is responsible for morphine-induced analgesia, whereas the alternatively spliced MOR1D isoform (through heterodimerization with the gastrin-releasing peptide receptor) is required for morphine-induced itching.^[23]

Deactivation

As with other

Long-term or high-dose use of opioids may also lead to additional mechanisms of tolerance becoming involved. This includes downregulation of MOR 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.[30]^[31][32] 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, so reduce the effects of opioid drugs by altering downstream pathways, regardless of MOR activation.^[33][34]

Tolerance and overdoses

Fatal opioid overdose typically occurs due to bradypnea, hypoxemia, and decreased cardiac output (hypotension occurs due to vasodilation, and bradycardia further contributes to decreased cardiac output).^[35][36][37] A potentiation effect occurs when opioids are combined with ethanol, benzodiazepines, barbiturates, or other central depressants which can result in rapid loss of consciousness and an increased risk of fatal overdose.^[35][36]

Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses.^[38] However, tolerance to respiratory depression is quickly lost during withdrawal and may be completely reversed within a week. Many overdoses occur in people who return to their previous dose after having lost their tolerance following cessation of opioids. This puts addicts who receive medical treatment for opioid addiction at great risk of overdose when they are released, as they may be particularly vulnerable to relapse.

Less commonly, massive overdoses have been known to cause

Opioid overdoses can be rapidly reversed through the use of opioid antagonists, naloxone being the most widely used example.^[35] Opioid antagonists work by binding competitively to µ-opioid receptors and displacing opioid agonists. Additional doses of naloxone may be necessary and supportive care should be given to prevent hypoxic brain injury by monitoring vital signs.