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
GABA. Activation of the MOR leads to different effects on dendritic spines depending upon the agonist, and may be an example of
functional selectivity at the μ-receptor.[22] 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-opioid receptor by an agonist such as
morphine causes
analgesia,
sedation, slightly reduced
blood pressure,
itching,
nausea,
euphoria,
decreased respiration,
miosis (constricted pupils), and decreased bowel motility often leading to
constipation. Some of these effects, such as analgesia, sedation, euphoria, itching 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
gastrin-releasing peptide receptor) is required for morphine-induced itching.[23]
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]
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
circulatory collapse from vasodilation and bradycardia.[39]
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.
Tramadol and
tapentadol carry additional risks associated with their dual effects as
SNRIs and can cause
serotonin syndrome and seizures. Despite these risks, there is evidence to suggest that these drugs have a lower risk of respiratory depression compared to morphine.[40]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Zhorov BS, Ananthanarayanan VS (March 2000). "Homology models of mu-opioid receptor with organic and inorganic cations at conserved aspartates in the second and third transmembrane domains". Archives of Biochemistry and Biophysics. 375 (1): 31–49.
doi:
10.1006/abbi.1999.1529.
PMID10683246.
^Zou R, Wang X, Li S, Chan HS, Vogel H, Yuan S (2022). "The role of metal ions in G protein-coupled receptor signalling and drug discovery". WIREs Computational Molecular Science. 12 (2): e1565.
doi:
10.1002/wcms.1565.
ISSN1759-0876.
S2CID237649760.
^Pan L, Xu J, Yu R, Xu MM, Pan YX, Pasternak GW (2005). "Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm". Neuroscience. 133 (1): 209–220.
doi:
10.1016/j.neuroscience.2004.12.033.
PMID15893644.
S2CID22410194.
^Martini L, Whistler JL (October 2007). "The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence". Current Opinion in Neurobiology. 17 (5): 556–564.
doi:
10.1016/j.conb.2007.10.004.
PMID18068348.
S2CID29491629.
^Marie N, Aguila B, Allouche S (November 2006). "Tracking the opioid receptors on the way of desensitization". Cellular Signalling. 18 (11): 1815–1833.
doi:
10.1016/j.cellsig.2006.03.015.
PMID16750901.
^DuPen A, Shen D, Ersek M (September 2007). "Mechanisms of opioid-induced tolerance and hyperalgesia". Pain Management Nursing. 8 (3): 113–121.
doi:
10.1016/j.pmn.2007.02.004.
PMID17723928.
^Garzón J, Rodríguez-Muñoz M, Sánchez-Blázquez P (May 2005). "Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter". Neuropharmacology. 48 (6): 853–868.
doi:
10.1016/j.neuropharm.2005.01.004.
PMID15829256.
S2CID23797166.
^Hooks SB, Martemyanov K, Zachariou V (January 2008). "A role of RGS proteins in drug addiction". Biochemical Pharmacology. 75 (1): 76–84.
doi:
10.1016/j.bcp.2007.07.045.
PMID17880927.
^Lopez-Gimenez JF, Vilaró MT, Milligan G (November 2008). "Morphine desensitization, internalization, and down-regulation of the mu opioid receptor is facilitated by serotonin 5-hydroxytryptamine2A receptor coactivation". Molecular Pharmacology. 74 (5): 1278–1291.
doi:
10.1124/mol.108.048272.
PMID18703670.
S2CID6310244.
^Kraus J (June 2009). "Regulation of mu-opioid receptors by cytokines". Frontiers in Bioscience. 1 (1): 164–170.
doi:
10.2741/e16.
PMID19482692.
^García-Fuster MJ, Ramos-Miguel A, Rivero G, La Harpe R, Meana JJ, García-Sevilla JA (November 2008). "Regulation of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of short- and long-term human opiate abusers". Neuroscience. 157 (1): 105–119.
doi:
10.1016/j.neuroscience.2008.09.002.
PMID18834930.
S2CID9022097.
^Houmes RJ, Voets MA, Verkaaik A, Erdmann W, Lachmann B (April 1992). "Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression". Anesthesia and Analgesia. 74 (4): 510–514.
doi:
10.1213/00000539-199204000-00007.
PMID1554117.
S2CID24530179.
External links
"Opioid Receptors: μ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.