Mu Receptors


Opioids Receptors and Classification

The mu receptors are a class of receptors that neuromodulate different physiological functions, but above all, nociception but also stress, temperature, respiration, endocrine activity, gastrointestinal activity, memory, mood, and motivation. Because these receptors bind opioids, they are also commonly referred to as mu-opioid receptors (MORs). However, opioid receptors are a very large family of receptors that includes in addition to MORs also delta-opioid receptors (DORs), kappa opioid receptors (KORs), and nociceptin receptor (NOR) also referred to as opioid-receptor-like receptor 1 (ORL1) which seems to have a critical role in the development of tolerance to mu-opioid agonists used as analgesics. Also, there are some other opioid receptors such as the zeta, the epsilon, the lambda, and the iota opioid receptors. Sigma receptors are no longer considered to be opioid receptors as the opioid antagonist naloxone does not reverse their activation. Although according to the International Union of Basic and Clinical Pharmacology (IUPHAR) recommendation the appropriate terminology for the three classical opioid receptors and the nociceptin receptor should be MOP ("Mu OPioid receptor"), DOP, KOP, and NOP respectively, in this chapter we will refer to the acronym MOR for indicating mu-opioid receptors as it is the most used in the scientific literature. 

Receptor Mechanism

Opioid receptors are part of the G protein-coupled receptors (GPCRs) family. Crystallographic studies have allowed researchers to characterize this important superfamily of receptors that control different aspects of cellular function and are implicated in a vast number of neurotransmitter processes. Their basic structure consists of a single polypeptide chain that crosses the cell membrane seven times (seven-transmembrane domain receptors), has an N-terminal extracellular domain of variable length, and a C-terminal intracellular domain, and interacts with heterotrimeric G proteins.[1] GPCRs divide into three distinct families (type A, B, and C) that share the same heptahelical structure but differ in various aspects, mainly due to the length of the N-terminal sequence and the location of the binding site for the agonist. The connection between the receptor and the first stage of signal transduction becomes established through the heterotrimeric (alpha, beta, and gamma subunits) G proteins. The main targets of G proteins through which GPCRs work are the adenyl cyclase that is the enzyme responsible for the formation of the second messenger (intracellular signal transduction) cyclic adenosine monophosphate (cAMP); the phospholipase C that is the enzyme responsible for the formation of inositol triphosphate and diacylglycerol; and several ion channels such as the calcium and potassium channels. According to this last mechanism, GPCRs can directly control the activity of ion channels through mechanisms that do not involve the second messengers (e.g., cAMP). Opioids, for example, reduce neuronal excitability through the opening of the G protein-dependent inward rectifying potassium (irk) channels (GIRK) and subsequent cell membrane hyperpolarization. The opening of the channel occurs by the direct interaction between the subunits (beta-gamma complex from the inactive heterotrimeric G protein complexes G-alpha-beta-gamma) of the G protein and the potassium ion channel. Several GIRK subtypes have been isolated, such as the GIRK1 to GIRK3 types (distributed broadly in the brain), and GIRK4 found primarily in the heart. Interestingly, this type of channel is highly studied as it could be a target for new drugs.[2]

Endogenous and exogenous opioids operate through both inhibitory and excitatory action at the presynaptic and postsynaptic sites. In particular, the MORs interact with a G protein of the inhibitory type, the G-alpha-iota/o class of adenylate cyclase inhibitory G-alpha proteins. Based on the structure of the alpha subunit, there are the G-alpha-iota forms (G-alpha-iota1, 2, and 3), G-alpha-omicron types (A and B), and G-alpha-zeta type. On the other hand, the beta-gamma heterodimer forms from one of the five different betas and one of the twelve different gamma subtypes. In the resting state, there is a G-alpha-beta-gamma complex, and the subunit α binds guanosine diphosphate (GDP). The binding of the opioid agonist (endogenous or exogenous) to the extracellular N-terminus domain of the MOR induces dissociation of GDP from the G-alpha subunit, which is replaced by guanosine triphosphate (GTP), and subsequent dissociation of the G-alpha-GTP from the beta-gamma heterodimer. The now active G-alpha-GTP and beta-gamma subunit complex interact with different intracellular signaling pathways such as the phospholipase C and the mitogen-activated protein kinase (MAPK) pathway, as well as irk-mediated hyperpolarization mechanisms and calcium channels processes. The intracellular signal ends with the action of the GTPase, which hydrolyzes the G-alpha bound GTP to GDP. G-alpha-GDP is not able to activate effector proteins and re-associates with the beta-gamma heterodimer to restore the inactive GDP-bound heterotrimer. Because the enzymatic GTP turnover lasts for approximately 2 to 5 minutes, a new signal may find the receptor still not ready to respond. However, the regulator of G-protein signaling (RGS) protein speed up the GTP hydrolysis up to 100-fold. This protein binds the G-alpha subunit and removes the active G-alpha-GTP and beta-gamma species. In turn, RGS works as a negative regulator of GPCR signaling. RGSs are a family of proteins and represent another interesting perspective for targeted therapy as their specific pharmacological inhibitors could potentiate opioids effects.[3]

MOR Subtypes and Tissue Expression

There are several subtypes of MOR, which are splice variant forms. These variant forms were designated MOR-1A through MOR-1X; some of the variants express truncated forms of the receptor. The B, C, and D variants differ in the amino acid composition at the C-terminus. All variants get transcribed from a single gene (OPRM1 gene, chromosomal location 6q24-q25).[4] Because different variants have undergone isolation in both human and invertebrate tissues, these subtypes get conserved during evolution.[5] Research has identified several single nucleotide polymorphisms in the human receptor. For instance, the variant receptor Ser268 -> Pro possesses an important reduction in coupling efficiency and is less desensitized upon agonist exposure.[6]

MORs are present in the central nervous system (CNS) and represent the most highly expressed of all the opioid receptors. These receptors get expressed in neurons throughout the dorsal horn of the spinal cord and in different brain regions (mainly somatosensorial cerebral cortex) involved in processing nociceptive information. In particular, in the spinal cord, MORs are localized (presynaptic and postsynaptic) into the substantia gelatinosa of Rolando (laminae I and II), which receives sensory information from primary afferent nerve fibers innervating the skin and deeper tissues of the body. Presynaptic MORs activation inhibits the release of excitatory neurotransmitters (e.g., substance P and glutamate), whereas the postsynaptic binding to MORs involves direct hyperpolarization of postsynaptic neurons and, in turn, inhibition of the afferent neural transmission of the painful information, and other types of information. Apart from the somatosensory system, MORs are localized in the extrapyramidal system and the limbic system including the limbic lobe, orbitofrontal cortex (involved in the process of decision-making), piriform cortex, entorhinal cortex (memory and associative functions), hippocampus (opioid-induced consolidation of new memories by increasing LTP in CA3 neurons)[7], fornix, septal nuclei, amygdala (emotional processes), nucleus accumbens involved in reward, pleasure, and addiction, diencephalic structures such as hypothalamus that regulates many autonomic processes, mammillary bodies. Immunohistochemistry, in situ hybridization, and radioligand binding, also demonstrated that MORs get distributed in the mesencephalon (ventral tegmental area, interpeduncular nucleus, pars reticulata of the substantia nigra, superior colliculus), pons (locus coeruleus), thalamus, and caudate-putamen. MORs are also localized in gastrointestinal tract where are responsible for the opioid-induced constipation effect; pupil (miosis); and in the immune cells (e.g., CEM x174 T/B lymphocytes, Raji B cells, CD4+, monocytes/macrophages, neutrophils) where, for instance, regulate interleukin-4 activity in T lymphocytes and modulate macrophage phagocytosis and macrophage secretion of TNF-alpha.[8] Numerous preclinic studies have taken place investigating the effects of opioids on cancer growth and progression.[9][10][11]

MOR Ligands

Endogenous Opioids

Endogenous opioids are the natural ligands of opioid receptors that play a role in neurotransmission, pain modulation, and other homeostatic and functional pathways of the brain and peripherally. Beta-endorphin serves as an agonist for MORs and less for DORs. This peptide is derived from a larger precursor peptide, proopiomelanocortin (POMC), and is secreted by the arcuate nucleus of the hypothalamus (via the anterior lobe of the pituitary gland) during stress and exercise, inducing euphoria, inhibition of postexercise pain, and muscular fatigue, and stimulating glucose uptake. Moreover, because beta-endorphin exerts a tonic inhibitory influence upon the gonadotropin-releasing hormone (GnRH) secretion, it is involved in the regulation of the reproductive function. Other endogenous opioids are the enkephalins that bind mainly the DORs and less the MORs, whereas the dynorphins bind mainly the KORs. Enkephalins are short (5-amino-acid) polypeptides, including met-enkephalin (YGGFM), and Leu-enkephalin (YGGFL). These pentapeptides are generated from a precursor protein called proenkephalin and are found primarily in the amygdala, brainstem, dorsal horn of the spinal cord, adrenal medulla, and other peripheral tissues. Again, dynorphins include dynorphin A (17 amino-acids of which the first five are Leu-enkephalin), dynorphin B (rimorphin), and dynorphin 1-8. They get secreted in the hippocampus, amygdala, hypothalamus, striatum, and spinal cord and are involved in numerous functions related to learning and memory, emotional control, stress response, and pain.[12] The effects of both endogenous and exogenous opioids are characteristically reversed by naloxone.

Exogenous Ligands

Drugs that activate MORs are useful for their pharmacological benefit in providing pain relief. These agents (i.e., opioid drugs) include the so-called weak opioids codeine and tramadol, and the strong opioids oxycodone, morphine, hydromorphone, meperidine, tapentadol, methadone, fentanyl, sufentanil, remifentanil.[13][14] Experiments conducted on MORs knockout mice proved that in addition to the pain-relieving effects, the binding of opioids to MORs could also induce various effects in multiple organ systems. These effects can assume the shape of side effects and are associated with acute and chronic opioids use. Acute effects include but are not limited to depressed respiration, slowing of the gastrointestinal motility, nausea, vomiting, constipation, dizziness, itch, cough suppression, miosis, hallucinations, dysphoria, and sedation.[15][16] Furthermore, the chronic use of opioids induces continued activation of the MORs-related signaling pathways (G protein signaling) and can lead to homeostatic changes, e.g., tolerance, hyperalgesia, and physical dependence. Again, MORs mediate opioid rewarding and euphoric effects.[17] Therefore, the misuse and/or abuse of prescribed opioid drugs after an initial therapeutic use or in patients that self-medicate led to the opioid crisis that broke out in North America in the early years of the 2000s.[18] In 2016, more than 20,000 deaths in the United States (US) resulted from an overdose of prescription opioids, and another 13,000 deaths resulted from heroin overdose. As a consequence, epidemiological data indicate that drug overdoses are the leading cause of death in US adults under age 50, and opioids account for more than half of all drug overdose deaths.

Issues of Concern

Tolerance and Physical Dependence

Issues of concern regarding the MOR agonists lie in their ability to cause opioid tolerance and physical dependence. Consistent stimulation of the MORs can ultimately result in drug tolerance, requiring higher doses to achieve the same effect. However, the phenomenon of opioid tolerance usually is of limited occurrence in cancer patients receiving treatment for pain as the need for increasing doses in those patients is mostly due to an increasing level of pain. The knowledge of the precise mechanisms underlying tolerance and dependence phenomena is of fundamental importance for the accurate management of opioid therapy and the development of new pharmacological strategies. For example, a lot of research has recently focused on the role of particular domains and amino acid residues of the MOR for proper receptor function. This research is usually carried out through the methodology of in vitro mutagenesis and the analysis of receptor chimeras. 

Furthermore, the effects linked to the timing of opioid administration require a better explanation. Studies on tolerance mechanisms demonstrated that high doses of exogenous opioids might produce MOR (and DOR) internalization. Thus an increased opioid intake is necessary to generate the same effect on a reduced number of receptors. Again, upon removal of the exogenous opioids from the system (e.g., through an opioid antagonist), the endogenous opioids are not able to activate the small number of remaining receptors. Physical dependence can develop after 2 to 10 days of continuous use when the drug gets stopped abruptly. The effect is the withdrawal syndrome, which according to the ICD-10 Clinical description, represents 'a group of symptoms of variable clustering and severity occurring on absolute or relative withdrawal of a substance after repeated, and usually prolonged and/or high-dose, use of that substance.' The withdrawal syndrome is usually accompanied by signs of physiological disturbance whereas the onset and duration of clinical manifestations including pain (e.g., abdominal cramping, bone pain, and diffuse muscle aching), autonomic symptoms such as diarrhea, rhinorrhea, diaphoresis, lacrimation, shivering, nausea, emesis, piloerection, central nervous system (arousal, sleeplessness, restlessness, tremors), and craving for the medication depend on the drug used. The addiction phenomenon is a potential consequence of drug dependence and is characterized by psychological and behavioral symptoms with a drug craving, compulsive use, and a strong tendency to relapse after withdrawal.

Research Perspectives

The changes produced by the use of opioids occur on a large scale and are documentable on the morphological level. Gray matter changes in patients with chronic pain are apparent after only one month of morphine administration, and these alterations can persist for up to 5 months after the end of the therapy.[19] On these bases, further research is needed to identify the precise residues that are responsible for the ligand selectivity, the mechanism of the ligand-dependent endocytosis (e.g., the phosphorylation patterns), and the potential modulation of the G protein/cAMP pathway against down-regulation mechanisms. Other research involves the allosteric modulators of the MORs activity. The compounds termed as BMS-986123 and BMS-986124 are silent allosteric modulators (SAMs). These agents neither potentiate nor inhibit the actions of an orthosteric agonist, although they can block the effects of the specific positive allosteric modulators (PAMs).

The genetic aspects represent an important variable to interpret the effects linked to the use/misuse of opioids. Genetic variations in the OPRM1 gene can influence the response to opioids, including the dose of medications needed to obtain pain relief. Interestingly, research has shown that these variations (single nucleotide polymorphism Asn40 -> Asp) can be associated with the risk of opioid addiction.[20] Furthermore, other genes (and their polymorphisms) related to neurotransmitter pathways (e.g., neurotransmitters and receptors of the dopaminergic and serotoninergic pathways), growth factors, and differentiation processes, are also involved in the opioid response and mechanisms of opioid tolerance. Of note, in vivo investigations demonstrated that MORs could physically associate with another opioid (e.g., mu-delta heteromers) or no-opioid receptors to form an entity termed as heteromers whose expression is dynamically regulated depending on a wide range of physiopathological conditions. The heterodimer formations can explain the key role of opioids in mediating various addictive agents such as ethanol, cocaine, nicotine, and cannabinoids. Heterodimers have specific ligand binding, signaling, and trafficking properties and can represent an interesting therapeutic target.[21] Eluxadoline is the first drug developed to target heteromers. It is a MOR agonist - DOR antagonist approved by the Food and Drug Administration (FDA) for the treatment of irritable bowel syndrome. Other attempts are underway with molecules (e.g., CYM51010) with an analgesic effect similar to morphine but with less tolerance.[22][23]

Opioid Addiction: Receptors and Strategies

Another challenge concerns the choice of opioid for replacing more destructive opioids via maintenance therapy in case of opioid addiction. This condition is a chronic disease that can cause major health, social, and economic problems. In this context, as MOR agonists with rapid onset of action and short half-lives such as heroin induce immediate reward followed by noticeable withdrawal symptoms, clinicians must be aware that these drugs have the greatest potential for destructive addictive behaviors. MOR agonists with delayed onset of action and longer half-lives, such as methadone, can induce dependence without necessarily destructive behaviors and reduced impact on mood, judgment, and psychomotor skills. Furthermore, buprenorphine is a partial MOR agonist that induces all the typical opioid effects, although only up to a certain limit called the ceiling effect. By increasing the dose, that is, a significant increase in the effect such as additional euphoria is not obtained, limiting cravings and withdrawal symptoms. The ceiling effect of buprenorphine means that there is also a limit on respiratory depression. Moreover, because buprenorphine has a very high affinity for the opioid receptors, other full agonists such as heroin have strong difficulties to displace it. However, the use of buprenorphine, while heroin, or other opioids, are already on the MORs can induce an antagonist effect with a sudden drop in receptors activation, which, in turn, can be experienced as withdrawal. The introduction of buprenorphine must occur when the strong opioid has dissipated from the receptor. Several tools, such as the Clinical Opioid Withdrawal Scale, can guide the replacing process for addiction treatment.[24]

Clinical Significance

The clinical significance of MORs lies in their ability to provide pain relief to patients. However, it is also critical to remember the importance of managing patients who have overstimulated MORs and are experiencing an opioid overdose. If a patient presents with opioid overdose, antagonism of the MOR is made possible by various medications, one of the most common being naloxone.[25]

Agonism of the MOR has proven incredibly helpful in the clinical management of individuals presenting with both chronic or acute pain. Still, it is essential to ensure that the administration of MORs agonists occurs in circumstances where appropriate and safe administration of the drug is available.[26] [Level 1] Several recommendations have been made to address the opioid epidemic. For example, the use of opioids should not be a consideration as the treatment of choice for chronic pain, especially non-cancer pain. Nonopioid pain agents or nonpharmacological strategies should always merit consideration as first choice strategies. However, since it is not always possible to manage pain with non-pharmacological or opioid-free approaches, the use of opioids must take place as part of a multimodal strategy and following specific precautions. Opioid therapy must be administered by starting at the lowest dose possible and avoiding doses of 90 morphine milligram equivalents (MME) or more. Again, immediate-release is preferable to longer-acting opioids that must be reserved for severe pain conditions requiring daily and around-the-clock treatment. Finally, concerning acute treatment (e.g., postoperative pain), the administration must last less than seven days. 

Nursing, Allied Health, and Interprofessional Team Interventions

The healthcare team, e.g., clinicians, nurses, pharmacists, etc., need to work together to address pain control in their patients accurately.  The healthcare team should schedule their patients for routine follow-up visits that include a history and physical exam to monitor for adverse drug effects and drug misuse. Monitoring for signs of drug misuse of MOR agonists is a very important responsibility for the healthcare team because of the epidemic rates of drug misuse worldwide, e.g., the USA, which lead to death because of respiratory depression. Methods for monitoring drug abuse as well as drug diversion include the following examples: assessment surveys, state prescription drug monitoring programs, urine screening, adherence check-lists, motivational counseling, and dosage form counting, e.g., tablet counting. [Level V]

Article Details

Article Author

Timothy F. Herman

Article Author

Marco Cascella

Article Editor:

Maria Rosaria Muzio


6/23/2022 9:41:42 AM



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