Introduction
Opioids Receptors and Classification
The mu (μ) receptors are a class involved in neuromodulating different physiological functions. These receptors primarily affect 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 large family of receptors that also includes delta (δ)-opioid receptors (DORs), kappa (κ)-opioid receptors (KORs), and nociceptin receptors (NORs), also referred to as opioid-receptor-like receptor 1 (ORL1), which appear to have a role in the development of tolerance to mu-opioid agonists used as analgesics.
Other opioid receptors include the zeta (ζ), epsilon (ε), lambda (λ), and iota (ι) opioid receptors. Sigma (σ) receptors are no longer considered opioid receptors as the opioid antagonist naloxone does not reverse their activation or associated effects. According to the International Union of Basic and Clinical Pharmacology (IUPHAR) recommendation, the appropriate terminology for the 3 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 abbreviation in the scientific literature.
Receptor Mechanism
Opioid receptors are part of the G-protein-coupled receptors (GPCRs) family, characterized by crystallographic studies. This important superfamily of receptors controls different aspects of cellular function and is implicated in various neurotransmitter processes. The basic GPCR structure consists of a single polypeptide chain that crosses the cell membrane 7 times (giving the alternate name "7-transmembrane domain receptor"), has an extracellular N-terminal domain of variable length and an intracellular C-terminal domain, and interacts with heterotrimeric G-proteins.[1]
The GPCRs are divided into 3 distinct families (types A, B, and C) that share a similar heptahelical structure but differ in various aspects, mainly due to the length of the N-terminal sequence and the location of the agonist binding site. The connection between the receptor and the first stage of signal transduction is established by the heterotrimeric G-protein consisting of the alpha (Gα), beta (Gβ), and gamma (Gγ) subunits.
The main targets of G-protein signaling include adenyl cyclase, the enzyme responsible for the formation of cyclic adenosine monophosphate (cAMP); phospholipase C, the enzyme responsible for the formation of inositol triphosphate (IP3) and diacylglycerol (DAG); and several ion channels including calcium and potassium channels. Cyclic AMP, IP3, and DAG are second messenger molecules that carry out intracellular signal transduction. GPCRs can directly control the activity of ion channels through mechanisms that do not involve second messengers. For example, opioids reduce neuronal excitability by opening the G-protein-dependent inward rectifying potassium channels (GIRK), causing cell membrane hyperpolarization.
The opening of an ion channel occurs via direct interaction of the β-γ subunit complex on the channel. Several GIRK subtypes have been isolated, including the GIRK1, GIRK2, and GIRK3 types (distributed broadly in the brain) and GIRK4 (heart). This channel type is the subject of active study as a potential target for new drugs.[2]
Endogenous and exogenous opioids operate through inhibitory and excitatory action at the presynaptic and postsynaptic sites. In particular, the MORs interact with members of the G-alpha-iota (ι)/-omicron (Ο) class of adenylate cyclase, a group of inhibitory G-proteins. Given the structure of the α subunit, there are various potential subunit and binding site combinations, including the G-α-ι forms (1, 2, and 3), G-α-Ο types (A and B), and G-α-zeta (ζ) types.
Additionally, the β-γ heterodimer forms from 1 of the 5 different β and 1 of the 12 different γ subtypes. In the resting state, the Gαβγ complex is wholly present, and the α subunit binds guanosine diphosphate (GDP). The binding of the opioid agonist (endogenous or exogenous) to the extracellular N-terminus of the MOR induces dissociation of GDP from the Gα subunit, which is replaced by guanosine triphosphate (GTP). Subsequently, Gα-GTP dissociates from the β-γ heterodimer.
The now active Gα-GTP and β-γ 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 channel processes. The intracellular signaling pathway ends with the action of the GTPase, which hydrolyzes the Gα-bound GTP to GDP. Gα-GDP cannot activate effector proteins and subsequently re-associates with the β-γ heterodimer to restore the inactive GDP-bound Gαβγ heterotrimer.
Because the enzymatic GTP turnover lasts approximately 2 to 5 minutes, a new signal attempt may not cause a response. However, a regulator of G-protein signaling (RGS) protein accelerates GTP hydrolysis up to 100-fold. A RGS protein acts as a negative regulator of GPCR signaling by binding the Gα subunit and removing the active Gα-GTP and β-γ heterodimer. The RGS protein family represents another potential therapeutic target, as their specific pharmacological inhibitors could potentiate opioid effects.[3]
MOR Subtypes and Tissue Expression
Several subtypes of MOR are splice variant forms designated MOR-1A through MOR-1X; some 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 are 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 are conserved during evolution.[5] Studies have identified several single nucleotide polymorphisms in the human receptor. For instance, the variant receptor Ser268 -> Pro significantly reduces coupling efficiency and is less desensitized upon agonist exposure.[6]
MORs are present in the central nervous system (CNS) and are the most commonly expressed opioid receptors. These receptors are expressed in the dorsal horn of the spinal cord and different brain regions (primarily the somatosensorial cerebral cortex) that are involved in processing nociceptive (pain) signals. In the spinal cord, MORs are localized (presynaptic and postsynaptic) to 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. The activation of presynaptic MORs inhibits the release of excitatory neurotransmitters (eg, substance P and glutamate), whereas activating postsynaptic MORs results in the direct hyperpolarization of postsynaptic neurons, causing inhibition of the afferent neural transmission of pain signals 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 (decision-making), piriform cortex, entorhinal cortex (memory and associative functions), hippocampus (opioid-induced consolidation of new memories by increasing LTP in CA3 neurons), fornix, septal nuclei, amygdala (emotional processes), nucleus accumbens (reward, pleasure, and addiction), diencephalic structures that regulate many autonomic processes (eg, hypothalamus), and the mammillary bodies. Immunohistochemistry, in situ hybridization, and radioligand binding have demonstrated that MORs are distributed in the mesencephalon (ventral tegmental area, interpeduncular nucleus, pars reticulata of the substantia nigra, superior colliculus), pons (locus coeruleus), thalamus, and the caudate putamen.[7]
MORs are expressed in the gastrointestinal tract (and are responsible for opioid-induced constipation), the pupil (miosis), and in immune cells (eg, CEM x174 T/B lymphocytes, Raji B cells, CD4+, monocytes/macrophages, neutrophils) that regulate interleukin-4 activity in T-lymphocytes and modulate macrophage phagocytosis and macrophage secretion of TNF-α.[8] Numerous preclinical studies have investigated 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 primarily as an agonist for MORs and minorly for DORs. This peptide is derived from the larger proopiomelanocortin (POMC) peptide and is secreted by the arcuate nucleus of the hypothalamus (via the anterior lobe of the pituitary gland) during stress and exercise. This peptide stimulates glucose uptake, induces euphoria, and inhibits post-exercise pain and muscular fatigue. Because β-endorphin exerts a tonic inhibitory influence upon the secretion of gonadotropin-releasing hormone (GnRH), it also regulates reproductive function.
Other endogenous opioids include the enkephalins that bind DORs and MORs and the dynorphins that 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.
The dynorphins include dynorphin A (17 amino acids long; the first 5 are Leu-enkephalin), dynorphin B (rimorphin), and dynorphin 1-8. They are 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 used to provide pain relief. These opioid drugs include the "weak" opioids codeine and tramadol and the "strong" opioids oxycodone, morphine, hydromorphone, meperidine, tapentadol, methadone, fentanyl, sufentanil, and remifentanil.[13][14]
Experiments conducted on MOR knockout mice revealed that, in addition to pain management, the binding of opioids to MORs can also induce various effects in multiple organ systems. These effects can appear similar to adverse effects and are associated with acute and chronic opioid use. Acute effects include, but are not limited to, respiratory depression, slowed gastrointestinal motility, nausea, vomiting, constipation, dizziness, pruritus, cough suppression, miosis, hallucinations, dysphoria, and sedation.[15][16]
Furthermore, chronic opioid use induces continued activation of the MOR-related signaling pathways (G-protein signaling) and can lead to homeostatic changes (eg, tolerance, hyperalgesia, physical dependence). MORs mediate opioid rewarding and euphoric effects.[17]
The misuse (or abuse) of prescribed opioid drugs after an initial therapeutic use or during self-medication is the root cause of the North American opioid crisis that began in the early 2000s.[18] In 2016, over 20,000 deaths in the United States occurred due to an overdose of prescription opioids; another 13,000 deaths occurred due to a heroin overdose. U.S. epidemiological data indicate that drug overdoses are the leading cause of death in adults younger than 50, and opioids cause more than half of all overdose deaths.
Issues of Concern
Tolerance and Physical Dependence
Concerns about MOR agonists involve opioid tolerance and physical dependence. Consistent stimulation of MORs can ultimately result in drug tolerance, requiring higher doses to achieve the same effect. However, opioid tolerance is usually of limited concern in cancer patients receiving pain treatment, as the need for increasing doses in those patients is usually due to rising levels of pain.
Knowledge of the precise mechanisms underlying tolerance and dependence phenomena is necessary for effective opioid therapy and the development of new pharmacological strategies. For example, studies have recently focused on the role of particular domains and amino acid residues of the MOR in proper receptor function. This research is usually carried out using 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 demonstrate 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. Upon removal of exogenous opioids from the system (eg, through an opioid antagonist), 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 before abrupt discontinuation. The result is withdrawal syndrome, which is defined in ICD-10 as '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.'
Signs of physiological disturbance usually accompany withdrawal syndrome. In contrast, the onset and duration of clinical manifestations, including pain (eg, abdominal cramping, bone pain, diffuse muscle aching), autonomic symptoms (eg, diarrhea, rhinorrhea, diaphoresis, lacrimation, shivering, nausea, emesis, piloerection, CNS 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 accompanied by drug craving, compulsive use, and a strong tendency to relapse after withdrawal.
Clinical Significance
The clinical significance of MORs lies in their ability to provide pain relief. However, clinicians must understand this therapy's effect on patients with overstimulated MORs during 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.[19]
Agonism of the MOR aids in the clinical management of chronic or acute pain. The healthcare team must ensure that the administration of MOR agonists occurs appropriately and safely.[20]
Several recommendations have been made to address the opioid epidemic. For example, opioids should not be considered for chronic pain, especially non-cancer pain. Non-opioid pain medications or nonpharmacological strategies merit consideration as first-choice strategies. However, since managing pain with nonpharmacological or opioid-free approaches is not always possible, opioids must be part of a multimodal strategy.
Opioid therapy should be initiated at the lowest dose possible. Doses of 90 morphine milligram equivalents (MME) or more are more likely to cause adverse drug effects, and clinicians should be cautious at this dose and higher.[21] Immediate release is preferable to longer-acting opioids, which are reserved for severe pain conditions requiring daily, continuous treatment. Finally, for acute treatment (eg, postoperative pain), the administration should last less than 7 days.
Research Perspectives
The changes produced by the use of opioids occur on a large scale that is morphologically documented. Gray matter changes in patients with chronic pain are apparent after only 1 month of morphine administration, and these alterations can persist for up to 5 months after terminating therapy.[22]
Further research is needed to identify the precise residues responsible for ligand selectivity, the mechanism of ligand-dependent endocytosis (eg, the phosphorylation patterns), and the potential modulation of the G protein/cAMP pathway against down-regulation mechanisms. Other research involves allosteric modulators of MOR activity, including compounds BMS-986123 and BMS-986124, which 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).
Genetic aspects are an essential variable for interpreting the effects linked to the use/misuse of opioids. Genetic variations in the OPRM1 gene can influence the response to opioids, including the dose needed to achieve pain relief. Studies have demonstrated that these variations (single nucleotide polymorphism Asn40 -> Asp) can be associated with an increased risk of opioid addiction.[23]
Other genes (and their polymorphisms) related to neurotransmitter pathways (dopaminergic and serotoninergic), growth factors, and differentiation processes are also involved in opioid response and tolerance. In vivo investigations demonstrated that MORs could physically associate with another opioid (eg, μ-δ heteromers) or non-opioid receptors to form heteromers regulated by various conditions. These heterodimer formations could explain the role of opioids in mediating addiction to substances such as ethanol, cocaine, nicotine, and cannabinoids. Heterodimers demonstrate specific ligand binding, signaling, and trafficking properties and represent a potential therapeutic target.[24]
Eluxadoline is the first drug developed to target these heteromers. This agent is a combination MOR agonist-DOR antagonist approved by the Food and Drug Administration (FDA) for treating irritable bowel syndrome. Other compounds (eg, CYM51010) are being developed for an analgesic effect similar to morphine with less tolerance.[25][26]
Opioid Addiction: Receptors and Strategies
Clinicians can administer "milder" opioids as maintenance therapy for opioid addiction, a chronic disease that can cause significant health, social, and economic problems. As MOR agonists with rapid onset of action and short half-lives (eg, heroin) induce immediate reward followed by noticeable withdrawal symptoms, clinicians must be aware that these drugs have the most significant destructive and addictive potential. A potential therapy strategy involves prescribing "milder" opioids to replace more dangerous ones.
MOR agonists with a delayed onset of action and longer half-life (eg, methadone) can induce dependence without precipitating destructive behaviors and have a reduced impact on mood, judgment, and psychomotor skills. Buprenorphine is a partial MOR agonist that induces all the typical opioid effects up to a certain limit; this is termed the ceiling effect. Increasing the dose does not increase effects such as euphoria, limiting cravings, and withdrawal symptoms.
The ceiling effect of buprenorphine also places a limit on respiratory depression. Additionally, because buprenorphine has a very high affinity for opioid receptors, other full agonists, such as heroin, have difficulty displacing it. Using buprenorphine while heroin (or another opioid ligand) is already bound to MORs can induce an antagonist effect with a sudden drop in receptor activation, which can be experienced as withdrawal. Buprenorphine should only be introduced when the full opioid agonist has dissociated from the receptor. Tools such as the Clinical Opioid Withdrawal Scale can guide this replacement process for addiction treatment.[27]
Enhancing Healthcare Team Outcomes
The interprofessional healthcare team needs to work collaboratively to address pain control in their patients sufficiently. The team should schedule their patients for routine follow-up visits, including a history and physical exam, to monitor for adverse drug effects and signs of drug misuse. Monitoring for signs of drug misuse of the μ-opioid receptor (MOR) agonists is crucial because of the epidemic rates of drug misuse, particularly in the USA, and death due to respiratory depression.
Methods for monitoring drug abuse as well as drug diversion include assessment surveys, state prescription drug monitoring programs, urine screening, adherence checklists, motivational counseling, and dosage form counting (eg, tablet counting).
Managing a MOR agonist overdose requires an interprofessional team of healthcare professionals, including physicians, advanced practice practitioners, nursing staff, laboratory technologists, and pharmacists. Without proper management, the morbidity and mortality from MOR agonist overdose is high. Once a patient with MOR agonist overdose is admitted, the emergency department clinician and assigned nurse are responsible for coordinating care, which includes the following:
Ordering drug concentrations in blood and or urine
Monitoring the patient for signs and symptoms of respiratory depression, cardiac arrhythmias, and narcotic bowel syndrome
Performing various maneuvers to limit drug absorption
Consulting with the pharmacist about the use of activated charcoal and naloxone
[28] Consulting with a toxicologist and nephrologist on further management, which may include dialysis
Consulting with the radiologist about imaging to ensure that the patient has not swallowed any drug packages
Consulting with the intensivist about intensive care and monitoring while in the hospital
Managing a MOR agonist overdose does not stop in the emergency department. Once the patient is stabilized, the interprofessional team must determine how and why the patient overdosed. Consult with a mental health counselor is indicated if the overdose was intentional, and risk factors for self-harm must be determined. The possibility of addiction and withdrawal symptoms must be considered. Only by working as an interprofessional team with open communication and shared decision-making can the morbidity of a patient with MOR agonist overdose be decreased. Initial short-term data reveal that naloxone administration can be life-saving.[28] The long-term outcomes of detoxification and drug rehabilitation remain unknown.[29][30]
