FRCA Notes

Opioid Receptors

Resources

  • Opiates are any naturally occurring substance with morphine-like properties (e.g. endogenous opioids, morphine, codeine)

  • Opioids include synthetic substances that have an affinity for opioid receptors
  • All opioids are amines in structure, and weak bases

  • A narcotic is a drug that possesses both analgesic and sedative properties
  • Each opioid receptor is coded for by a single gene
  • Pharmacologically defined subtypes of each receptor can occur, however, owing to the consequence of a number of processes at the genetic level e.g. alternative gene splicing

Original (classical) receptors

  • The Mu (μ) receptor (MOP) - so-called because morphine was the first described agonist
    • There are at least two MOP receptor subtypes

  • The Kappa (κ) receptor (KOP) - so-called because ketocyclazocine was an agonist
    • There are multiple KOP receptor subtypes e.g. κ1a, κ1b, κ2a, κ2b and κ3

  • The Delta (δ) receptor (DOP) - so-called because it was isolated from tissue located in the vas deferens
    • There are two DOP receptor subtypes

Other opioid receptors

  • The Nociceptin/Orphanin-FQ peptide (NOP) receptor - so-called because endogenous opioid nociceptin/orphanin-FQ (N/OFQ) is a ligand

  • The Zeta (ζ) receptor - now commonly referred to as the opioid-growth factor receptor (OGFr)
    • Found in a variety of organ tissues, it mediates met-enkephalin induced cellular growth and regulation of cancer cell proliferation
    • Not typically included in lists of opioid receptors

  • The sigma (σ) opioid receptor is no longer classified as such because it does not fulfil the criteria of an opioid receptor, namely naloxone does not reverse the effect of its stimulation

Provision of anti-nociception (analgesia)

  • The analgesic action of endogenous & exogenous opioids is by modulating both the afferent and efferent parts of the pain pathway
  • This occurs via two mechanisms:
  1. Reducing afferent signalling in the substantia gelatinosa of the spinal cord
    • Activation of pre-synaptic opioid receptors reduces neurotransmitter release e.g. substance P
    • This action occurs at the interface between primary and second-order neurons, as well as at second-to-third order transmission

  2. Increasing activity at descending inhibitory pathways to the dorsal horn from the peri-aqueductal gray via the nucleus raphe magnus
    • Resting tone in GABA-ergic interneurones reduce descending inhibitory pathway activity
    • Opioids inhibit GABA release from these interneurones
    • This 'inhibits the inhibitors' i.e. causes activation of the inhibitory descending pathways
    • There is therefore reduced activity at afferent nociceptive pathways in the dorsal horn

Classic cellular mechanism

  • All four main opioid receptors (MOP, KOP, DOP and NOP) are metabotropic, Gi (inhibitory) G-protein coupled receptors

  • The classic ligand-receptor effect is that of opioids binding the opioid receptor at the orthosteric site, triggering a typical Gi-protein coupled receptor cascade
    • Closing of voltage-sensitive calcium channels
    • Stimulation of potassium efflux by increasing potassium channel conductance
    • Adenylyl cyclase inhibition and reduced cAMP production

  • This results in:
    • Hyperpolarisation of the cell membrane
    • Reduced neuronal cell excitability
    • Inhibition of neurotransmitter release
    • Reduction in nerve impulse transmission
  • This G-protein pathway is responsible for the analgesic effects of opioid receptor activation

Newer understanding of opioid receptor mechanisms

  • Greater understanding of opioid receptor pharmacology has seen a move away from the classic 'lock and key' ligand-receptor binding model
    • Opioid receptors exist as monomers, but can interact physically to create dimers which are either homo-dimers (e.g. two MOP receptors) or hetero-dimers (e.g. an MOP and DOP receptor)
    • Receptors are also subject to allosteric modulation (i.e. binding of a molecular at a site other than the 'main', orthosteric site)
    • This leads to varying downstream effects of the receptors depending on the way in which they are stimulated

  • Opioid receptors also couple to multiple downstream signalling pathways, and therefore, have ‘pluridimensional efficacy’
  • The most relevant is the β-arrestin-2 pathway, which is the 'off' switch for opioid receptors
    • Once the opioid G-protein coupled receptor is activated (phosphorylated), β-arrestins are recruited
    • β-arrestins both block G-protein signalling and internalise (endocytose) the receptor
    • β-arrestins also act as a scaffold for activation of mitogen-activated protein kinase (MAPK) pathways
    • The β-arrestin pathway is heavily linked to the adverse effects of opioids including ventilatory depression and GI side-effects

  • In addition to the classic G-protein and β-arrestin pathways, opioid receptors are linked to pathways such as:
    • Those involving extracellular signal-regulated protein kinases 1 and 2
    • The p38 pathway
    • The Jun N-terminal kinase pathway

  • This leads to the concept of biased agonism at opioid receptors: activation of the G-protein pathway but not the β-arrestin pathway could provide potent analgesia without side-effects

Central

  • Cerebral cortex
  • Peri-aqueductal gray
  • Nucleus tractus solitarius and raphe magnus
  • Thalamus
  • Spinal cord: laminae I and II of the dorsal horn, especially the substantia gelatinosa

Peripheral

  • High concentration in the enteric nervous system
  • Activation of opioid receptors in the enteric nervous system increases smooth muscle tone leading to loss of peristalsis

  • Peripheral afferent nerve terminals (pre-synaptic)

  • Coded for by the MOR (OPRM1) gene on chromosome 6
    • Undergoes alternative splicing in different tissues, leading to receptor subtypes
    • Mutations exist in the OPRM1 gene that increases the EC50 of morphine and morphine-6-glucuronide

Distribution

  • Widely located throughout the CNS:
    • Supraspinal areas
      • Cerebral cortex
      • Basal ganglia - highest concentration of MOP receptors is found in the caudate putamen of the basal ganglia
      • Amygdala

    • Peri-aqueductal gray
      • A high density of MOP receptors is found at the origin of the descending inhibitory control pathway
      • Analgesia is mediated by blocking the resting, inhibitory GABAergic activity which itself reduces anti-nociceptive outflow from the PAG

    • Spinal cord
      • Pre-synaptically on primary afferent neurones within the dorsal horn
      • Acts to inhibit nociceptive transmission by inhibiting glutamate release and transmission of nociceptive stimuli in C- and Aδ-fibres

Effects of MOP agonism

  • Respiratory: respiratory depression by reducing chemoreceptor sensitivity to CO2
  • Cardiovascular: bradycardia
  • CNS:
    • Spinal and supraspinal analgesia, particularly to thermal pain
    • Euphoria
    • Sedation
    • Meiosis due to stimulation of Edinger-Westphal nucleus
    • Altered thermoregulation
  • Gastrointestinal:
    • Inhibition of gut motility by reducing peristalsis and secretions, leading to constipation
    • Nausea and vomiting
  • Psychiatric: tolerance, dependence
  • Other:
    • Altered hormonal and immune function
    • Pruritus (action on peripheral opioid receptors)
    • Urinary retention (action on peripheral opioid receptors)

  • Coded for by the OPRK1 gene on chromosome 8
  • Found predominantly in the spine

Effects of KOP agonism

  • CNS:
    • Spinal analgesia
    • Sedation
    • Dysphoria
    • Meiosis due to stimulation of Edinger-Westphal nucleus
    • Theoretical neuroprotective effect via ability to inhibit post-ischaemic glutamate release
  • Inhibition of ADH
  • Less pruritus than MOP agonism

  • As such the main advantage of κ-receptor stimulation is that it provides analgesia but doesn't cause respiratory depression
  • However, most κ-agonists are also μ-antagonists, limiting their use
  • Trials of pure synthetic KOP agonists (spiradoline and enadoline) were beset by side-effects such as diuresis, sedation and dysphoria at sub-analgesic doses

  • Coded for by the OPRD1 gene on chromosome 1

Distribution

  • Less widely spread throughout the CNS and mostly confined to spinal areas
  • Highest density of receptors in the CNS are in the:
    • Olfactory bulb
    • Cerebral cortex
    • Nucleus accumbens
    • Caudate putamen of the basal ganglia

Effects of DOP agonism

  • Respiratory depression
  • CNS:
    • Spinal analgesia
    • Inhibition of other neurotransmitter release
    • Regulating mood and movement
    • Growth hormone release
  • Reduced GI tract motility vs. MOP agonism

  • Evidence points to effects of DOP receptors in moderating MOP-derived effects, including both analgesic synergism and reduction in MOP-mediated side-effects

  • Formerly known as LC123 or ORL-1
  • Classified as a non-opioid member of the opioid receptor family
  • Similar structure and localisation to the classical opioid receptors but insensitive to naloxone
  • Natural ligand is nociceptin/orphanin FQ

Distribution

  • Acts predominantly at spinal levels, but some supraspinal effect in the rostral ventromedial medulla
    • Supraspinal receptor agonism leads to pro-nociceptive/anti-analgesic effects by reversing the action of other opioid agonists
    • Spinal receptor agonism causes either hyperalgesia (low doses of agonist) or analgesia (high doses of agonist)
    • Synthetic NOP receptor antagonists produce long-lasting analgesia

Effects of NOP agonism

  • Receptor agonism produces cellular effects similar to those of classic opioids i.e. reduced neuronal excitability, inhibition of neurotransmitter release
  • Clinical effects of this include effects on locomotion, stress/anxiety, learning and memory, reward/addiction and urogenital activity

  • The system plays a role in development of opioid tolerance:
    • Knockout mice partially lose tolerance to morphine
    • Chronic morphine-tolerant mice show N/OFQ up-regulation
    • Selective NOP antagonists attenuate morphine tolerance
    • NOP receptor and MOP receptor co-activation with cebranopadol produces analgesia with delayed induction of tolerance and lack of respiratory depression

Multi-target strategy

  • There is marked interaction between opioid receptor subtypes, e.g. due to signalling interactions or formation of dimers
  • For example, providing MOP agonism (e.g. morphine) and DOP antagonism (e.g. naltrindole) in tandem can lead to analgesia with reduced morphine tolerance
  • Multi-receptor targeting with non-selective ligands flies in the face of the classic pharmacological dogma that selectivity reduces adverse effect profile
  • A multi-valent ligand which is able to cause multiple opioid receptor effects simultaneously could prove clinically highly effective by maintaining analgesic properties and reducing side-effect burden

  • For example:
    • The bivalent ligand UFP-505 is a MOP agonist/DOP antagonist although not clinically available
    • The trivalent ligand DPI-125 demonstrates DOP, MOP and KOP agonism but with selectivity for DOP receptors and produces analgesia, reduced ventilatory depression and reduced abuse liability
    • The mixed opioid-NOP ligand cebranopadol is a highly efficacious partial NOP and MOP agonist, which demonstrates anti-nociceptive, -inflammatory and -neuropathic effects with no ventilatory depression and slowly-developing tolerance
    • The mixed opioid-NOP ligand AT-121; is also a highly efficacious partial NOP and MOP agonist which (in animal models) demonstrates analgesia without ventilatory depression, hyperalgesia or dependence

Biased agonism

  • Biased agonism is the principle that a particular ligand drives one signalling pathway instead of another one, which produces a therapeutic advantage
  • For example, opioid receptor agonists which drive the Gi-pathway but not the β-arrestin-2 pathway could provide high-quality analgesia but with reduced adverse effects such as tolerance or respiratory depression
  • This can be achieved by avoiding stimulation of the sixth/seventh transmembrane domain of the opioid G-protein coupled receptor, which is responsible for propagating the arrestin pathway

  • Thus far, drugs designed to produce biased agonism (oliceridine, PZM21) have instead produced partial agonism
    • They cause relative amplification of the Gi pathway compared to the arrestin pathway, leading to a response similar to that of a biased agonist
    • There is some suggestion that the mixed opioid-NOP ligand cebranopadol demonstrates Gi-signalling biased agonism

Allosteric modulators

  • Allosteric modulators bind to sites on the opioid receptor other than the main orthosteric site
  • They modify the activity of drugs which bind to the orthosteric site
  • They can be positive, negative or neutral (silent)
  • Positive allosteric modulators can enhance selective endogenous opioid action, resulting in reduced need for exogenous opioids and/or lower doses
  • This could result in similar levels of analgesia without the adverse effects of exogenous opioids
  • Positive allosteric modulators of the opioid receptors have been demonstrated in animal models to produce good quality analgesia with reduced ventilatory depression, constipation and reward

Co-administration

  • MoxDuo is a mixture of morphine and oxycodone in a 3:2 ratio
    • It was designed in the hope of providing opioid synergy, itself demonstrated in animal studies, thus reducing both the total opioid dose and the side-effect profile
    • Phase III clinical trials of MoxDuo vs. either constituent drug in isolation failed to demonstrate synergy, and the adverse event rate was similar

  • Targinact is a mixture of oxycodone and naloxone
    • Naloxone, owing to first-pass metabolism, does not enter the CNS in appreciable amounts
    • The hope was that this would lead to analgesia (oxycodone acting on the CNS) but reduced gastrointestinal side-effects (naloxone acting on gastrointestinal opioid receptors)
    • Studies to date demonstrate improved side-effect profile vs. oxycodone alone in patients with moderate-severe chronic pain which can be managed by opioids

Epigenetics

  • Epigenetics involves altering DNA expression without altering the underlying nucleotide sequence
  • Opioid receptor expression and function is regulated by epigenetic mechanisms and could be manipulated to alter pain processing and management
  • Data demonstrates that epigenetics plays a role in several pain syndromes and opioid addiction/misuse
    • In both short-term therapeutic opioid use and opioid use disorders, hypermethylation of MOP receptor promoters occurs, reducing central MOP receptor expression
    • Dose-dependent, enhanced histone acetylation occurs in heroin users
    • Histone deacetylase upregulation plays a role in several neuropathic pain syndromes, ultimately reducing MOP expression and MOP-mediated analgesia
    • A wide range of pain syndromes are associated with alterations to microRNA function, which is also implicated in tolerance by altering MOP receptor gene translation