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ICU Primary Snippet 30- Opioid Receptors – Classification, Distribution and Activation

Dr Swapnil Pawar April 1, 2024 21


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    ICU Primary Snippet 30- Opioid Receptors – Classification, Distribution and Activation
    Dr Swapnil Pawar

Outline the classification, structure and distribution of opioid receptors. Describe intracellular events following opioid receptor activation

Written by Dr Madhuri Anupindi

Classification:

  • MOP or mu opioid receptor
  • DOP or delta
  • KOP or kappa
  • NOP: nociceptin, does not bind or respond to the opioid antagonist naloxone

Structure

  • G protein coupled receptors: consists of seven hydrophobic transmembrane alpha helices connected by three intracellular hydrophobic and three extracellular loops, an extracellular N-terminus and an intra-cellular C-terminus
  • Ligands are endogenous opioids such as endophins, enkephalins and nociception or exogenous opioids such as morphine
  • Ligands bind to the binding pockets located in the transmembrane helices
    • Binding pocket has two distinct regions:
      • Intracellular side: opioids can attach but it is non-specific
      • Extra-cellular side: divergent residues that confer selectivity to opioid receptor types

Distribution:

  • Opioid receptors are distributed pre-synaptically in axon terminals and post-synaptically in neuronal cell bodies and dendrites throughout the central nervous system and peripheries:
    • CNS: present in the anterior cingulate cortex, primary somatosensory cortex, periaqueductal gray, rostral ventral medulla, locus ceruleus, limbic system and substantia gelatinosa in the dorsal horn of the spinal cord
    • Peripheries: peripheral terminals of sensory nerves, gastrointestinal autonomic nervous system, cardiac tissue, baroreceptors in carotid bodies and vagi, mechanoreceptors of airways and lungs
  • Mu receptors: has 3 subtypes, is the most highly expressed of all opioid receptors
    • Endogenous ligands: beta-endorphin, endomorphin 1 and 2
    • Agonism: responsible for most of the analgesic effects of opioids but also for respiratory depression, cardiovascular depression, sedation, meioisis, nausea, diuresis and constipation
    • Dependence and tolerance of opioids is also thought to be due to persistent activation of mu receptors
  • Kappa receptors: has 3 subtypes
    • Endogenous ligands: dynorphin A and B
    • Agonism: analgesia, sedation, dysphoria and meioisis
  • Delta receptors: 2 subtypes, less widely distributed, mainly found in olfactory bulb, cerebral cortex and caudate putamen
    • Endogenous ligand: enkephalins
    • Agonism: analgesia and decreased gastric motility
  • NOP receptor: one subtype
    • Endogenous ligand: nociceptin/orphanin FQ
    • Agonism: hyperalgesia at low doses and analgesia at higher doses, implicated in development of tolerance to opiates

Opioid receptor activation:

  • Ligand binding to the opioid active site results in conformation change of the receptor à activates intracellular G protein à inhibits voltage gated calcium channel, inhibits adenylyl cyclase which reduces cAMP production, and activates potassium channels resulting in hyperpolarisation à reduces neuronal excitability and inhibits release of neurotransmitters such as glutamate and substance P from nociceptive fibres
    • Pre-synaptically: inhibits neurotransmitter release
      • g. Periaqueductal grey (PAG) in the midbrain is involved in central control of nociceptive transmission. The pathway from the PAG to the spinal cord is called the descending inhibitory control pathway as it inhibits nociceptive transmission in afferent fibres
        • At rest GABA inhibits efferent outflow from the PAG à reduces antinociceptive outflow
        • Activation of opioid receptor à inhibits GABA à stimulates antinociceptive outflow to spinal cord
      • Post-synaptically the opioid receptors inhibit neurotransmission by hyperpolarising neurons mainly via activation of G protein gated inwardly rectifying potassium channels à reduces excitability

 

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