23B09: Exam Report

Outline the classification, structure and distribution of the opioid receptors (50% marks). Describe the intracellular events following opioid receptor activation (50% marks)

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This question was asked in a specific way to provide candidates with a template for their answer.

The classification most commonly used for opioid receptors (μ(MOP), δ(DOP), k(KOP) & NOP) and a description of the important characteristics or differences between them was expected.

A description of their central and peripheral distribution was required including specific central nervous system sites such as pre and post synaptic locations in the brain (ie. the periaqueductal gray, locus ceruleus and amygdala) and spinal cord (ie. primary afferent neurons in the dorsal horn).

Opioid receptors as a class are transmembrane spanning G protein receptors that have significant downstream effects including presynaptic inhibition of neurotransmitters of primary afferent neurons such as noradrenaline and substance P, and postsynaptic inhibition of membrane depolarization of dorsal horn nociceptive neurons.

Specifity of detail in descriptions of these actions was expected.

K3i / 23B09: Outline the classification, structure and distribution of the opioid receptors (50% marks). Describe the intracellular events following opioid receptor activation (50% marks)

Opioid receptors

Are transmembrane spanning GiPCR (G Inhibitory Protein Coupled Receptors)

Opioid receptors are present throughout the CNS

  1. Brain (cortex, amygdala, locus coeruleus, periaqueductal grey, respiratory centre etc)
  2. Spinal cord (primary afferent neurons in the dorsal horn)
  3. Peripherally (terminal sensory nerves, soft tissue etc)

When stimulated by opiates, GiPCR (inhibitory) are activated via the following steps:

  1. Decreasing conversion of GDP to GTP
  2. Decreasing α subunit binding (G-protein coupled receptors contain three units: α, β, γ)
  3. Decreasing dissociation of α-GTP subunit
  4. Inhibiting activation of adenylyl cyclase
  5. Decreasing levels of intracellular cAMP
  6. Decreasing protein kinase A
  7. Decreasing phosphorylation of various proteins
  8. Decreasing signal amplification and transmission to the target molecules

Pre-synaptically

  • Activation causes closure of voltage gated calcium channels and a reduction in neurotransmitter release (such as noradrenaline and substance P).

Post-synaptically

  • Activation causes stimulation of potassium efflux from the cell, leading to hyperpolarization of the membrane and inhibition of membrane depolarization (such as in dorsal horn nociceptive neurons).

Overall

  • This leads to a reduction in neuronal cell excitability, resulting in reduced transmission of nociceptive impulses.

There have been 4 different opioid receptors

  1. Mu (MOP) – broad distribution with wide range of effects, only receptor to cause N/V
  2. Kappa (KOP) – contribute to analgesia at the spinal level; does not tend to cause respiratory depression
  3. Delta (DOP) – less widely distributed; also contributes to analgesia
  4. NOP – produces effects similar to MOP stimulation

Opioid Receptor effects

1) Mu (MOP)

  1. Analgesia (spinal and brain)
  2. Euphoria and dysphoria (likely due to supraspinal actions, possibly at the level of the limbic system). The euphoria is often useful in reducing the emotional aspect of pain.
  3. Respiratory depression
    1. ↓↓ RR more than ↓VT, overall dose-dependent ↓ MV
    2. Reduced chemoreceptor sensitivity to PaCO2, ↑apnoeic threshold
  4. Constipation
    1. Reduced GIT secretions and motility via direct action on visceral smooth muscle, mediated by inhibition of the auerbach (myenteric) nerve plexus (involves all three opioid receptors – MOP, DOP and KOP)
  5. Miosis (via stimulation of the Edinger-Westphal nucleus)
  6. Nausea and vomiting (via CTZ) – Only opioid receptor to cause nausea/vomiting
  7. Sedation
  8. Bradycardia
  9. Inhibition of gut motility
  10. Urinary retention
  11. Physical dependence

2) Kappa (KOP)

  1. Analgesia (predominantly spinal)
  2. Sedation
  3. Miosis
  4. Dysphoria
  5. Less respiratory depression

3) Delta (DOP)

  1. Analgesia
  2. Respiratory depression
  3. Urinary retention
  4. Physical dependence
  5. Minimal constipation

4) N (NOP)

  1. Anxiety
  2. Depression
  3. Change in appetite
  4. Hyperalgesia at low doses and Analgesic at high

Author: Daniel Chan