25A19: Exam Report

  1. Describe the intracellular events that occur following opioid receptor activation (25% of marks).

  2. Describe the locations where opioids produce analgesia and the mechanisms by which they exert these effects (45% of marks).

  3. Outline the mechanism by which morphine causes the following side effects:

    1. Respiratory depression (15% of marks).

    2. Constipation (15% of marks)

43% of candidates passed this question.

  1. Opioids act on several receptors and a reasonable understanding of these is required to answer this question. A description of the intracellular events following ligand binding on G protein coupled opioid receptors, as well as pre and postsynaptic effects on calcium channels and potassium channels was required to score well in the first part.
  2. A detailed description of the peripheral, spinal cord and supra-spinal opioid receptors including their activation and transmission pathways was required for a comprehensive answer.
  3. Here the receptor, location and mechanism that brings about these common opioid side effects was needed to answer this component of the question.

K4ii / 25A19: Describe the intracellular events that occur following opioid receptor activation

a) Describe the intracellular events that occur following opioid receptor activation

Opioid receptors are transmembrane spanning GiPCR (G Inhibitory Protein Coupled Receptors). When stimulated by opiates, GiPCR (inhibitory) are activated via the following steps:

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

b) Receptor locations for modulation of pain pathways

Peripheral sites

Free nerve endings of nociceptive primary afferent neurons in inflamed or injured tissues

  • Opioid receptor activation ↓excitability of peripheral nociceptors by ↓Na+ and ↓Ca2+ influx
  • This attenuates nociceptor sensitisation caused by inflammatory mediators (bradykinin, PG)

Spinal Cord level

Pre-synaptic terminals of primary afferent neurons in the dorsal horn (laminae I and II)

  • Activation of opioid receptors
    → ↓Ca2+ influx
    → ↓release of glutamate and substance P (both excitatory neurotransmitters)

Post synaptic neurons projecting to the brain

  • Activation of opioid receptors
    → ↑K+ efflux
    → ↑membrane hyperpolarisation and ↓AP propagation
    → ↓ascending nociceptive transmission

Midbrain / Brainstem

Periaqueductal grey (Opioid receptor activation triggers descending pain inhibition pathways)

Locus coeruleus (Mediates descending noradrenergic inhibition)

Rostroventral Medial Medulla (Mediates descending serotonergic inhibition)

  • Activation of opioid receptors
    → Descending inhibitory pathways
  • Release of Serotonin and Noradrenaline
    → ↓ Nociceptive transmission

Limbic / Cortex

Amygdala and prefrontal cortex (Changes modulation of pain)

  • Activation of opioid receptors
    → Euphoria
    → ↓Distress
    → ↓Pain perception
    → ↓Emotional reactivity

Peripherally

Sensory neurons and soft tissues

Opioid

Spine

Dorsal horn

Opioid and NMDA

Brainstem

Periaqueductal grey

Locus coeruleus

Rostroventral medial medulla

Opioid

Noradrenergic

Serotonergic

Limbic

Amygdala

Posterior hypothalamus

Opioid

Dopaminergic

Cortex

Prefrontal cortex

Opioid

ci) Respiratory Depression

  • Morphine activates MOP receptors in the medullary respiratory centres
    1. ↓Chemoreceptor sensitivity to PaCO₂ → ↑apnoeic threshold
    2. ↓RR is more prominent than ↓TV
  • Overall leading to dose-dependent ↓ MV

cii) Constipation

  • Morphine activates MOP, KOP and DOP in the myenteric plexus (Auerbach’s) of the GI tract
    1. ↓ Peristalsis → ↑GI transit time
    2. ↓ Intestinal secretions → hard dry stools
    3. ↑ Sphincter tone
  • Overall leading to constipation

Author: Daniel Chan