Question 12(p.2)

Describe the mechanism of action of the analgesic effect of opiates (70% marks). Explain the mechanisms by which morphine causes respiratory depression and constipation (30% marks).

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College Answer

This was a multi-part question, for which many candidates failed to apportion their  time as indicated by the question. Most patients who enter Intensive Care receive opioid analgesia so candidates were expected to have detailed knowledge about the mechanics of action of opiates. For a good answer candidates were expected to 
mention that opiate agonists produce analgesia by binding to Mu receptors (which are G protein coupled) in the central and peripheral nervous system and spinal cord and their cellular mechanism of action eg presynaptic neurone - close voltage gated Ca channels and prevent neurotransmitter release and post synaptic neurone -
hyperpolarise and inhibit post synaptic neurone. The fact that opiates also affect emotional side of pain and cause euphoria which may help with pain perception was often omitted.
Mechanism of respiratory depression is mediated via mu receptor. It occurs at normal analgesic doses, and decreases the chemosensitivity of the respiratory centre to PaCO2 Mechanism of constipation results from increased tone and decreased motility of the GIT via action on visceral smooth muscle mediated by intramural nerve plexus and all three opioid receptors. Many candidates had poor organisation and poor knowledge of all aspects of this question.
Syllabus: G2d 2b
Reference: Pharmacology, Rang and Dale pgs 600-601, Basic and Clinical 
Pharmacology, Katzung pg 492



Mechanism of opioid-induced analgesia is by two main effects:

  • Spinal μ-receptor effect:
    • Presynaptic inhibition of neurotransmitter (glutamate) release from primary nociceptive afferent neurons
    • Thus, decreased transmission of nociceptive signals to the dorsal horn neurons
  • Midbrain μ-receptor effect:
    • Inhibition of GABA-ergic input into the periaqueductal grey matter
    • Thus, decreased inhibition of descending efferent regulatory fibres which project from the periqaueductal grey matter to the dorsal horn
    • Thus, increased descending inhibition of dorsal horn neurons.

Mechanism of opioid-induced respiratory depression is mediated by two main mechanisms: 

  • Brainstem μ-receptor effect:
  • Medullary chemoreceptor (also a μ-receptor effect):
    • Opioids decrease the sensitivity of the medullary chemoreceptors to hypoxia and hypercapnia
    • This blunts the normal response to hypoventilation

Mechanism of opioid-induced constipation:

  • δ- and κ-opioid receptors are expressed in the enteric nervous system (Townsend et al, 2004)
  • This produces direct activation of smooth muscle cells, leading to:
    • Constant tonic contraction of smooth muscle
    • Inhibition of normal intestinal secretions
    • Inhibition of peristalsis
  • Little tolerance seems to develop to this effect


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Waldhoer, Maria, Selena E. Bartlett, and Jennifer L. Whistler. "Opioid receptors." Annual review of biochemistry 73.1 (2004): 953-990.

Pasternak, Gavril W. "Molecular biology of opioid analgesia." Journal of pain and symptom management 29.5 (2005): 2-9.

Chahl, Loris A. "Opioids-mechanisms of action." (1996).

Manzke, Till, et al. "5-HT4 (a) receptors avert opioid-induced breathing depression without loss of analgesia." Science 301.5630 (2003): 226-229.

Townsend, DeWayne, Philip S. Portoghese, and David R. Brown. "Characterization of specific opioid binding sites in neural membranes from the myenteric plexus of porcine small intestine." Journal of Pharmacology and Experimental Therapeutics 308.1 (2004): 385-393.