Question 24

College Answer

This question was poorly answered with a low pass rate; which was unexpected for this core topic. In general, completed answers demonstrated good understanding of the analgesic  mechanisms of opiates, but only superficial understanding of respiratory depression and constipation. Better answers explained the decreased responsiveness of the respiratory centre to CO2, and the effects of opiates on the enteric nervous system and peristalsis.

Discussion

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:
  • The target is the pre-Bötzinger complex in the ventrolateral medulla (Manzke et al, 2003)
  • This the respiratory pacemaker centre
  • Here, opioids decrease the rate of firing, and at high doses produce a Mobitz-type effect, where some breaths are skipped
• 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

Bernards, Christopher M. "Understanding the physiology and pharmacology of epidural and intrathecal opioids." Best Practice & Research Clinical Anaesthesiology 16.4 (2002): 489-505.

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.