2016B12 Explain the mechanisms by which intravenous morphine produces analgesia.
Your answer should focus on the location and function of mu opioid receptors.

· Cellular effects

· Supraspinal

· Spinal

· Peripheral

· Complication of analgesia: opioid-induced hyperalgaesia and tolerance

Signalling cascade

Effects

· ↓cAMP

· ↓VDCC activation

· ↑K⁺ efflux -> hyperpolarisation

Receptor	Mu mostly (K and N/OFQ may be pro-nociceptive)
Locations	· Brainstem: peri-aqueductal grey matter, rostral ventromedial medulla, nucleus raphe magnus · Other: thalamus, hypothalamus, cortex
Effects of opioids	· ↑Descending modulation · Central effects
Diagramme	Rostral ventromedial medulla cells: · Note many other ascending/descending inputs/outputs · Note noradrenaline is anti-nociceptive; serotonin is both pro- and anti-nociceptive

Receptor	· M, K, D
Location	· Dorsal horn, especially layer 2 · Major: pre-synaptic = 1° afferent = nociceptor · Minor: post-synaptic = 2° afferent = projection neuron (nociceptive specific or wide dynamic range)
Effect	· ↓Ascending nociceptive signal · No direct effect on glutamatergic transmission; ineffective for chronic or neuropathic pain
Diagramme

Tolerance

· ↓Duration then ↓intensity of effect of a given drug dose with long term use

· Occurs over days-weeks

· Multiple causes: e.g. downregulation of receptors, upregulation of cAMP

Hyperalgaesia

· ↑Pain with chronic opioid use; including hyperalgaesia and allodynia

· Multiple causes: ↑NMDA activation, descending facilitation, receptor dysfunction (Gi -> quasi G_s)