Opioid Receptor Signalling, Analgesia & Adverse Effects

Intracellular events following opioid receptor activation

• Opioid receptors — μ (MOR), κ (KOR), δ (DOR) and NOP — are 7-transmembrane G-protein-coupled receptors coupled predominantly to inhibitory Gi/Go proteins.
• Agonist binding causes receptor conformational change, GDP–GTP exchange on the Gα subunit and dissociation of Gα from Gβγ.
• Inhibition of adenylyl cyclase → ↓ cAMP → ↓ protein kinase A activity.
• Presynaptic: Gβγ inhibits voltage-gated Ca²⁺ channels → ↓ Ca²⁺ influx → ↓ release of glutamate, substance P and CGRP.
• Postsynaptic: activation of inwardly rectifying K⁺ channels → ↑ K⁺ conductance → membrane hyperpolarisation → ↓ neuronal excitability.

Net effect: reduced presynaptic neurotransmitter release plus reduced postsynaptic excitability → inhibition of nociceptive neurotransmission.

Sites and mechanisms of opioid analgesia

Peripheral action

• Opioid receptors are present on peripheral nociceptive afferents, particularly in inflamed tissue.
• Activation reduces Ca²⁺ influx and excitatory transmitter release, reducing nociceptor signalling.

Spinal action

• Presynaptic: μ receptors on Aδ- and C-fibre terminals inhibit voltage-gated Ca²⁺ channels → ↓ glutamate, substance P and CGRP release.
• Postsynaptic: μ receptors on dorsal horn neurons increase K⁺ conductance → hyperpolarisation → ↓ firing.
• Overall effect: ↓ ascending nociceptive transmission.

Supraspinal action

• Important sites include the periaqueductal grey and rostral ventromedial medulla.
• Opioid receptor activation inhibits GABAergic interneurons → disinhibition of descending antinociceptive neurons.
• Descending pathways then suppress nociceptive transmission in the spinal dorsal horn.

Higher cerebral effects

• Opioids modify pain perception and the emotional response to pain.
• Euphoria and sedation may reduce the affective component of pain.

Morphine adverse effects

Respiratory depression

• Receptor: predominantly μ-opioid receptor.
• Site: brainstem respiratory centres, including the ventrolateral medulla / pre-Bötzinger complex and medullary chemoreceptor pathways.
• Mechanism: Gi/Go-mediated neuronal inhibition reduces excitability of respiratory rhythm-generating neurons and blunts the ventilatory response to PaCO₂.
• Respiratory rate and minute ventilation fall, with reduced responsiveness to hypercapnia and hypoxia → hypercapnia may develop.

Constipation

• Receptors: principally μ, with κ and δ receptors also contributing.
• Site: enteric nervous system / intramural nerve plexuses throughout the gastrointestinal tract.
• Mechanism: inhibition of excitatory enteric neurotransmitter release → ↓ propulsive peristalsis, ↑ segmental/non-propulsive tone and ↑ sphincter tone.
• Prolonged transit permits greater water absorption from luminal contents → constipation.

Summary: opioid receptor activation inhibits adenylyl cyclase, closes presynaptic Ca²⁺ channels and opens postsynaptic K⁺ channels. Analgesia is produced at peripheral, spinal and supraspinal sites, while morphine causes respiratory depression through μ-mediated brainstem inhibition and constipation through opioid effects on the enteric nervous system.

Open CICMWrecks Pharmacopeia — Morphine