Canonical Question

PainPharm – Receptors

V5 H4.ii Historical V4 K4.ii 1 appearance

Master answer

Serpentine, inhibitory G protein-coupled receptors (GiPCR)
ligands are endogenous opioids
- dynorphins, enkephalins, endorphins, endomorphins and nociceptin
4 types – MOR (), DOR (), KOR (), NOR

Receptor	Subtypes	Location			Clinical Effects
		Brain	Spinal Cord	Other
MOR (μ)	μ₁, μ₂, μ₃	cortex (laminae III and IV) thalamus striosomes periaqueductal gray rostral ventromedial medulla	substantia gelatinosa	peripheral sensory neurons intestinal tract	μ₁: analgesia physical dependence μ₂: respiratory depression miosis euphoria reduced GI motility physical dependence μ₃: possible vasodilation
DOR (δ)	δ₁, δ₂	pontine nuclei amygdala olfactory bulbs deep cortex	–	peripheral sensory neurons	Analgesia Antidepressant Convulsant Physical dependence May modulate MOR mediated respiratory depression
KOR (κ)	κ₁, κ₂, κ₃	hypothalamus periaqueductal gray claustrum	substantia gelatinosa	peripheral sensory neurons	Central analgesia anticonvulsant, depression, dissociative, hallucinogenic diuresis, miosis, dysphoria sedation, stress Visceral nociception antagonist
NOR (Nociceptin)	ORL₁	cortex amygdala hippocampus septal nuclei habenula hypothalamus	spinal cord	–	anxiety, depression appetite development of tolerance to μ-opioid agonists

Each receptor consists of an extracellular N-terminus, 7 transmembrane helical twists, 3 extracellular and intracellular loops, and an intracellular C-terminus
Once the receptor is activated, it releases a portion of the G protein, which diffuses within the membrane until it reaches its target (either an enzyme or an ion channel).
These targets alter protein phosphorylation via inhibition of cyclic AMP (cAMP) which acts as a second messenger within the cell resulting in
- the activation of protein kinases (short term effects) and
- gene transcription proteins and/or gene transcription (long term effects)
Neurotransmitter release from neurons is normally preceded by depolarisation of the nerve terminal and Ca++ entry through voltage-sensitive Ca++ channels.
- Opioid receptors located on the presynaptic terminals of the nociceptive C-fibers and A delta fibers, when activated by an opioid agonist, will indirectly inhibit these voltage-dependent calcium channels →
- decreasing cAMP levels and blocking the release of pain neurotransmitters such as glutamate, substance P, and calcitonin gene-related peptide from the nociceptive fibers →
- resulting in analgesia

Opiod receptor activation → Increases adenylyl cyclase, reducing cAMP
- Presynaptically inhibits voltage-gated Ca²⁺ channels
  - Decreases Ca²⁺ influx
  - Reduces neurotransmitter release
- Post-synaptically activates K⁺ channels
  - Causes K⁺ efflux
  - Leads to membrane hyperpolarisation
Overall this leads to a reduction in neuronal cell excitability, resulting in reduced transmission of nociceptive impulses.

Sources: Notes,
https://www.painphysicianjournal.com/current/pdf?article=OTg3&journal=42

Exam	Exact wording	Relationship	Success
2023B Q09	Outline the classification, structure and distribution of the opioid receptors (50% marks). Describe the intracellular events following opioid receptor activation (50% marks).	historical_member	20.00%