3. Pharmacology
          3.5. Opioids
 3.5.2. Opioid receptors

Opioid receptors

[SH4:p87-p90; "Opioid receptors" CEACCP 2005 Vol 5(I) p22-25]

[Anthony Coorey, Brisbane Primary Course 2005 "Opioid Pharmacology"]

4 opioid receptors

4 receptors
* All G-protein-coupled receptors
* All coupled to inhibitory G proteins

  • MOP (Mu)
  • DOP (Delta)
  • KOP (kappa)
  • NOP (nociceptin orphanin FQ peptide receptor)


  • G protein-coupled receptors also include muscarinic, adrenergic, GABA, and somatostatin receptors


1. MOP

  • Last to be cloned
  • Responsible for supraspinal and spinal analgesia

Mu1 receptors

  • Activation of mu1 receptor causes
    * Analgesia

Mu2 receptors

  • Activation of mu2 receptor causes
    * Hypoventilation
    * Bradycardia
    * Physical dependence

Mu1 vs mu2 receptors

  • Distinction is not supported by cloning
    * Distinction may be due to posttranslation modification instead

Mu receptor agonists

  • All endogenous opioid agonists (except N/OFQ), i.e.
    * Beta-endorphin
    * Endomorphin 1&2
    * Leu-enkephalin, met-enkephalin
    * Dynorphin A&B
    * But mostly by beta-endorphin and endomorphin 1&2
  • Exogenous mu receptor agonists include:
    * Morphine
    * Meperidine
    * Fentanyl
    * Sufentanil
    * Alfentanil
    * Remifentanil
  • Specific mu receptor ANTAGONIST
    * Naloxone

2. DOP

  • First to be cloned
  • Modulates mu receptor activities
  • DOP is activated by
    * Met-enkephalin and leu-enkephalin (endogenous)
    --> LE increases and ME decreases MOP receptor activity
  • Other effects include:
    * May also decrease GIT motility and respiratory depression
    * May dampen locomotor behaviour tonically
    * May regulate mood


3. KOP

  • Second opioid receptor to be cloned
  • Blocks type N Ca2+ channels
    --> Inhibition of neurotransmitter release (?substance P)
  • Activation causes:
    * Less respiratory depression (or none at all [CEACCP article])
    * May be associated with dysphoria and diuresis
    * Analgesia, but also attenuates analgesia caused by MOP agonists (see notes on NRM)
    * Sedation
    * May be neuroprotective (by inhibition of post-ischaemic glutamate release)
  • KOP is activated by
    * Opioid agonist-antagonists
    * Dynorphin A&B (endogenous)
  • Prototype KOP agonist = ketocyclazocine (a non-peptide benzomorphan)

4. NOP

  • Similar to classic opioid receptors
    --> Decreases neuronal excitability and inhibition of neurotransmitter release
  • NOP is activated by N/OFQ
  • Supraspinally, NOP activation causes pronociceptive/anti-analgesic effect (See notes on NRM)
  • Spinally, NOP activation causes
    * At low dose --> Hyperalgesia
    * At high dose --> Analgesia
  • Endogenous level of N/OFQ
    * Sets the pain threshold
    * Causes inhibition of micturition reflex
    * Causes development of tolerance in chronic exposure to morphine


ANTAGONISTS at NOP receptors could potentially

  • Reduce opioid tolerance
  • Analgesia

Location of opioid receptors

Opioid receptors are located in area in brain and spinal cord

  • Area in the brain
    * Periaqueductal gray (PAG) matter of brainstem
    * Amygdala
    * Corpus striatum
    * Hypothalamus
  • Spinal cord
    * Substantia gelatinosa

MOP receptors

MOP receptors are located:

  • Throughout CNS (cerebral cortex, amygdala (of limbic system))
  • High density in caudate putamen (of basal ganglia) and periaqueductal gray (PAG)
  • Presynaptically, on primary afferent neuron, within dorsal horn of spinal cord
    --> Inhibition of glutamate release
    --> Inhibition of nociceptive stimuli from C and A-delta nerves

Descending inhibitory control pathway

  • Efferent outflow from the periaqueductal gray (PAG, an area in the midbrain)
    --> Descends to the spinal cord
    --> Inhibits nociceptive transmission in afferent fibres
  • Opioids can act on PAG
    --> Inhibit release of GABA in PAG (GABA is inhibitory)
    --> Increased output from PAG
    --> Increased spinal inhibition of nociceptive transmission in afferent fibres


  • High density of MOP receptors are found in PAG

DOP receptors

  • DOP receptors are less widely distributed
  • Highest density in
    * Olfactory bulb
    * Cerebral cortex
    * Nucleus accumbens
    * Caudate putamen
  • Located presynaptically, on primary afferent neuron (??? in dorsal horn)
    --> Inhibition of neurotransmitter release

KOP receptors

  • KOP receptors are located on primary cells within nucleus raphe magnus (NRM) in midbrain

[???] Need reference. I think because dynorphin (agonist for KOP) are found both in dorsal horn and NRM, and it does have analgesic action (although it counters analgesia due to MOP actions). I wonder if KOP in dorsal horn has analgesic action, and NRM has antianalgesic action. The role of KOP in NRM (which is to antagonise MOP agonist's analgesic action) is discussed in the article. But no mention of how KOP mediates its analgesic action.

Nucleus raphe magnus (NRM)

  • NRM is part of the descending inhibitory control pathway
  • Dampens nociceptive transmission at the level of the spinal cord
  • Consists of primary cells and secondary cells
    * Primary cell inhibits nociceptive transmission in the spinal cord
    * Secondary cells inhibits primary cell
  • MOP receptors are only on secondary cells
    --> Inhibition of secondary cells
    --> Decreased GABA release from secondary cells
    --> Increased activity in primary cells
    --> Increased inhibition of nociceptive transmission in the spinal cord
    --> Analgesia
  • KOP (and NOP) are located only on primary cells
    --> Inhibition of primary cells
    --> Counters the indirect stimulation of primary cells by the MOP pathway
    --> Anti-analgesia (counters MOP agonists)

NOP receptors

  • NOP receptors are, like KOP receptors, located on primary cells within nucleus raphe magnus (NRM) in midbrain
  • NOP receptor stimulation has anti-analgesic effect

Endogenous opioids

  • 3 families, each with a separate precursor from a different genetic site and a characteristic anatomical distribution
    * 4 families if including N/OFQ
  • All have a common structure with tyrosine at the amino terminus
    * The differing activities relating to differing substitutions at the carboxyl terminus

1. Endorphins

  • Precursor = pro-opiomelanocortin (POMC)
  • Peptide = beta-endorphin (ACTH and MSH also produced from POMC)
  • Distribution
    * Anterior pituitary, hypothalamus, periaqueductal grey matter, and thalamus
    * BUT not spinal cord
    * Can be secreted peripherally from adrenal medulla
  • Role
    * Stimulates all 3 classical opioid receptors (MOP, DOP, and KOP receptors)

2. Endomorphine 1&2

  • Precursor = unknown
  • Role
    * Stimulates MOP receptors

3. Enkephalins

  • Precursor = proenkephalin A
  • Peptides = leu-enkephalin, met-enkephalin
  • Distribution
    * Widespread throughout brain and in dorsal horn of spinal cord
  • Role
    * Binds to DOP receptors
    --> Modulates MOP receptor activities
    --> LE increases and ME decreases MOP receptor activity

4. Dynorphins

  • Precursor = prodynorphin
  • Peptides = dynorphin A and alpha neoendorphin (?dynorphin B)
  • Distribution
    * Periaqueductal gray matter, thalamus, and dorsal horn of spinal cord
  • Role
    * Stimulates KOP receptors

5. Nociceptin orphanin FQ peptides

  • Precursor = pre-pro-N/OFQ (pp-noc)
  • Role
    * Stimulates NOP receptors


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