Aop: 233

AOP Title


Mu Opioid Receptor Agonism leading to Analgesia via K Channel Opening

Short name:


Mu Opioid Receptor Agonism to Analgesia via K Channel

Graphical Representation


Click to download graphical representation template



Timothy E H Allen, University of Cambridge, teha2@cam.ac.uk

Point of Contact


Timothy Allen   (email point of contact)



  • Timothy Allen



Author status OECD status OECD project SAAOP status
Not under active development Under Development

This AOP was last modified on June 15, 2020 16:29


Revision dates for related pages

Page Revision Date/Time
Mu Opioid Receptor Agonism June 08, 2017 12:02
Release of G Proteins June 08, 2017 12:04
Opening of G protein gated inward rectifying K channels June 08, 2017 12:04
hyperpolarisation, neuron September 16, 2017 10:16
Analgesia June 08, 2017 12:08
Mu Opioid Receptor Agonism leads to Release of G Proteins June 08, 2017 12:09
Release of G Proteins leads to Opening of GIRK channels June 08, 2017 12:11
Opening of GIRK channels leads to hyperpolarisation, neuron June 08, 2017 12:12
hyperpolarisation, neuron leads to Analgesia June 08, 2017 12:12



Agonism of the opioid receptors leads to the release of G proteins mimicking the body’s natural analgesia pathways (which are activated by endorphins). The released G proteins move to effectors in the cell to initiate their function. For the Gβγ, one of these is the K+ ion channel. Opening of the voltage-sensitive K+ channel allows K+ ions to flow out of the neuron, leading to a decrease in the concentration of K+ ions in the presynaptic neuron. An increase in the negative charge within the neuron is known as hyperpolarization.  Hyperpolarization of a cell membrane inhibits action potentials by increasing the stimulus required to move the membrane potential to the action potential threshold. Mu opioid receptors are found in peripheral sensory nerves explaining their analgesic activity.

This putative AOP has been constructed using literature knowledge to provide qualitative information to link in silico predictions to adverse outcomes.

Background (optional)


Summary of the AOP


Events: Molecular Initiating Events (MIE)


Key Events (KE)


Adverse Outcomes (AO)


Sequence Type Event ID Title Short name
1 MIE 1425 Mu Opioid Receptor Agonism Mu Opioid Receptor Agonism
2 KE 1426 Release of G Proteins Release of G Proteins
3 KE 1427 Opening of G protein gated inward rectifying K channels Opening of GIRK channels
4 KE 763 hyperpolarisation, neuron hyperpolarisation, neuron
5 AO 1428 Analgesia Analgesia

Relationships Between Two Key Events
(Including MIEs and AOs)


Title Adjacency Evidence Quantitative Understanding
Mu Opioid Receptor Agonism leads to Release of G Proteins adjacent High Not Specified
Release of G Proteins leads to Opening of GIRK channels adjacent High Not Specified
Opening of GIRK channels leads to hyperpolarisation, neuron adjacent High Not Specified
hyperpolarisation, neuron leads to Analgesia non-adjacent High Not Specified

Network View





Life Stage Applicability


Taxonomic Applicability


Sex Applicability


Overall Assessment of the AOP


Below direct quotes from literature sources provide evidence for each KE and KER.

Mu opioid receptor agonism leading to release of G proteins

“When the [G protein coupled] receptor is occupied, the alpha subunit is uncoupled and forms a complex which interacts with cellular systems to produce and effect” LA Chahl 1996

“Once the [opioid] receptor is activated, it releases a portion of the G protein, which diffuses within the membrane until it reaches its target” AM Trescot 2008

“Following activation by an agonist…the Gα and Gβγ subunits dissociate from one another and subsequently act on various intracellular effector pathways” R Al-Hasani 2011

“The activation of the three (μ, δ, κ) opioid receptors leads to Gi/o protein activation” K Ikeda 2002

Release of G proteins leading to opening of G protein coupled inward rectifying K channel 

“After Gαi dissociation from Gβγ, the Gα protein subunit moves on to directly interact with the G-protein gated inward rectifying potassium channel, Kir3. Channel deactivation happens after the GTP to GDP hydrolysis and Gβγ removal from interaction with the channel” R Al-Hasani 2011 (this is highlighted in red as I believe it counters the first part of the statement and confirms, as other evidence suggests that the βγ subunit is responsible for K channel opening)

“The activated Gi/o protein activates the GIRK (G protein-activated inwardly rectifying potassium) channel” K Ikeda 2002

“GIRK channels are activated by various GPCRs, such as Mu opioid receptor” K Ikeda 2002

“GIRK channel opening is triggered by the direct action of Gβγ released from PTX (pertussis toxin) -sensitive G proteins, including Gi and Go” K Ikeda 2002

“Single-channel current measurements unexpectedly indicate that the βγ, and not the α subunits, are responsible for activating the muscarinic-gated potassium channel” DE Logothetis 1987

Opening of G protein coupled inward rectifying K channel leading to hyperpolarization of presynapse

“Opioids open voltage-sensitive K+ channels and thus increase outward movement of K+ from neurons” LA Chahl 1996

“[see previous statement] This process causes hyperpolarization and inhibits tonic neural activity” R Al-Hasani 2011

“Activation of GIRK channels induces hyperpolarization of the neurons via efflux of potassium ions and ultimately reduces neural excitability and heart rate” K Ikeda 2002

Hyperpolarization of presynapse leading to analgesia

“Opioids have been proposed to inhibit neurotransmitter release… by enhancing outward movement of potassium ions” LA Chahl 1996

“increased outward movement of K+ is the most likely mechanism for the postsynaptic hyperpolarization and inhibition of neurons induced by opioids throughout the nervous system. However, it remains to be definitively established that this mechanism is also involved in the presynaptic action of opioids to inhibit neurotransmitter release” LA Chahl 1996

“There appears to be two mechanisms by which the transmission of pain sensations are depressed; hyperpolarization of interneurons within the dorsal cord and depressing the release of the neurotransmitters associated with pain transmission” J Lipp 1991

“activation of GIRK channels…produce cell membrane hyperpolarization” A Ledonne 2011

Neuronal Location

“the functionally exclusive localization of opioid receptors to primary afferent (but not sympathetic) neurons” C Stein 2013

“Opiate receptors are manufactured by primary sensory neurons (dorsal root ganglion or DRG cells) and transported centrally” RE Coggeshall 1997

“Opiate receptors have also been demonstrated peripherally in fine cutaneous nerves by light microscopic techniques” RE Coggeshall 1997

Domain of Applicability


Essentiality of the Key Events


Evidence Assessment


Quantitative Understanding


Considerations for Potential Applications of the AOP (optional)




Al-Hasani R., Bruchas M.R. (2011) Anesthesiology. 115, 1363.

Chahl L.A. (1996) Aust. Prescr. 19, 63.

Coggeshall R.E. (1997) Brain Res. 764, 126.

Ikeda K. (2002) Neurosci. Res. 44, 121.

Ledonne A., Berretta N., Davoli A., et al. (2011) Front. Sys. Neurosci. 5, 1.

Lipp J. (1991) Clin Neuropharmacol. 14, 131.

Logothetis D.E., Kurachi Y., Galper J., et al. (1987) Nature 325, 321.

Stein C. (2012) Madame Curie Bioscience Database (online)

Trescot A.M., Datta S., Lee M., Hansen H. (2008) Pain Phys. 11, S133.