This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Mu Opioid Receptor Agonism leading to Analgesia via K Channel Opening
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 04, 2021 14:53
Revision dates for related pages
|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.
AOP Development Strategy
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||1425||Mu Opioid Receptor Agonism||Mu Opioid Receptor Agonism|
|KE||1426||Release of G Proteins||Release of G Proteins|
|KE||1427||Opening of G protein gated inward rectifying K channels||Opening of GIRK channels|
|KE||763||hyperpolarisation, neuron||hyperpolarisation, neuron|
Relationships Between Two Key Events (Including MIEs and AOs)
|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|
Life Stage 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
“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
Known Modulating Factors
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.