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AOP: 233

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Mu Opioid Receptor Agonism leading to Analgesia via K Channel Opening

Short name

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Mu Opioid Receptor Agonism to Analgesia via K Channel

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Handbook Version v1.0

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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

Point of Contact

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Timothy Allen (email point of contact)

Contributors

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Timothy Allen

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on April 29, 2023 16:03

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

Abstract

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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

Context

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Strategy

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Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1425

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

1428

Analgesia

Relationships Between Two Key Events (Including MIEs and AOs)

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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

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

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 Gα_i dissociation from Gβγ, the Gα protein subunit moves on to directly interact with the G-protein gated inward rectifying potassium channel, K_ir3. 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

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Essentiality of the Key Events

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Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

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.