This AOP is licensed under a Creative Commons Attribution 4.0 International License.

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

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Mu Opioid Receptor Agonism to Analgesia via K Channel

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

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

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Timothy Allen (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Timothy Allen

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help

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

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

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

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)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

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

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

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

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

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.