Aop: 234

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 Ca Channel Inhibition

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 Ca 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

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  • 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
Inhibition of N-type Ca ion channels June 23, 2017 06:50
Inhibition of neurotransmitter vesicle release June 23, 2017 06:52
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 Inhibition of Ca Channels June 23, 2017 06:53
Inhibition of Ca Channels leads to Inhibition of neurotransmitter release June 23, 2017 06:53
Inhibition of neurotransmitter release leads to Analgesia June 23, 2017 06:53

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 analgesic 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 Ca2+ ion channel. The inhibition of Ca ion channels prevents the flow of Ca2+ ions into neurons, a key step in the release of neurotransmitters which carry the signal across the synapse to another neuron. A reduction in the ability of neurons to transmit signals between one another causes an analgesic effect in the individual. 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

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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 Mu Opioid Receptor Agonism
KE 1426 Release of G Proteins Release of G Proteins
KE 1429 Inhibition of N-type Ca ion channels Inhibition of Ca Channels
KE 1430 Inhibition of neurotransmitter vesicle release Inhibition of neurotransmitter release
AO 1428 Analgesia 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

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 a 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 inhibition of N-type Ca ion channel 

“Opioids inhibit N-type Ca2+ channels and thus inhibit neurotransmitter release” LA Chahl 1996

“transient overexpression of Gβγ in sympathetic neurons mimics and occludes the voltage-dependent Ca2+ channel modulation produced by noradrenaline” SR Ikeda 1996

“Opioid receptors located on the presynaptic terminals of the nociceptive C-fibers and A delta fibers, when activated by an opioid agonist, will indirectly inhibit…voltage-dependent calcium channels…blocking the release of pain neurotransmitters…resulting in analgesia” AM Trescot 2008

Inhibition of N-type Ca ion channel leading to inhibition of neurotransmitter release

“The Ca2+ dependence of neurotransmitter release is a fundamental property of chemical synapses” DA Rusakov 2006

“Recent work has established that different geometric arrangements of calcium channels are found at different presynaptic terminals, leading to a wide spread of calcium signals for triggering neurotransmitter release” GJ Augustine 2001

“The intracellular calcium concentration has important roles in the triggering of neurotransmitter release” E Neher 2008

“In the nerve terminal, it is well established that the most prominent [action of Ca2+] triggering of neurotransmitter release achieves its unique properties by activating a relatively low-affinity Ca2+ sensor” E Neher 2008

Inhibition of neurotransmitter release leading to analgesia

“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

“The opioid drugs produce analgesia by actions at several levels of the nervous system, in particular, inhibition of neurotransmitter release  from the primary afferent terminals in the spinal cord” LA Chahl 1996

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. (2011Anesthesiology. 115, 1363.

Augustine G.J. (2001Curr. Opin. Neurobiol. 11, 320.

Chahl L.A. (1996Aust. Prescr. 19, 63.

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

Ikeda S. R. (1996Nature 380, 255.

Ikeda K. (2002Neurosci. Res. 44, 121.

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

Neher E., Sakaba T. (2008)  Neuron 59, 453.​

Rusakov D. A. (2006Neurosci. 12, 317.

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

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