API

Aop: 233

AOP Title

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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

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

Contributors

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  • Timothy Allen

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development


This AOP was last modified on June 23, 2017 06:48

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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.


Background (optional)

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This optional section should be 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.

Instructions

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Summary of the AOP

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Stressors

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Describes stressors known to trigger the MIE and provides evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. The evidence supporting the stressor will typically consist of a brief description and citation of literature showing that particular stressors can trigger the MIE.

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Molecular Initiating Event

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Title Short name
Mu Opioid Receptor Agonism Mu Opioid Receptor Agonism

Key Events

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Title Short name
Release of G Proteins Release of G Proteins
Opening of G protein gated inward rectifying K channels Opening of GIRK channels
hyperpolarisation, neuron hyperpolarisation, neuron

Adverse Outcome

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Title Short name
Analgesia Analgesia

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
Mu Opioid Receptor Agonism leads to Release of G Proteins Directly leads to Strong Not Specified
Release of G Proteins leads to Opening of GIRK channels Directly leads to Strong Not Specified
Opening of GIRK channels leads to hyperpolarisation, neuron Directly leads to Strong Not Specified
hyperpolarisation, neuron leads to Analgesia Indirectly leads to Strong Not Specified

Network View

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Life Stage Applicability

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Is the AOP specific to certain tissues, life stages / age classes? Indicate if there are critical life stages, where exposure must occur, to results in the final adverse effect. Or specify if there are key events along the pathway which are dependent on the life stage although the AOP is known to be initiated regardless of life stage. Indicate also if the AOP is associated also with age- or sex-dependence.

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Taxonomic Applicability

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Indicate the relevant domain of applicability in terms of taxa.

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Sex Applicability

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Graphical Representation

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Click to download graphical representation template

Overall Assessment of the AOP

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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

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The relevant domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Domain of applicability is informed by the “Description” and “Taxonomic Relevance” section of each KE description and the “Description of the KER” section of each KER description. The relevant domain of applicability of the AOP as a whole will most often be defined based on the most narrowly restricted of its KEs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the domain of applicability of the AOP as a whole would generally be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE descriptions, the rationale for defining the relevant domain of applicability of the overall AOP should be briefly summarised on the AOP page.

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Essentiality of the Key Events

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The essentiality of various of the KEs is influential in considering confidence in an overall hypothesised AOP for potential regulatory application being secondary only to biological plausibility of KERs (Meek et al., 2014; 2014a). The defining question for determining essentiality (included in Annex 1) relates to whether or not downstream KEs and/or the AO is prevented if an upstream event is experimentally blocked. It is assessed, generally, then, on the basis of direct experimental evidence of the absence/reduction of downstream KEs when an upstream KE is blocked or diminished (e.g., in null animal models or reversibility studies). Weight of evidence for essentiality of KEs would be considered high if there is direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important key events [e.g., stop/reversibility studies, antagonism, knock out models, etc.) moderate if there is indirect 25 evidence that experimentally induced change of an expected modulating factor attenuates or augments a key event (e.g., augmentation of proliferative response (KEupstream) leading to increase in tumour formation (KEdownstream or AO)) and weak if there is no or contradictory experimental evidence of the essentiality of any of the KEs (Annex 1).

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Weight of Evidence Summary

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This involves evaluation of the Overall AOP based on Relative Level of Confidence in the KERs, Essentiality of the KEs and Degree of Quantitative Understanding based on Annexes 1 and 2. Annex 1 (“Guidance for assessing relative level of confidence in the Overall AOP”) guides consideration of the weight of evidence or degree of confidence in the predictive relationship between pairs of KEs based on KER descriptions and support for essentiality of KEs. It is designed to facilitate assignment of categories of high, moderate or low against specific considerations for each a series of defined element based on current experience in assessing MOAs/AOPs. In addition to increasing consistency through delineation of defining questions for the elements and the nature of evidence associated with assignment to each of the categories, importantly, the objective of completion of Annex 1 is to transparently delineate the rationales for the assignment based on the specified considerations. While it is not necessary to repeat lengthy text which appears in earlier parts of the document, the entries for the rationales should explicitly express the reasoning for assignment to the categories, based on the considerations for high, moderate or low weight of evidence included in the columns for each of the relevant elements. 24 While the elements can be addressed separately for each of the KERs, the essentiality of the KEs within the AOP is considered collectively since their interdependence is often illustrated through prevention or augmentation of an earlier or later key event. Where it is not possible to experimentally assess the essentiality of the KEs within the AOP (i.e., there is no experimental model to prevent or augment the key events in the pathway), this should be noted. Identified limitations of the database to address the biological plausibility of the KERs, the essentiality of the KEs and empirical support for the KERs are influential in assigning the categories for degree of confidence (i.e., high, moderate or low). Consideration of the confidence in the overall AOP is based, then, on the extent of available experimental data on the essentiality of KEs and the collective consideration of the qualitative weight of evidence for each of the KERs, in the context of their interdependence leading to adverse effect in the overall AOP. Assessment of the overall AOP is summarized in the Network View, which represents the degree of confidence in the weight of evidence both for the rank ordered elements of essentiality of the key events and biological plausibility and empirical support for the interrelationships between KEs. The AOP-Wiki provides such a network graphic based on the information provided in the MIE, KE, AO, and KER tables. The Key Event Essentiality calls are used to determine the size of each key event node with larger sizes representing higher confidence for essentiality. The Weight of Evidence summary in the KER table is used to determine the width of the lines connecting the key events with thicker lines representing higher confidence.

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Quantitative Considerations

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The extent of quantitative understanding of the various KERs in the overall hypothesised AOP is also critical in consideration of potential regulatory application. For some applications (e.g. doseresponse analysis in in depth risk assessment), quantitative characterisation of downstream KERs may be essential while for others, quantitative understanding of upstream KERs may be important (e.g., QSAR modelling for category formation for testing). Because evidence that contributes to quantitative understanding of the KER is generally not mutually exclusive with the empirical support for the KER, evidence that contributes to quantitative understanding should generally be considered as part of the evaluation of the weight of evidence supporting the KER (see Annex 1, footnote b). General guidance on the degree of quantitative understanding that would be characterised as weak, moderate, or strong is provided in Annex 2.

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Considerations for Potential Applications of the AOP (optional)

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At their discretion, the developer may include in this section discussion of the 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. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale. Detailing such considerations can aid the process of transforming narrative descriptions of AOPs into practical tools. In this context, it is necessarily beneficial to involve members of the regulatory risk assessment community on the development and assessment team. The Network view which is generated based on assessment of weight of evidence/degree of confidence in the hypothesized AOP taking into account the elements described in Section 7 provides a useful summary of relevant information as a basis to consider appropriate application in a regulatory context. Consideration of application needs then, to take into consideration the following rank ordered qualitative elements: Confidence in biological plausibility for each of the KERs Confidence in essentiality of the KEs Empirical support for each of the KERs and overall AOP The extent of weight of evidence/confidence in both these qualitative elements and that of the quantitative understanding for each of the KERs (e.g., is the MIE known, is quantitative understanding restricted to early or late key events) is also critical in determining appropriate application. For example, if the confidence and quantitative understanding of each KER in a hypothesised AOP are low and or low/moderate and the evidence for essentiality of KEs weak (Section 7), it might be considered as appropriate only for applications with less potential for impact (e.g., prioritisation, category formation for testing) versus those that have immediate implications potentially for risk management (e.g., in depth assessment). If confidence in quantitative understanding of late key events is high, this might be sufficient for an in depth assessment. The analysis supporting the Network view is also essential in identifying critical data gaps based on envisaged regulatory application.

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References

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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.