Aop: 234

AOP Title


Mu Opioid Receptor Agonism leading to Analgesia via Ca Channel Inhibition

Short name:


Mu Opioid Receptor Agonism to Analgesia via Ca Channel

Graphical Representation


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

Point of Contact


Timothy Allen   (email 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 15, 2020 16:29


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



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.

Background (optional)


Summary of the AOP


Events: Molecular Initiating Events (MIE)


Key Events (KE)


Adverse Outcomes (AO)


Sequence Type Event ID Title Short name
1 MIE 1425 Mu Opioid Receptor Agonism Mu Opioid Receptor Agonism
2 KE 1426 Release of G Proteins Release of G Proteins
3 KE 1429 Inhibition of N-type Ca ion channels Inhibition of Ca Channels
4 KE 1430 Inhibition of neurotransmitter vesicle release Inhibition of neurotransmitter release
5 AO 1428 Analgesia Analgesia

Relationships Between Two Key Events
(Including MIEs and AOs)


Title Adjacency Evidence Quantitative Understanding
Mu Opioid Receptor Agonism leads to Release of G Proteins adjacent High
Release of G Proteins leads to Inhibition of Ca Channels adjacent High
Inhibition of Ca Channels leads to Inhibition of neurotransmitter release adjacent High
Inhibition of neurotransmitter release leads to Analgesia non-adjacent High

Network View





Life Stage Applicability


Taxonomic Applicability


Sex 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 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


Essentiality of the Key Events


Evidence Assessment


Quantitative Understanding


Considerations for Potential Applications of the AOP (optional)




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.