1. Release of pain-signalling neurotransmitters is regulated by endogenous endorphins or by exogenous opioid agonists by acting presynaptically to inhibit substance P release, causing analgesia 2. Reduction or inhibition of neurotransmission, due to opioid-induced presynaptic inhibition.

Opioids Flashcards by Salimah Ali

Opioids system =

Opioid receptors + endogenous ligands

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MOR

μ-opioid receptors.

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What are endogenous ligands?

They can be selective. For example, selectively bind to MOR. Some are non-selectively and can bind to any receptor.

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Can opioid endogenous ligands bind to NOP?

No. It has its own ligand (nociceptin/orphanin) that can only bind to it.

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4 levels of the nervous system that morphine acts on

Nociceptors
Spinal cord
Supraspinal sties
Limbic system

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Where are opioid receptors found?

CNS: cortex, thalamus, periaqueductal grey, spinal cord
Peripheral neurons
Inflamed tissue
Immune cells
Respiratory and GI tract

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What is the overall effect of opioids?

The reduction and inhibition of the neurotransmission (reduced release of substance P) that results in and analgesic effect.

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What causes release of substance P?

Activation of peripheral nociceptive fibres causes release of substance P and other pain-signalling neurotransmitters from nerve terminals in the dorsal horn of the spinal cord

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MOA opioids

Release of pain-signalling neurotransmitters is regulated by endogenous endorphins or by exogenous opioid agonists by acting presynaptically to inhibit substance P release, causing analgesia
Reduction or inhibition of neurotransmission, due to opioid-induced presynaptic inhibition.

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MOA opioids Involves changes in transmembrane ion channels conductance…

– Increase potassium conductance (hyperpolarization)
– Inactivation of calcium channels
This leads to inhibition of neurotransmitter release

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What leads to a reduction in the intracellular cyclic AMP levels?

Binding of an opioid agonist to a G-protein-coupled opioid receptor leads to dissociation of alpha and beta subunit form delta. This leads to inhiation of Adenylate cyclase.

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Sedation and anxiolysis (Pharmacological effects to opioids)

– Drowsiness and lethargy
– Apathy
– Cognitive impairment
– Sense of tranquillity

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Depression of respiration (Pharmacological effects to opioids)

Main cause of death from opioid overdose

- Combination of opioids and alcohol is especially dangerous

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Cough suppression (Pharmacological effects to opioids)

-Opioids suppress the “cough centre” in the brain

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Pupillary constriction (Pharmacological effects to opioids)

-pupillary constriction in the presence of analgesics is characteristic of opioid use

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Nausea and vomiting (Pharmacological effects to opioids)

Stimulation of receptors in an area of the medulla called the chemoreceptor trigger zone causes nausea and vomiting
Unpleasant side effect, but not life threatening

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Gastrointestinal symptoms (Pharmacological effects to opioids)

-Opioids relieve diarrhoea as a result of their direct actions on the intestines

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Other effects (Pharmacological effects to opioids)

Opioids can release histamines causing itching or more severe allergic reactions including bronchoconstriction
Opioids can affect white blood cell function and immune function

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Receptor type μ location

Brain and spinal cord

Receptor type μ effects

Analgesia, respiratory depression, euphoria, addiction, ALL pain messages blocked

Receptor type κ location

Brain and spinal cord

Receptor type κ effects

Analgesia, sedation, all non-thermal pain messages blocked

Receptor type δ location

Brain

Receptor type δ effects

Analgesia, antidepressant dependence

Why are opioids highly addictive when repeatedly used?

Their strong rewarding effects of enhancing dopamine levels.

Why might opioids not be additive to some types of pain such as cancer pain?

As the pain relief is rewarding enough, so the drug will not be desired for other effect. The rewarding effect is not seen when pain is present.

Pharmacological tolerance of opioids

Development of tolerance to analgesic effects of morphine leads to increased doses.

At the cellular level there are two different processes of opioid induced tolerance

‘within process’ and ‘between process’

‘between process’

drug of administration recruits different neuronal circuits that oppose the primary effect; activation of pronociceptive processes after opioid administration that counteract opioid analgesia e.g. engaging NMDA receptors

‘within process’

drug of administration elicits opposing reaction within the same system; involve desensitization, internalization, down-regulation and phosphorylation of opioid receptor or heterodimerization with other receptor.

What can happen with prolong use of morphine in terms if the NMDA receptor?

Tolerance. This is due to the morphine causing activation of the NMDA receptor. This triggers the activation of pain singling protein, inhibiting morphine’s analgesic activity.

How can NMDA receptor antagonists prevent or even reverse morphine tolerance?

By decreasing the activation of pronociceptive processes that are triggered by opioids.

What could be the effects of blocking NMDA receptor?

Could reduce hypersensitivity in chronic pain and improve the analgesic efficacy of morphine by reducing tolerance

What does an increase in intracellular calcium cause in terms of morphine tolerance?

The increase in intracellular calcium and subsequent kinase activation that occurs following MOR receptor activation by morphine can remove the Mg2+ block of the NMDA receptor and this activation contributes to the development of morphine tolerance.

Opioid-induced hyperalgesia

Enhanced pain response to a noxious stimulus. | Pain experienced may be the same as the underlying pain or not.

Two possible outcomes of long-term use of opioids?

Hyperalgesia or tolerance. Both decreasing the effectiveness of the given dose of drug.

Hyperalgesia can be a symptom of what?

Opioid withdrawal when abruptly stopped.

How many proposed mechanisms of OIH development?

Mechanisms of OIH 1

The central glutamatergic system (NMDA, CRGP, sub P)

Mechanisms of OIH 2

Spinal dynorphins (with CCK),

Mechanisms of OIH 3

Descending facilitation (from RVM, on and off cells),

Mechanisms of OIH 4

Genetic mechanisms (genetic polymorphism; 500 genes!),

Mechanisms of OIH 5

Decreased reuptake of neurotransmitters from the primary afferents.

What is considered the most common Mechanisms of OIH?

1. The central glutamatergic system (NMDA, CRGP, sub P)

Opioids examples (3)

Morphine Codeine Oxycodone

Opioids pain target

Nociceptive, inflammatory, some neuropathic, idiopathic pain relief.

How do opioids work?

Activates the mu-opioid receptor system.