Opioids

Question 1

Opioids system =

Answer 1

Opioid receptors + endogenous ligands

Question 2

MOR

Answer 2

μ-opioid receptors.

Question 3

What are endogenous ligands?

Answer 3

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

Question 4

Can opioid endogenous ligands bind to NOP?

Answer 4

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

Question 5

4 levels of the nervous system that morphine acts on

Answer 5

1. Nociceptors
2. Spinal cord
3. Supraspinal sties
4. Limbic system

Question 6

Where are opioid receptors found?

Answer 6

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

Question 7

What is the overall effect of opioids?

Answer 7

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

Question 8

What causes release of substance P?

Answer 8

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

Question 9

MOA opioids

Answer 9

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.

Question 10

MOA opioids Involves changes in transmembrane ion channels conductance…

Answer 10

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

Question 11

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

Answer 11

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.

Question 12

Sedation and anxiolysis (Pharmacological effects to opioids)

Answer 12

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

Question 13

Depression of respiration (Pharmacological effects to opioids)

Answer 13

• Main cause of death from opioid overdose

- Combination of opioids and alcohol is especially dangerous

Question 14

Cough suppression (Pharmacological effects to opioids)

Answer 14

-Opioids suppress the “cough centre” in the brain

Question 15

Pupillary constriction (Pharmacological effects to opioids)

Answer 15

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

Question 16

Nausea and vomiting (Pharmacological effects to opioids)

Answer 16

• 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

Question 17

Gastrointestinal symptoms (Pharmacological effects to opioids)

Answer 17

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

Question 18

Other effects (Pharmacological effects to opioids)

Answer 18

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

Question 19

Receptor type μ location

Answer 19

Brain and spinal cord

Question 20

Receptor type μ effects

Answer 20

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

Question 21

Receptor type κ location

Answer 21

Brain and spinal cord

Question 22

Receptor type κ effects

Answer 22

Analgesia, sedation, all non-thermal pain messages blocked

Question 23

Receptor type δ location

Answer 23

Brain

Question 24

Receptor type δ effects

Answer 24

Analgesia, antidepressant dependence

Question 25

Why are opioids highly addictive when repeatedly used?

Answer 25

Their strong rewarding effects of enhancing dopamine levels.

Question 26

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

Answer 26

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.

Question 27

Pharmacological tolerance of opioids

Answer 27

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

Question 28

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

Answer 28

‘within process’ and ‘between process’

Question 29

‘between process’

Answer 29

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

Question 30

‘within process’

Answer 30

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.

Question 31

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

Answer 31

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.

Question 32

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

Answer 32

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

Question 33

What could be the effects of blocking NMDA receptor?

Answer 33

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

Question 34

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

Answer 34

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.

Question 35

Opioid-induced hyperalgesia

Answer 35

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

Question 36

Two possible outcomes of long-term use of opioids?

Answer 36

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

Question 37

Hyperalgesia can be a symptom of what?

Answer 37

Opioid withdrawal when abruptly stopped.

Question 38

How many proposed mechanisms of OIH development?

Answer 38

5

Question 39

Mechanisms of OIH 1

Answer 39

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

Question 40

Mechanisms of OIH 2

Answer 40

Spinal dynorphins (with CCK),

Question 41

Mechanisms of OIH 3

Answer 41

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

Question 42

Mechanisms of OIH 4

Answer 42

Genetic mechanisms (genetic polymorphism; 500 genes!),

Question 43

Mechanisms of OIH 5

Answer 43

Decreased reuptake of neurotransmitters from the primary afferents.

Question 44

What is considered the most common Mechanisms of OIH?

Answer 44

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

Question 45

Opioids examples (3)

Answer 45

Morphine Codeine Oxycodone

Question 46

Opioids pain target

Answer 46

Nociceptive, inflammatory, some neuropathic, idiopathic pain relief.

Question 47

How do opioids work?

Answer 47

Activates the mu-opioid receptor system.