Pharmacology of pain

Question 1

D: pain

Answer 1

An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage*.

Question 2

d: nociception

Answer 2

The neural process of encoding noxious stimuli.

Question 3

Nociceptors are either……

Answer 3

Nociceptors are either

thinly myelinated Aδ-fibres

or unmyelinated C-fibres

Question 4

Nociceptor cell bodies are located in ……..

do their axons have specialised endings?

Answer 4

Nociceptor cell bodies are located in the dorsal root ganglia (DRG; trigeminal ganglia, TG, for the head) and their axon terminals do not have specialised endings, rather so-called free-endings.

Question 5

describe Congenital insensitivity to pain

Answer 5

Question 6

can nociceptors be polymodal?

Answer 6

yes - they can repsond to heat, cold, chemicals and mechanical stimuli

some are silent and recruited during inflammation.

can be multimodal or unimodal

Question 7

t or F

Many ion channels are activated by distinct stimuli at the peripheral terminals giving rise to a receptor potential

Answer 7

T

Question 8

Examples of noxious stimuli and the ion channels activated:

heat

protons

AATP

mechanical stimuli

Answer 8

• Heat–TRPV1, TRPM3, anoctamin-1, TRPA1
• Cold–TRPM8,TRPA1(yes,senseshot/cold!)
• Protons–ASICs,TRPV1,TASKs
• ATP–P2X3
• Mechanical stimuli–Piezo1/2,TACAN

Question 9

describe nociceptor sensitisation

Answer 9

Following injury, stimuli that previously caused no pain now do (allodynia) and stimuli that previously caused some pain cause even more (hyperalgesia).

Question 10

what is Allodynia

Answer 10

Allodynia is something most of us are familiar with – think of taking a shower when sunburned – hot water that would usually cause no pain now does!

Question 11

Answer 11

Question 12

can many internally released factors act as potent stimulators of nociceptors?

Answer 12

yes - allows detection of tissue damage

Question 13

give some examples of how substances released from damagaed cells can cause pain

Answer 13

Question 14

what are sensitising agents?

Answer 14

A second class of sensitising agents do not directly excite the nociceptive nerve terminals, but instead enhance responses to excitatory agents. This class includes prostaglandins and nerve growth factor (NGF).

Some agents both excite and sensitize nociceptors, examples include bradykinin, ATP and H+.

Question 15

When stimulated, nociceptive nerve terminals also do what?

many things***

Answer 15

When stimulated, nociceptive nerve terminals also release factors such as calcitonin gene-related peptide (CGRP) and substance P (SP), peptides that cause vasodilatation and an increase in the permeability of blood vessels; these effects are both direct and indirect through SP inducing mast-cell degranulation.

The inflammation caused by the release of CGRP and SP from nerve terminals causes a redness (“flare”) surrounding the site of injury and is referred to as neurogenic inflammation.

Question 16

Arachidonic acid can be metabolised to prostanoids by….

Answer 16

Arachidonic acid can be metabolised to prostanoids by cyclooxygenases (COX),

Question 17

what are the isoforms of COX

Answer 17

COX-1 and COX-2.

Question 18

which 2 reactions does COX catalyse

Answer 18

COX catalyses two reactions: AA is first cyclised and oxygenated forming the endoperoxide PGG2;

the hydroperoxyl in PGG2 is then reduced to form PGH2.

Question 19

what does PGE synthase do?

Answer 19

PGE synthase produces PGE2 from PGH2, which acts upon nociceptors to cause excitatory stimuli to have greater effect, i.e. the nociceptor has been sensitised: compare the response to bradykinin (Brad.) in the figure above before and after of PGE2.

Question 20

Answer 20

Question 21

how does PGE cause sensitisation

Answer 21

Question 22

describe neuropathic pain

Answer 22

Peripheral nerve damage can result in pain that often outlasts the initial nerve injury, sometimes indefinitely:

• • Phantom limb pain – sensation of pain in an amputated limb, long after its removal
• • Infectious disease (e.g. leprosy, HIV and hepatitis)
• • Diabetic neuropathy
• • Trigeminal neuralgia
• • Postherpetic neuralgia

Question 23

describe how NSAIDS lower pain

Answer 23

Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibiting COX enzymes and therefore the production of prostaglandins (PGs).

Question 24

how do most NSAIDS act - mechanism of action?

Answer 24

Most NSAIDs act by entering a hydrophobic channel on the enzyme and forming hydrogen bonds with an arginine residue at position 120, which prevents the entrance of fatty acids, like arachidonic acid, into the catalytic domain.

Aspirin is an exception; it enters the active site and acetylates a serine at position 530, which irreversibly inactivates COX, an action that explains certain long-lasting actions of aspirin.

Question 25

which COX isoform is constitutive

Answer 25

cox 1

Question 26

which cox isoform is upregulated in inflammation?

Answer 26

cox 2

Question 27

how come aspirin has long acting effects on COX enzymes?

Answer 27

Aspirin acetylates serine 530 in active site – irreversible inactivation

Question 28

how come some drugs are COX 2 specific?

Answer 28

The bulky side group of COX-2 enables some drugs with large, sulphur-containing side groups to selectively act upon COX-2, but not COX-1.

Question 29

. Inhibition of COX-2 is thought to result in.......... whereas inhibition of COX-1 is responsible for .......

Answer 29

. Inhibition of COX-2 is thought to result in the anti-inflammatory/analgesic effect, whereas inhibition of COX-1 is responsible for most unwanted side effects

Question 30

where are NSAIDS most effective?

Answer 30

NSAIDs are most effective in inflammatory conditions when COX-2 is upregulated, e.g. arthritis, muscular pain, toothache, bursitis and dysmenorrhoea (period pain). A less well-characterised route of analgesia may be centrally where PGs are thought to facilitate nociceptor neurotransmission.

Question 31

give some details on Aspirin

Answer 31

weakly COX-1 selective, irreversible acetylation, used mainly for cardiovascular protective effects of **inhibiting platelet derived thromboxane;** used in migraine

Question 32

describe teh characteristics of Ibuprofen/phenylbutazone

Answer 32

Ibuprofen/phenylbutazone – weakly COX-1 selective, symptomatic relief in rheumatoid arthritis, gout and soft tissue disorders

Question 33

describe the characteristics of paracetamol

Answer 33

Paracetamol – analgesic/antipyretic, poor anti-inflammatory, but good antipyretic **(not really an NSAID)**

Question 34

describe the characteristics of Etoricoxib/robenacoxib –

Answer 34

Etoricoxib/robenacoxib – **COX-2 selective,** osteoarthritis and rheumatoid arthritis

Question 35

side effects of NSAIDS?

Answer 35

largely due to COX 1 activity ## Footnote **gastrointestinal bleeding** (PGs inhibit gastric acid secretion and increase the release of protective mucin, patients often take a drug to counteract the effects on acid secretion), **renal insufficiency** (PGE2/PGI2 involved in maintenance of renal blood flow), **stroke/myocardial infarction** (COX-2 is constitutively expressed in endothelial/vascular smooth muscle cells, inhibition results in decreased PGI2 production, PGI2 is vasodilatory and decreases platelet aggregation) and **bronchospasm** (COX inhibition implicated, mechanism unclear).

Question 36

what is an opioid

Answer 36

An opioid is a substance producing morphine-like effects that are reversed by antagonists such as naloxone, an opiate is a substance found in the opium poppy Papaver somniferum.

Question 37

opioids are antagonists by

Answer 37

naloxone

Question 38

4 opioid receptors?

Answer 38

4 receptors - μ, κ, δ or ORL1 (and subtypes), all Gi/Go-protein coupled receptors

Question 39

how do opioid receptors decrease pain

Answer 39

All receptors are Gi/Go-protein coupled receptors and the βγ subunit interacts with **inwardly rectifying** **potassium channels**, GIRKs, to **promote opening** (neuronal **hyperpolarisation** = action potential firing less likely) and to inhibit the opening of CaVs (mainly N-type; decreased Ca2+ entry = decreased neurotransmitter release). Adenylate cyclase activity is also decreased.

Question 40

nhibition of adenylate cyclase activity counteracts the sensitising effect of ....

Answer 40

nhibition of adenylate cyclase activity counteracts the sensitising effect of PGs

Question 41

Opioids can also reduce the affective component of pain due to their ability to evoke \_\_\_\_\_\_\_\_, which is also \_-mediated.

Answer 41

Opioids can also reduce the affective component of pain due to their ability to evoke euphoria, which is also μ-mediated.

Question 42

Opioids are generally used for .....

Answer 42

Opioids are generally used for both acute (e.g. post-operative) and chronic (e.g. cancer) pain, not always considered sensible in treating neuropathic pain because the dose often needed to provide analgesia is coupled with excessive side effects.

Question 43

how does peripheral opioid analgesia work?

Answer 43

inhibition of adenylate cyclase acts against sensitising effect of PGs

Question 44

how does spinal opioid analgesia work?

Answer 44

Spinal – presynaptically to reduce nociceptor neurotransmitter release – postsynaptically to decrease spinal cord dorsal horn neurone excitability

Question 45

how does supraspinal analgesia wokr?

Answer 45

Supraspinal – numerous brain regions, including periaqueductal grey region

Question 46

T or F or opioids Less efficacious in neuropathic pain – dose needed for analgesia often produces excessive side effects

Answer 46

T

Question 47

describe morphine

Answer 47

Morphine – widely used for treating acute/chronic pain

Question 48

describe dimorphine

Answer 48

Diamorphine (heroin) – higher blood-brain-barrier permeability = more rapid onset than morphine, a prodrug

Question 49

describe codeine

Answer 49

Codeine – less potent than morphine, also fewer side effects, used for mild pain, often combined with an NSAID

Question 50

descibe buprenorphine

Answer 50

Buprenorphine – partial agonist, i.e. moderate analgesia/less respiratory depression than full agonist; used post-surgery in rodents/cats/dogs, and as a patch for chronic pain in humans

Question 51

describe naloxone

Answer 51

Naloxone – broad spectrum opioid receptor antagonist, rapid reversal of opioid-induced respiratory depression

Question 52

describe NSAID/opioid combination therapy –

Answer 52

NSAID/opioid combination therapy – different mechanisms of action = additive analgesia, less of each drug required = less side effects, e.g. co-codamol = paracetamol + codeine

Question 53

descxribe teh side effecst of opioids

Answer 53

* **Respiratory depression** – μ-mediated, respiratory centre and central chemoreceptors * **Nausea/vomiting** – δ/μ-mediated * **Constipation** – μ, κ and δ-mediated * Chronic use complicated by tolerance and physical dependence

Question 54

can antidepressatns relieve pain?

Answer 54

Serotonin selective reuptake inhibitors (SSRIs, e.g. fluoxetine) are largely inefficacious Serotonin-noradrenaline reuptake inhibitors (SNRIs, e.g. duloxetine) and tricyclic antidepressants (TCAs, e.g. amitriptyline, also block serotonin and noradrenaline reuptake) both relieve several forms of neuropathic pain Emphasises role of the descending, inhibitory pain control pathway from the locus coeruleus, which is is noradrenergic

Question 55

describe Gabapentin/pregabalin

Answer 55

developed as a GABA analogue for treatment of epilepsy, has no activity at GABA receptors is efficacious against neuropathic pain in some patients, no effect on acute pain. Decreases cell surface expression of the CaV α2δ1 subunit The CaV α2δ1 subunit increases CaV current density and is often upregulated in neuropathic pain Gabapentin therefore causes decreased CaV currents in spinal cord = less neurotransmitter release = less pain Pregabalin developed as more potent analogue with better pharmacokinetic properties

Question 56

how do NaV inhibitors block pain

Answer 56

Lidocaine is a local anaesthetic, works by blocking NaV subunits Can be applied topically as patch Inhibits spontaneous peripheral neurone discharges often observed in neuropathic pain – **useful in trigeminal neuralgia patients to provide pain relief when eating a meal** Carbamazepine also blocks NaVs, used as an anti-epileptic, but also an option for neuropathic pain, especially trigeminal neuralgia

Question 57

describe Ziconotide

Answer 57

Synthetic analogue of N-type CaV blocker ω-conotoxin MVIIA from Conus magus **Intrathecal** administration to prevent widespread, deleterious side effects Expensive/invasive/dangerous method, i.e. reserved for patients refractory to other treatments

Question 58

fat

Answer 58

mamba