Pain II

Question 1

What is p11 (function)?

Answer 1

[localised at plasma membrane surface]
A subunit of Nav1.8

Role in membrane trafficking (e.g. exocytosis, endocytosis, cell-cell adhesion)

Controls translocation of Nav1.8 to plasma membrane

Question 2

(E) p11 KO?

Answer 2

(E)

p11 KO -> reduced TTX-resistant Na+ current

p11 KO -> marked deficits in mechanical and thermally-evoked activity in spinal cord

Question 3

What are lipid rafts?

Answer 3

Cholesterol and sphingolipid-enriched domains of membrane

Question 4

Outcome of disruption of lipid rafts by MβCD?

Answer 4

Unresponsiveness to mechanical stimuli

Question 5

Current hypothesis of AP propagation in unmyelinated sensory neurons?

Answer 5

[in unmyelinated fibres = c-fibres]

Na+ channels clusters correlate w/ lipid rafts
|
[Na+ influx]
|
Depolarisation spreads but reduced magnitude (less myelination) but reaches next cluster before potential decays and drops sub-threshold

AP fires and continues

Question 6

Overview of current analgesic types?

Answer 6

• NSAIDs
• opiates
• target VGCC (Ca2+ channels)
• NGF antibody]- (up and coming)

Question 7

NSAID overall mechanism of action?

Answer 7

Inhibit COX -> prevents prostaglandin biosynthesis

Question 8

Types NSAID (classed by MoA)?

Answer 8

• aspirin
• ibuprofen and mefenamic acid
• paracetamol
• Celebrex

Question 9

Aspirin MoA?

Answer 9

Irreversible inactivation of COX (irreversible acetylation)

Question 10

Ibuprofen and mefenamic acid MoA?

Answer 10

Reversible, competition of COX

Question 11

Paracetamol MoA?

Answer 11

Reversible, non-competitive inhibition of COX

Scavenges hydroperoxides that stimulate COX -> no anti-inflam effect

[technically not an NSAID]

Question 12

Role of COX-1?

Answer 12

Makes prostaglandins vital for protecting stomach through mucus production and maintenance of renal blood flow

Question 13

Role of COX-2?

Answer 13

Inducible form that mediates pain of inflammation by sensitising peripheral nociceptors

Question 14

Celebrex MoA?

Answer 14

COX-2 inhibitor

Doesn’t block COX-1 that protects the stomach lining, so doesn’t produces stomach problems

Question 15

Why does the brain have a receptor for the opium poppy?

Answer 15

Brain needs receptors for similar compounds produced by the body:

• enkephalins
• endorphins (α,β,γ)

Question 16

Drugs that target VGCCs (Voltage-gated Calcium Channel)?

Answer 16

• Gabapentin

- Pregabalin (Pfizer)

Question 17

MoA of gabapentin and pregabalin (Pfizer)?

Answer 17

[POSTULATED]

Binds to α2δ subunit of VGCC, preventing translocation of α1 subunit to plasma membrane

Question 18

Example of NGF antibody?

Answer 18

Tanezumab (Pfizer)