L11: Pain Flashcards
What are the 5 types of pain?
Somatic Visceral Neuropathic Migraine Phantom
What are the 3 types of nerve fibre?
C fibres: chronic pain
A-d fibres: acute pain
A-B fibres: Touch
Which laminae are in the dorsal horn, ventral horn and central canal?
Where so each of the fibres
Dorsal horn (I-VI) Ventral horn (VII-IX) Central canal (X)
Which laminae does each fibre terminate?
C fibres : I & II
A-d fibres: I,II & V
A-B : V & VI
List pain mediators that are involved in pain, and their receptors/ origin.
Bradykinin: polypeptide made from Kininogen (in response to tissue damage and coagulation) bind to receptors B1/2. Activate phospholipase cB and PLA2. This produces Arachindonic acid which is converted to prostanoids .
Prostanoids : Include prostaglandins. Bind to EP2 receptors.
Cyclooxygenase: Enzyme that makes prostaglandin E2. Induced by proinflammatory cytokines. (Aspirin inhibits COX and PGE2 production.)
NGF:Regulates peripheral sensitivity of nociceptive neurons. Increased levels lead to hyperalgesia. TrkA expressed on C fibres.
Which neurotransmitter is involved in gate control?
GABA: Inhibitory interneurons in Laminae I-III are all GABA rich. These mediate gate control by sybaosing on neurons containing glutamate and substance p.
What are examples of TRP channels, and how are they activated?
TRPV1: Non selective action channel. Activated by Capsaicin, noxious heat and low PH.
Anandamide is the endogenous ligand for TRPV1, made from arachindonic acid.
P2X3: Non selective action channel activated by ATP. For ATP evoked nociceeptor stimulation .
P2X4: ATP activates microglial P2X4 upon nerve injury. Microglia release BDNF, which reduces KCC2 expression, increasing intracellular Cl-.
How does tactile allodynia come about?
There is lack of inhibition from AB fibres.
This is due to activation of microglia by P2X4 in nerve injury, which secretes BDNF to trigger downregulation of KCC2, increasing intracellular Cl-. GABA becomes excitatory and reduces inhibitory potential of interneurons.
What is the motif for Na+ and Ca2+ selective ion filters?
Na+: DEKA. Overall one negative charge.
Ca2+: EEEE
What is tetrodotoxin, and which Na channels are not sensitive to TTX?
This is a neurotoxin found in puffer fish- acts as a Na+ channel blocker.
1.5, 1.8, 1.9.
What did Kenji’s experiment with TTX involve?
He created a mutation in the Nav1.8 TTX resistant pain channel. Ser-> Phe mutation increased TTX sensitivity 21,000 fold.
Describe the sliding helix and paddle models.
Sliding helix: When depolarisation occurs, intracellular compartment becomes positive compared to outside. This causes spiral of positively charged residues twisting 30 degrees, opening the protein pore.
Paddle: Membrane depolarisation causes helix to jump across membrane and almost become extracellular, opening protein pore.
What is the difference between closing time lengths in 1.7,1.8 and 1.9?
- 7 has sharp influx, and closes rapidly.
- 8 Same but a bit slower.
- 9 Does produce spike, and does not close rapidly. It is a leak channel.
What do each of the channels contribute to?
- 7: Sets the threshold for generating action potentials
- 8: contributes to continuous firing activity during sustained depolarisation due to rapid repriming.
- 9: Important for setting resting membrane potential (-70mv) by producing persistent current.
List some analgesics and their mode of aciton.
NSAIDs: Inhibit COX, preventing prostaglandin synthesis.
COX inactivation: Aspirin. Reversible competitive- Ibuprofen.
Reversible non-competitive- paracetamol.
(Celebrex is COX 2 specific but causes heart attack)
Opiates: Enkephalins and endorphins endogenous ligands. Gabapentin and Pregabalin developed.
NGF antibody: Tanezumab. Patients suffered from bone fractures (but this was due to secrete aspirin)
