L4 - Sensory Neuropathies Flashcards
What is nociception?
Transduction of noxious stimuli and also cognitive and emotional processing of it
Where are the cell bodies of nociceptive neurons found?
Dorsal root ganglion (DRG)
What is the circuitry from the DRG?
Primary sensory neurons in DRG project dendrites to peripheral tissue
What are the main types of dendrites of these neurons and what receptors do they both express?
C fibres (slow) Adelta fibres (fast and myelinated)
What are the features of Adelta fibres?
Cause immediate response
Mechanosensitive and mechanothermal
Large diameter
What happens at the dorsal horn?
Major input to CNS
Second order processing
Immediate response
Modulation of signal
Where can modulation of the signal occur?
At high levels of comms between 2nd order neurons
Feed through descending inhibitory pathways
What does the amygdala do?
Processes info relevant to aversive properties of pain
What kind of receptors are on the presynapse of nociceptive neurons?
Enkephalin
What does enkephalin do?
Inhibits release of glutamate and substance P
What does the inflammatory soup do?
Released in reponse to damage
Potentiate or maintain initial nociceptive signal
What are part of the inflammatory soup?
Protons, ATP, NTs alter neuronal excitability directly
Bradykinin, NGF bind to metabotropic receptors (longer signal)
What is a hallmark physiological response to injury?
Tissue acidosis
What do endogenous vanilloids generally do and what are some exampkes?
Act to inhibit TRPV activation
Capsaicin, olvanil, anandamide
What is hyperalgesia?
Resducing threshold for stimulation
How is nociception modulated?
Modification of TRPV1 to lower threshold activation
What does damage to nociceptor neurons lead to?
Increase in Na and reduction of K channels resulting in ectopic activation
Why does damage to neurons lead to ectopic activation?
Long term activity results in long term changes
What two things is sensory integration in the dorsal horn subject to?
Activity dependent central sensitisation
Txn dependent central sensitisation
What protein acts to reduce inhibitory input in txn dependent central sensitisation of the dorsal honr?
Cox2 induction
What is DREAM?
Inhibitory TF in the dorsal horn neuron nucleus
What is sprouting?
Activity can lead to nerve sprouting
Ectopic connections onto other circuits
What is excitotoxic shock?
Too much activity can kill a neuron leading to disinhibition
What is neuralgia?
Pain in distribution of nerve or nerves
What is neuropathy?
Disturbance of function in nerves
What is neuritis?
Special type of neuropathy with inflammatory process
What is allodynia?
Condition where normally non-painful stimuli become painful
What are the features of Charcot-Marie-Tooth (CMT) disease?
2.6m affected
Nerves to extremmeites degenerate with muscle weakness
no cure
18 types identified by genetics
What are the two types of CMT disease>
CMT type 1 - demyelinating disease
CMT type 2 - diminished responses in sensory neurons
What can the loss of the myelin sheath cause?
Reduced transmission
Spontaneous production of action potentials
What can demylination lead to?
Mitochondrial fission/fusion (enlarged mito seen in many forms of neuropathy)
Why does demyelination lead to excessive metabolic demand?
Whole axon requires ATP for pumps instead of just nodes of Ranvier
What is the cascade of CMT pathology?
Schwann cells myelinate poorly Fail to support axons Axonal transport defects Progressive axonal loss Muscle denervation and sensory losses
What are some mitochondrial fission/fusion related genes prevalent in neuropathies?
GDAP1
mitofusin2
dynamin related protein 2
How does fusion of mitochondria occur?
Mfn’s(GTPases) mediate tethering of pre-fusogenic mito
OPA1 on inner membrane (dominant mutation in domiant optic atrophy)
How does fission of mitochondria cocur?
Fis1 covers outer membrane
Drp coalesces in spots of constriction
GDAP1 promotes fission
What 2 bad things can happen to mitochondria ?
Heterogeneity in pop, some with poor function
Mitochondrial aggregation
What is HSAN1 and what are its features?
-Hereditary, sensory, autonomic neuropathy type 1
- Distal sensory loss, sweating, slow healing wounds, amputation of legs
Mutations in SPT1LC1 and Rab7
What neurological diseases are associated with sphingolipid metabolism?
HSAN1
Bovine spinal muscular atrophy
LSDs
what is SPTLC1?
Subunit of serine palmitoyl-transferase enzyme - an enzyme involved in the de nova synthesis of sphingolipids
You should look at the last few slides of this lecture
do it mate, remember cancer and cell cycle
