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B32PAI - Biology & Physiology > Peripheral and Central Sensitisation > Flashcards

Peripheral and Central Sensitisation Flashcards

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1
Q

How does hypersensitivity (e.g. allodynia/hyperalgesia) come about?

A
  • Inflammation of area exposed to noxious stimuli (e.g. sunburn)
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2
Q

How is hypersensitivity beneficial?

A
  • Helps to protect and preserve by provoking avoidance of further contact w/such stimuli
  • Aids healing and repair
  • Adaptive process; self-limiting
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3
Q

How can hypersensitivity occur outside of normal noxious stimuli?

A

Neuronal damage:

  • Mechanical trauma
  • Metabolic disease e.g. diabetes
  • Neurotoxic chemicals (e.g. chemotherapy)
  • Infection
  • Tumour invasion
  • Spinal cord injury
  • Stroke
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4
Q

What is allodynia?

A

Pain in response to normally innocuous stimuli

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5
Q

What is hyperalgesia?

A

Pain in response to a noxious stimulus with an exaggerated/excessive response

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6
Q

What is the function of inflammatory pain?

A

Healing/repair

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7
Q

Where is inflammatory pain observed clinically?

A
  • Post-operative

- Arthritis

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8
Q

What is the function and stimulus of neuropathic pain?

A
  • No function; pathological

- Neural damage/ectopic (random) firing

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9
Q

What is the clinical setting of neuropathic pain?

A
  • PNS and CNS lesions
  • Diabetic neuropathy
  • Trigeminal neuralgia (bad face pain)
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10
Q

What changes occur with the nociceptive at peripheral sensitisation?

A
  • Nociceptor activation thresholds lowered (from initial high)
  • Nociceptor starts firing more; experienced as pain
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11
Q

What changes with central sensitisation occur with a nociceptive input?

A

Spinal cord pain neurons are changed so that they show increased responsiveness to peripheral input.

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12
Q

What occurs at the nociceptive terminal upon tissue damage and inflammation?

A
  • Chemical environment changes

- Cells residing within/infiltrating injured area produce many factors to generate an “inflammatory soup” to signal pain

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13
Q

What consists of the inflammatory soup?

A
  • Neurotransmitters
  • Peptides (substance P, CGRP, Bradykinin)
  • Lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids)
  • Neurotrophins
  • Cytokines
  • Chemokines
  • Proteases
  • Protons
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14
Q

How do the factors in the inflammatory soup work?

A
  • Nociceptors express receptors that recognise these factors; e.g. ligand-gated ion channels
  • Factors bind, leading to depolarisation or alteration of the activation threshold (sensitisation)
  • Nociceptor excitation
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15
Q

How do prostaglandins sensitise the nociceptor?

A
  • Prostaglandin E2 binds to PGE2 receptor
  • Activates Gs-protein (activates adenylyl cyclase converting ATP to cAMP > cAMP activates protein kinase A; PKA)
  • This facilitates VGSCs (NaV 1.8/1.9)
  • Changes nociceptor excitability
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16
Q

How do NGFs (nerve growth factors) activate TRPV1?

A
  • TrkA is receptor for NGF; TrkA is present on the nociceptor terminal close to TRPV1
  • Membrane phospholipid PIP2 (purple) normally tonically inhibits TRPV1, keeping it inactive
  • NGF binds to TrkA
  • TrkA autophosphorylates and activates phospholipase C-γ (PLC-γ)
  • PLC-γ converts membrane phospholipid PIP2 into DAG (diacylglycerol (green)) and IP3 (inositol 3-phosphate)
  • Less PIP2 available to inhibit TRPV1, becomes disinhibited and produces sensitisation
17
Q

How are ASICs activated and what is the resulting effect?

A
  • Acid Sensitive Ion Channels activated by H+ (even v. small changes in pH)
  • They are Na+ gating; depolarising upon activation
18
Q

How can ASICs be used for analgesia?

A
  • ASIC3 can be inhibited by a peptide toxin
19
Q

What is ATP a receptor for and what they do they do?

A
  • P2X receptors; group of ligand-gated ion channels
  • Cation (Na+/Ca2+) gating and depolarising
  • Direct excitation of nociceptor
20
Q

What is the structure of the P2X receptor?

A
  • Heteromultimers of subunits consisting of 2T1P; 2 transmembrane + 1 Pore domain.
21
Q

What is the principle P2X subtype?

A

P2X3.

22
Q

How does Bradykinin (BK) affect sensitisation?

A
  • BK binds to BK2 receptor (at nociceptor terminal)
  • Activates Gq-protein
  • Activates Phospholipase C-β
  • Converts membrane PIP2 into DAG and inositol-(1,4,5) triphosphate
  • DAG activates protein kinase C
  • Thus increasing the response of TRPV1 to heat (phosphorylated)
  • Thus BK reduces the thermal activation threshold of TRPV1
23
Q

What happens with central sensitisation?

A
  • Increase of presynaptic calcium channels after nerve damage (CaV2.2 and α2δ subunit upregulated)
  • Loss of μ-opioid receptors on presynaptic terminal after nerve damage (reduced analgesia)
  • Increase of postsynaptic signalling via NMDA receptors
24
Q

What changes occur at the nociceptor terminal after nerve damage?

A

Changes in gene expression; adaptive/maladaptive:
- Reduction of expression of certain K+ channels (affecting resting membrane potential and facilitates membrane excitability)
- Re-programming of the localisation of VGSCs:
Ectopic (out of place) AP generation; instead of AP generated at end of nociceptor as per detecting noxious stimuli, APs now generated anywhere in the nociceptor particularly at the site of damage.
- Overall = increased firing of nociceptor

25
Q

Which receptor is involved in normal nociceptor signalling; where are the others?

A
  • AMPA receptor; Glutamate binds from cleft, initiates brief depolarisation at postsynaptic terminal
  • NMDA receptor present on postsynaptic membrane too but pore blocked by Mg2+ during normal nociceptor activity.
  • mGluR1 present but j.chillin’ doin’ nothing for now
26
Q

What circumstances see NMDA/mGluR1 activation?

A

Increased nociceptor signal e.g. inflammation/nerve damage

27
Q

What events unfold at the central terminal w/increased nociceptor signalling?

A
  • Sufficient depolarisation of postsynaptic terminal (high Glu levels in cleft) from AMPA receptor activation releases Mg2+ from NMDA
  • NMDA signalling occurs; Ca2+ channel; influx of Ca2+ into postsynaptic terminal
  • mGluR1 activated; activates IP3 and DAG signalling pathways
  • Intracellular signalling pathways important for maintaining higher level of signalling; PKC (protein kinase C) activated by Ca2+ influx/IP3 + DAG pathways, feeds back to AMPA and phosphorylates it, affecting its capacity to signal
28
Q

How does ketamine demonstrate its analgesic effects?

A
  • Ketamine blocks NMDA; reduced signalling yields analgesic effect (no Ca2+ influx/thus no PKC etc.)
29
Q

What information do Aβ fibres normally convey and where do they normally project to?

A
  • Low threshold mechanical signals (e.g. brush stroke)

- Project to wide dynamic range projection neurons/interneurons normally found at Lamina V of the dorsal horn

30
Q

What happens to Aβ fibres after injury?

A
  • Sprouting; Aβ fibres sprout from OG Lamina V up to Lamina I/II to nociceptor specific projection neurons (normally reserved for high threshold pain/fed by C fibres)
31
Q

What does Aβ sprouting mean for the patient?

A
  • Allodynia sensation; a brush stroke will be perceived as pain; Aβ fibre still transmits low threshold mechanical signals but this is now connected to nociceptor/pain projection neuron too
32
Q

What is one theory that explains Aβ sprouting?

A

Damaged C fibres communicate laterally to Aβ fibres and signal it to start sprouting; protective response etc

B32PAI - Biology & Physiology (5 decks)

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