Peripheral and Central Sensitisation Flashcards Preview

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

Flashcards in Peripheral and Central Sensitisation Deck (32)
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How does hypersensitivity (e.g. allodynia/hyperalgesia) come about?

- Inflammation of area exposed to noxious stimuli (e.g. sunburn)


How is hypersensitivity beneficial?

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


How can hypersensitivity occur outside of normal noxious stimuli?

Neuronal damage:
- Mechanical trauma
- Metabolic disease e.g. diabetes
- Neurotoxic chemicals (e.g. chemotherapy)
- Infection
- Tumour invasion
- Spinal cord injury
- Stroke


What is allodynia?

Pain in response to normally innocuous stimuli


What is hyperalgesia?

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


What is the function of inflammatory pain?



Where is inflammatory pain observed clinically?

- Post-operative
- Arthritis


What is the function and stimulus of neuropathic pain?

- No function; pathological
- Neural damage/ectopic (random) firing


What is the clinical setting of neuropathic pain?

- PNS and CNS lesions
- Diabetic neuropathy
- Trigeminal neuralgia (bad face pain)


What changes occur with the nociceptive at peripheral sensitisation?

- Nociceptor activation thresholds lowered (from initial high)
- Nociceptor starts firing more; experienced as pain


What changes with central sensitisation occur with a nociceptive input?

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


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

- Chemical environment changes
- Cells residing within/infiltrating injured area produce many factors to generate an "inflammatory soup" to signal pain


What consists of the inflammatory soup?

- Neurotransmitters
- Peptides (substance P, CGRP, Bradykinin)
- Lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids)
- Neurotrophins
- Cytokines
- Chemokines
- Proteases
- Protons


How do the factors in the inflammatory soup work?

- 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


How do prostaglandins sensitise the nociceptor?

- 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


How do NGFs (nerve growth factors) activate TRPV1?

- 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


How are ASICs activated and what is the resulting effect?

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


How can ASICs be used for analgesia?

- ASIC3 can be inhibited by a peptide toxin


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

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


What is the structure of the P2X receptor?

- Heteromultimers of subunits consisting of 2T1P; 2 transmembrane + 1 Pore domain.


What is the principle P2X subtype?



How does Bradykinin (BK) affect sensitisation?

- 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


What happens with central sensitisation?

- 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


What changes occur at the nociceptor terminal after nerve damage?

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


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

- 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


What circumstances see NMDA/mGluR1 activation?

Increased nociceptor signal e.g. inflammation/nerve damage


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

- 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


How does ketamine demonstrate its analgesic effects?

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


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

- 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


What happens to Aβ fibres after injury?

- 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)