Peripheral and Central Sensitisation Flashcards
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?
Healing/repair
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?
P2X3.
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)
What does Aβ sprouting mean for the patient?
- 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
What is one theory that explains Aβ sprouting?
Damaged C fibres communicate laterally to Aβ fibres and signal it to start sprouting; protective response etc
