- somatic (cutaneous-sharp or deep tissues-dull) - visceral (organ tissue-dull in thorax/abdo/pelvis) - neuropathic (nerve lesions, not receptors) - migraine - phantom (in absent limb)

Pain I Flashcards by Charan Muraleedharan

Types of pain?

somatic (cutaneous-sharp or deep tissues-dull)
visceral (organ tissue-dull in thorax/abdo/pelvis)
neuropathic (nerve lesions, not receptors)
migraine
phantom (in absent limb)

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Difference between nociception and pain

Nociception: sensing damage

Pain: experience for brain

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Acute pain vs Chronic pain?

Acute: sudden, self-limiting]- < 6 months

Chronic: sudden or gradual, remission/exacerbation ]- >6 months

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Sensory neurons involved in pain and relative diameters?

Aβ fibres: large diameter (>50μm)
aδ fibres: medium diameter (25-50μm)
C-fibres: small diameter (20-25 μm)

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Difference between Aβ, aδ, and C-fibres (not diameter)?

Aβ fibres: heavily myelinated (touch, not pain)
aδ fibres: thinly myelinated (acute pain)
C-fibres: unmyelinated (chronic pain)

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Areas of the brain that are involved in pain?

SI: primary sensory cortex
SII: secondary sensory cortex
anterior insula
cingulate gyrus

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Specificity Theory of Pain (Descartes)?

Intensity of pain is directly related to amount of associated injury

NB: DOES NOT APPLY FOR CHRONIC PAIN

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Gate Control Theory of Pain (Ronald Melzack, Patrick Wall)?

Gates open: pain messages get through more easily -> maybe intense pain

Gate closed: pain messages are prevented from reaching brain -> might not be experienced at all

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Chemical factors that mediate pain?

Bradykinin
Prostanoids
Nerve Growth Factor (NGF)

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Activation mechanism of bradykinin for pain?

Binds to receptor (GPCR) -> PLA2 activation -> converts arachidonic acid to prostanoids

AND PLC -> PKC

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Activation mechanism of prostanoids (PGE2) in pain?

-> nociceptive neurons release COX -> arachidonic acid (AA) -via COX-> AA synthesises PGE2

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What triggers prostanoid activation?

pain
immune cells (in response to inflammation)
pro-inflammatory cytokines (TNF-a)]- induces COX-2

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Aspirin effect on prostanoids?

Blocks COX -> reduced PGE2

[painkiller]

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Mechanism of NGF in pain?

NGF binds to TrkA -> increased peripheral sensitivity of nociceptive neurons AND increased Na+ channels

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Clinical effect of NGF antibody?

Painkiller

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Where is TrkA expressed?

Selectively expressed on unmyelinated nociceptive sensory neurons (C-fibres)

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Neurotransmitters for pain and their receptors?

Glutamate (AMPA, NMDA)]- excitatory

- GABA (GABA-A, GABA-B)]- inhibitory

Glutamate’s role in pain pathway?

Tissue damage -> sensory neuron releases glutamate -> post synaptic Na+ influx -> AP -> pain signal to CNS

Effect of GABA on pain pathway?

If too much pain -> brain central descending inhibitory pathway releases GABA -> Cl- influx -> hyperpolarisation -> decreased AP

Effect of NMDA receptor stimulation on pain pathway?

c-fos production
prostanoid production
nitric oxide production

Channels involved in pain pathways?

TRP channels
ATP-gated channels
Ca2+ channels
Na+ channels

Structure of TRP channels?

[only expressed by nociceptive sensory neurons]

non-selective cation channel (Na+/Ca2+)

Gated by capsaicin, anandamide, increase temperature, decrease pH

TRP KO -> ?

TRPV1 antagonists -> ?

TRP KO -> impaired detection to painful heat stimuli

TRPV1 antagonists -> block pain (but temp fluctuates)

Why are ATP-gated channels important?

ATP not normally in the extracellular domain i.e. it’s a marker of tissue damage/cell death

Types of ATP-gated channel?

- P2X (3,4)]- ligand gated ionotropic | - P2Y (G-protein coupled)

What is P2X-3

Non-selective cation channel (Na+, Ca2+)

What is tactile alloydynia?

Increased sensitivity so even light touch can cause pain

Mechanism of tactile alloydynia

?-> ATP release-> P2X4 on microglia -> more BDNF -> reduced KCC2 (Cl efflux pump) -> increase intracel Cl GABA release -> Cl- moves down conc gradient -> intracel Cl > extracel Cl -> depolarisation -> pain (AP) -> [brain senses more pain] -> more GABA release -> cycle continues NB: GABA-r is open but retrograde Cl flow due to conc gradient

Structure of Ca2+ channels in pain?

4 subunits (α1, β, γ, α2δ) ion-selective filter EEEE α1 chaperones α2δ to membrane (blocked by CCB) 4th transmembrane domain is +ve (voltage sensor)

Structure of Na+ channel in pain?

9 α-subunits]- Nav1.7, 1.8, 1.9 are involved in pain Ion-selective filter: D+E+K-A pore loops hang off within pore Inactivation gate (IFN) tripeptide can black Na) entry Voltage sensor: every 3rd position of the 4th trans-membrane segment has +ve charge

Outcome of point mutation of DEKA-> DEEA

[DEKA is ion-selective filter on Na+ channel] DEEA is Ca2+ permeable -> not viable

Outcome of tetrodotoxin (TTX) from Fugu fish?

Blocks Na+ (except 1.5.,1.8,1.9) Resp failure (heart and pain unaffected) [NB: serine in Nav1.8 confers resistance to TTX]

Location and properties of Nav1.7?

- found at sensory nerve endings - quick to open, quick to close - long refractory period

Outcomes of Nav1.7 mutation?

- unable to feel pain - paroxysmal extreme pain disorder (gain of function, constant Na+ in pain signal) - inherited erythromelalgia (gain of function, L858H mutation -> prolonged opening)

Location and properties of Nav1.8?

NB: key subtype in pain pathway - located at axons, exclusively at C-fibres - slower to close - minimal refractory period

PGE2/bradykinin effect on Nav1.8?

Enhances TTX resistance Na+ current (lower threshold)

Outcome of Nav1.8 KO?

Don't feel pain

Gain of function mutation of Nav1.8 -> ?

Gain of function mutation -> painful neuropathy

Overview of Nav1.9?

- Leaky, persistent current | - Sets RMP

Nav1.9 KO -> ?

Nav1.9 KO -> normal response to mechanical and thermal stimuli