Pain I Flashcards
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)
Difference between nociception and pain
Nociception: sensing damage
Pain: experience for brain
Acute pain vs Chronic pain?
Acute: sudden, self-limiting]- < 6 months
Chronic: sudden or gradual, remission/exacerbation ]- >6 months
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)
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)
Areas of the brain that are involved in pain?
- SI: primary sensory cortex
- SII: secondary sensory cortex
- anterior insula
- cingulate gyrus
Specificity Theory of Pain (Descartes)?
Intensity of pain is directly related to amount of associated injury
NB: DOES NOT APPLY FOR CHRONIC PAIN
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
Chemical factors that mediate pain?
- Bradykinin
- Prostanoids
- Nerve Growth Factor (NGF)
Activation mechanism of bradykinin for pain?
Binds to receptor (GPCR) -> PLA2 activation -> converts arachidonic acid to prostanoids
AND PLC -> PKC
Activation mechanism of prostanoids (PGE2) in pain?
-> nociceptive neurons release COX -> arachidonic acid (AA) -via COX-> AA synthesises PGE2
What triggers prostanoid activation?
- pain
- immune cells (in response to inflammation)
- pro-inflammatory cytokines (TNF-a)]- induces COX-2
Aspirin effect on prostanoids?
Blocks COX -> reduced PGE2
[painkiller]
Mechanism of NGF in pain?
NGF binds to TrkA -> increased peripheral sensitivity of nociceptive neurons AND increased Na+ channels
Clinical effect of NGF antibody?
Painkiller
Where is TrkA expressed?
Selectively expressed on unmyelinated nociceptive sensory neurons (C-fibres)
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
