Pain processing Flashcards
(31 cards)
What does initial injury or tissue damage lead to
Injury or tissue damage releases bradykinin and prostaglandins,
which activate or sensitize nociceptors.
What does activation of nociceptors lead to
Activation of nociceptors leads to the release of substance P and
CGRP (calcitonin gene– related peptide).
Substance P acts on mast cells in the vicinity of sensory endings to
evoke degranulation and the release of histamine, which directly
excites nociceptors.
Substance P produces plasma extravasation, and CGRP produces
dilation of peripheral blood vessels; the resulting oedema causes
additional liberation of bradykinin.
How are peripheral nociceptors unique?
The unique anatomy of the peripheral nociceptor allows them to
propagate potentials in any direction – antidromic potentials,
including
* Potentials backpropagating amongst the peripheral endings
* Antidromic potentials incoming from CNS
Describe the different types of TRP channels
Transient receptor potential (TRP)
channels – large family
* TRPV1 is exclusively expressed by
nociceptors
* activated by capsaicin and heat
* Sensitised by low pH and other
chemicals
* TRPA1 – putative cold receptor – but
likely plays a role in sensitisation
* TRPV2 – putative heat receptor, but
likely sensitisation dependent
* TRPV1 and TPRA1 may play a role in
mechanotransduction, likely of higher
importance in the context of
sensitisation
How do GPCR’s modulate TRP channels
- Bradykinin (BK) binds to GPCR (G protein coupled receptors)
- This leads to activation of phospholipase C (PLC), which then leads to the hydrolysis of
membrane phosphatidylinositol bisphosphate (PIP2), the production of inositol 1,4,5-
triphosphate (IP3) and release of calcium from intracellular stores - PLC regulated TRP channel activity and subsequent sensitisation of TRPV1 (sensitised)
leads to influx of extracellular calcium.
Describe what ASIC’s are
- Acid-sensing channels
- voltage-independent cation channels that
are activated by acidic pH; - primarily permeable to sodium and elicit
cell depolarization, leading to secondary
intracellular accumulation of calcium - expressed in sensory neurons of the DRG
and trigeminal ganglion. - ASIC3 is an essential pH sensor for pain
and is primarily located in nociceptive
fibres innervating the skeletal and cardiac
muscle, joints, and bone – where
anaerobic metabolism leads to build-up
of lactic acid and protons
What are HCN channels
- Hyperpolarization-activated cyclic nucleotide-
gated (HCN) channels are activated by
membrane hyperpolarization; - permeable to Na+ and K+ and are
constitutively open at voltages near the
resting membrane potential. - In many cases, activation is facilitated by
direct interaction with cyclic AMP. - Opening of HCN channels elicits membrane
depolarization toward threshold for action
potential generation and reduces membrane
resistance and thus the magnitude of
excitatory and inhibitory potentials. - Preclinical experiments suggest HCN channels
have a prominent role in both inflammatory
and neuropathic pain.
Explain central sensitisation
Persistent injury results in repetitive activation of
C fibres
→ Increased response of dorsal horn neurons
→ The gradual enhancement in the excitability of
WDR dorsal horn neurons → “windup”
→ N-methyl-d-aspartate (NMDA)-type glutamate
receptors likely involved
→ Mechanism that is very
similar to LTP in other
circuits
→ And may involve BDNF
Explain the nociceptive projections in the dorsal horn
- Aα fibres project directly to
the motor neurons in the
ventral spinal cord (not on
the image) - Aβ fibres project to lamina
IV – where they contact
neurons that have their cell
bodies in the lamina V - Aδ fibres project to laminae
I, II, IV and V where they
contact cells with their cell
bodies in laminae I, II and V - C fibres project to laminae I
and II where they contact-
either directly or indirectly -
also neurons from layers I,
II and III
Describe the 2nd order projection neurons of the pain pathway
- Projection neurons in the layer V of the
deep dorsal horn have relatively large
receptive fields, - Respond to low-threshold and
nociceptive input - Show WDR (wide dynamic range)
characteristics. - projection cells in lamina I have much
smaller receptive fields - invariably respond to both noxious
thermal and mechanical stimuli - some cells also show moderate responses
to innocuous mechanical stimuli. - Express NK1R – neurokinin 1 receptor
- Projection neurons constitute only 1% of
all neurons in the dorsal horn grey matter - Majority of the other neurons are
interneurons
Explain lamina 1’s possible role in pathological pain
- Some evidence suggests that the
lamina I projection cells may be more
important for pathological pain states
than for acute pain. - In an animal model ablation of NK1r-
expressing cells resulted in a
reduction of neuropathic and
inflammatory hypersensitivity - The acute pain thresholds remained
normal
Explain the gate control theory for pain
Gate-control Theory of Pain
* Ronald Melzak and Patrick Wall 1960s
* The nociceptive neurons may open the
gate for central transmission of pain
* The activation of low threshold
mechanoreceptors will close the gate
for the nociceptive input
* The effect of soft touch has on pain
* The concrete anatomical correlates
have not been identified
If another modality such as soft touch is activated, the A beta fibre can activate an inhibitory interneuron to lead to reduced or weakened pain activation
Today we know supraspinal mechanisms are known to be involved in this mechanism
How can C fibres be labelled
- Intracellular recording and labelling of
individual C fibers revealed their
central arbors in laminae I-II of the
dorsal horn. - Our knowledge about C fiber
termination within the dorsal horn
comes from studies using simple
differentiation between peptidergic
(PEP) and non-peptidergic (NP) fibres - Using neurochemical markers such as
neuropeptides (CGRP/SP), or binding
of the lectin IB4 - Also distinguished by the trophic
factors that regulate their connectivity
How can laminae 1-3 of the dorsal horn modulate pain
- Around one-third of neurons in
laminae I–III of the dorsal horn are
inhibitory interneurons, and that
many of these use GABA and glycine
as co-transmitters - intrathecal administration of
GABAA and glycine receptor
antagonists in awake animals resulted
in hypersensitivity to tactile stimuli. - Conclusion: dorsal horn can gain
access to pathways that process pain-
relevant information, which is
normally suppressed by local
GABAergic/glycinergic inhibition.
Describe the 3 major ascending pathways for pain
Three major ASCENDING pathways:
1. Spinothalamic tract
Third-order neurons ascend to terminate
in the somatosensory cortex
Primarily transmits signals important for
pain localisation
Hence they have small receptive fields
2. Spinoreticular tract
Primarily involved in the emotional
aspects of pain and pain perception
3. Spinomesencephalic tract
Activates PAG neurons, which descend
via indirect projections to the spinal cord
- to modulate pain sensation
Describe the role of the limbic system in pain processing
- the limbic brain areas ACC and insula are
specifically activated by somatosensory
nociceptive stimuli - receive direct inputs from the thalamus
and show strong activation in pathological
pain states – diffuse pain/ache - Cingulate cortex –emotional states
- Insula – internal state (contribution of
autonomic component)
How can central sensitisation affect phantom limb symptom
- The persistent peripheral drive and
subsequent central sensitisation can
result in severely altered cortical
representation of ascending spinal
input - In a patient with phantom limb
symptom the cortical representation
of the mouth has extended into the
areas normally representing hand and
arm
How is pain perception regulated
- The anterior cingulate and insula
regions of the cerebral cortex are
activated when the hand is placed on
the grill but not when warm and cool
stimuli are applied separately. - Excitation of nociceptive
spinothalamic neurons by cool stimuli
does not produce pain - The grill stimulus has a similar effect
but excites the cool-specific cells to a
lesser extent, thus reducing their
suppressive effect on cold pain
Describe the PAG/locus coeruleus role in pain modulation
- The descending controls originate in the
periaqueductal grey (PAG) or locus coeruleus
(LC) - The LC carries the noradrenergic descending
projection → inhibitory effect on transmission
at the 1st synapse - The PAG projections synapse in the RVM from
where the serotonergic descending controls
project to the dorsal horn – facilitatory (or
inhibitory) effect - PAG is the site for opioid induced analgesia
Takes place through noradrenergic and serotonergic pathways
Explain how the spinal cord is modulates pain
- Descending controls act
directly or indirectly on the
1st synapse - Activation of the opioid receptors at the presynapse,
modulates activity of VGCCs and subsequently reduces
synaptic vesicle release - At the postsynapse, opioids hyperpolarise the
membrane potential
Describe mechanisms by which peripheral sensitisation can occur
*emergence of mechanical or thermal
transducers (or both) at or near the cut
ends of damaged axons or within the
ganglia
*de novo expression of transducers in
neurons that do not normally express
them → identity switch
*decreases in inhibitory transducers
(for example, opioid receptors) and/or
increases in excitatory transducers (for
example, P2X3)
*changes in the expression or release
of endogenous ligands, receptors or
both
Describe how BDNF can contribute to peripheral sensitization
BDNF (brain derived neurotrophic factor) derived from immune, epithelial, and Schwann
cell can presumably interact with peripherally situated TrkB receptors (on Adelta afferents)
to functionally alter the nociceptive circuit.
Explain 2 tests that can be carried out to test mechanical stimuli in rodents
Manual Von Frey test.
* Rodents are placed individually in small cages
with a mesh or barred floor.
* Monofilaments of differing forces are applied
perpendicularly to the hind paw.
* If the rodent withdraws, licks or shakes the
paw, it is considered to have had a positive
response.
Randall-Selitto test (handheld device).
* The rodent is restrained, and the hind paw (or
tail) is placed between a pointed probe tip
and flat surface.
* The pressure is increased until withdrawal or
vocalization occurs.
Explain 2 tests that can be carried out to test thermal stimuli in rodents
A) Tail flick test (radiant heat).
* Rodents are restrained and a
focused beam of light is
applied to tail.
* The time taken to “flick” or
withdraw the tail from the
heat stimulus is recorded.
(B) Hot plate test
* Rodent is placed on a metal
surface maintained at a constant
temperature (e.g. 54°C)
* the time taken to elicit a
nocifensive behavior (e.g., hind
paw withdrawal or licking) is
recorded.
(C) Hargreaves test
* Rodents are placed individually in
small enclosures with a glass floor.
* infrared heat source is focused on
the plantar surface of the hind
paw and
* the time taken to withdraw from
the heat stimulus is recorded.
