Pain 1 Flashcards
What are examples of healthy pain and pathological pain?
healthy pain:
- escape from danger
- awareness of harm
- treatment of tissue damage
- learning about harmful environment
pathological pain:
- migraine
- neuropathic pain
- back pain
- joint pain (arthritis)
- toothache
In general, what pathway does pain travel in?
- pain is detected by sensory receptors in the skin
- these travel via the somatic sensory neurones to the spinal cord
- neurones ascend through the medulla oblongata to the sensory cortex
Which part of the brain perceives pain?
the pain signal first goes to the thalamus
the thalamus sends the signal to a few different areas for interpretations
it also sends signals to the limbic system, which is the emotional centre of the brain
What are the 5 different sensory receptors in the skin?
- Meissner corpuscle
- Pacinian corpuscle
- Ruffini’s corpuscle
- Merkel’s disks
- free nerve endings
Which sensory receptors are found just beneath the epidermis?
Meissner corpuscles and Merkel’s disks
Meissners corpuscles sit between the dermal pupillae
Merkel’s disks are aligned with the dermal pupillae
Where are pacinian corpuscles located?
they are large encapsulated endings located in the subcutaneous tissue
Where are Ruffini’s corpuscles located?
they are located deep in the dermis
the long axis of the corpuscle is orientated parallel to the skin
they form 20% of receptors in the skin
How is conduction velocity associated with axon diameter?
conduction velocity is positively correlated with axon diameter
(larger diameter axons have faster conduction velocity)
What types of axons of sensory afferents innervating somatosensory receptors have a large diameter?
large diameter, rapidly conducting afferents (I / II) are associated with low threshold mechanoreceptors
e.g. proprioceptors of skeletal muscle, mechnoreceptors of skin
what types of axons of sensory afferents innervating somatosensory receptors have a small diameter?
small diameter, slow conducting afferents (III / IV) are associated with nociceptors and thermoreceptors
both type III and IV fibres are involved in conducting pain sensation
What are the two categories of pain perception?
Which fibres do they travel in?
different fibres convey different aspects of pain sensation
first pain:
- conveyed through fast Ad fibres
second pain:
- conveyed through slow C-fibres
What is the difference in sensation between first and second pain?
a single painful stimulus yields two successive and distinct sensations
first pain:
- brief, pricking and well localised
second pain:
- longer-lasting, burning and less well localised
What are the characteristics of first pain?
What types of receptors produce this kind of pain?
What is the duration like?
conducted via fast Ad fibres
- sharp or prickling
- easily localised
- occurs rapidly
- short duration
mechanical or thermal nociceptors
What are the characteristics of second pain?
What types of receptors detect this pain?
carried by slow C-fibres
- dull ache, burning
- poorly localised
- slow onset
- persistent
sensory receptors are polymodal nociceptors
What are the spinal connections of the nociceptive axon terminals?
- afferent terminals enter the dorsal horn and project into the zone of lissauer
- afferent terminals synapse onto neurones of lamina I and lamina II (substantia gelatinosa)
What are the connections between the primary afferent pain fibres and the spinal cord?
AB myelinated fibres:
- synapse with PKCy+ neurones and lamina V
Peptidergic C fibres:
- synapse with lamina I
Ad myelinated fibres:
- synapse with outer lamina II and lamina V
nonpeptidergic C fibres:
- synapse with inner lamina II
What are the 3 different neurones involved in the spinal pain pathway?
first order neurones:
- pseudounipolar neurones have a cell body in the DRG
second order neurones:
- cell body in Rexed lamina of spinal cord or cranial nerve nuclei in the brainstem
- decussate in anterior white commisure
- ascend cranially in the spinothalamic tract to the VPL of the thalamus
third order neurone:
- cell body in the VPL of the thalamus
- project via posterior limb of internal capsule to terminate in ipsilateral postcentral gyrus
- this is the primary somatosensory cortex
What are the specialised receptors that some first order neurones have?
What type of receptors are these?
nociceptors which are activated through various noxious stimuli
nociceptors exist as the free nerve endings of the primary afferent neurone
as they are free nerve endings, they are unencapsulated receptors
What are the 3 different types of nociceptors?
What type of stimulus do they detect?
mechanical nociceptors:
- detect sharp, prickling pain
thermal / mechano-thermal nociceptors:
- detect sensations which elicit pain which is slow and burning or cold and sharp in nature
polymodal nociceptors:
- detect mechanical, chemical and thermal stimuli
How are signals from mechanical, thermal and mechano-thermal nociceptors transmitted?
they are transmitted to the dorsal horn via Ad fibres
these are myelinated and have a low threshold for firing and fast conduction speed
they are responsible for transmitting the first pain
they permit localisation of pain
Where do Ad fibres terminate?
rexed lamina I
they mainly release the neurotransmitter glutamate
How do polymodal nociceptors transmit their signals to the dorsal horn?
via C-fibres
these are unmyelinated and have a slow conduction speed
they have large receptive fields and poor localisation of pain
Where do C fibres terminate?
in rexed laminae I and II
they release the neurotransmitter substance P
What are the roles of the cingulate cortex and insular cortex in pain perception?
cingulate cortex:
- acute pain perception
- development of chronic pain after peripheral nerve injury
insular cortex:
- part of the limbic system
- subjective feeling of pain and induce learning about the pain in other brain areas
What is meant by ‘dissociated sensory loss’?
a pattern of neurological damage caused by a lesion to a single tract in the spinal cord
it involves preservation of fine touch and proprioception
and
selective loss of pain and temperature
In a unilateral spinal lesion, how would senses be affected?
- sensory loss of touch, pressure, vibration and proprioception BELOW** the lesion on the **SAME side
- diminished sensation of pain BELOW the lesion on the OPPOSITE side
- this is dissociated sensory loss
What are the 3 neurones involved in the trigeminal pathway for pain and temperature?
1st order neurone:
- from the face
- projects to pars interpolaris & pars caudalis of the medulla / upper cervical cord
2nd order neurone:
- ascends contralaterally to thalamus via trigeminothalamic tract
3rd order neurone:
- projects to cortex from VPM of thalamus
this pathway innervates speicialised structures
What is meant by the gate control theory of pain?
a gating mechanism that exists within the dorsal horn of the spinal cord
small nerve fibres (pain receptors) and large nerve firbes (mechanoreceptors) synpase on projection cells and inhibitory interneurones
projection neurones travel to the brain via the spinothalamic tract
According to gate control theory, what happens when no input comes in?
the inhibitory interneurone prevents the projection neurone from sending signals to the thalamus
the gate is closed
According to gate control theory, what happens when there is normal somatosensory input?
(more / only large fibre stimulation)
both the inhibitory interneurone and projection neurone are stimulated
the inhibitory interneurone prevents the projection neurone from sending signals to the brain
the gate is closed
According to gate control theory, what happens when there is more/only small fibre stimulation?
(nociception)
the inhibitory interneurone is inactivated
the projection neurone sends signals to the thalamus informing it of pain
the gate is open
According to gate control theory, what is the role of the descending pathways from the brain?
descending pathways from the brain close the gate by inhibiting the projector neurones and dimishing pain perception
What are the 2 different types of pain?
physiological pain:
- this involves acute pain
pathological pain:
- this involves inflammatory and chronic pain
What is the primary event in somatosensation?
the generation of an action potential in an afferent fibre ending
What regulators of neuronal excitability are specific for nociceptive neurones?
voltage-gated sodium channels:
- Nav1.7
- Nav1.8
- Nav1.9
sensory TRP channels:
- TRPV1
- TRPM8
- TRPA1
purinergic ligand-gated channels:
- P2X2
- P2X3
What is meant by congenital insensitivity to pain?
a rare disease characterised by inability of experience to feel pain
What tends to cause congenital insensitivity to pain?
mutations within nociceptor-specific voltage-gated sodium channel Nav1.7
population genetics can be used to pin-point pain-related genes
What are the 4 different types of inflammatory mediators of pain?
- act to directly activate ligand-gated ion channels
- act via activation of G-protein coupled receptors
- act via activation of receptor tyrosine kinases
- gasotransmitters
What types of inflammatory mediators act to directly activate ligand-gated ion channels?
- ATP activates P2X receptors
- H+ activates TRPV1
What inflammatory mediators act via activation of G-protein coupled receptors?
- prostaglandins
- substance P
- bradykinin
- proteases
- histamine
What inflammatory mediators act via activation of receptor tyrosine kinases?
- NGF
- BDNF
What are examples of gasotransmitters?
these are gaseous signalling molecules
- CO
- NO
- H2S
What are the 3 mechanisms involved in signalling cascades of inflammatory nociception?
- activation / sensitisation of sensory channels
- modulation of ion channels through intracellular signalling cascades
- modulation of gene expression
What is the role of central sensitisation?
central sensitisation contributes to sustained pain states
it is a condition of the nervous system that is associated with the development & maintenance of chronic pain
when it occurs, the nervous system goes through the process of wind-up and gets regulated in a persistent state of high reactivity
What is the definition of central sensitisation?
the process through which a state of hyperexcitability is established in the central nervous system
this leads to enhanced processing of nociceptive (pain) messages
What are the 3 main mechanisms of central sensitisation?
- NMDA-mediated signalling
- disinhibition
- microglia activation
What is familial hemiplegic migraine (FHM)?
an autosomal dominant subtype of severe migraine accompanied by visual disturbances known as aura
What causes the aura in familial hemiplegic migraine?
aura is caused by cortical spreading depression (CSD)
this is a slowly advancing wave of tissue depolarisation in the cortex
What is the cause of more than half of the cases of familial hemiplegic migraine?
gain-of-function mutations within neuronal Cav2.1 voltage-gated Ca2+ channel gene
the mutation results in increased Ca2+ flow into dendrites and excessive release of the excitatory neurotransmitter glutamate
What initiates cortical spreading depression (CSD)?
CSD is ignited by local elevation of extracellular K+ levels in pockets of intense excitatory transmission
How is CSD threshold altered in FHM patients?
the threshold for CSD initiation is reduced in FHM patients with mutations in the Cav2.1 Ca2+ channel
the higher Ca2+ level in dendrites facilitates glutamate release
this increases the likelihood that K+ levels will reach the CSD threshold
