Pain Flashcards
What are nociceptors?
free sensory nerve endings that can be found through the skin, subcutaneous tissue and viscera
Responsible for converting noxious (thermal, mechanical and chemical) stimuli to the CNS
What are the two main classes of nociceptor?
Medium diameter Aδ fibres → responsible for mediating sharp, well-localised pain
Unmyelinated small-diameter C fibres → responsible for mediating slow, aching pain
What can nociceptors further be broken down into?
Mechanical Thermal Polymodal Silent: - Not activated by noxious stimuli Their firing threshold is reduced by inflammatory mediators, such as NGF
Describe nociceptive transmission to the spinal cord
Signal carried by these fibres passes via Lissauer’s tract to the lamina of the dorsal horn where they terminate and synapse onto transmission interneurons
Cell bodies lie in either dorsal root lamina or trigeminal lamina
Which layer of the dorsal horn are nociceptive neurons found in?
Marginal layer (lamina I) and substantia gelatinosa (lamina II)
Where do Adelta fibres synapse? Where do C fibres synapse?
Aδ fibres synapse onto laminae I and V (nucleus proprius), while C fibres synapse in lamina II
What may contribute to the poorly localised character of many pain conditions?
These neuropeptides are efficiently taken back up into nerve terminals, so diffuse away and have excitatory influences on many dorsal horn neurons in proximity to the release site
What causes referred pain?
Primary afferent nociceptive neurons arising from both the viscera and the cutaneous areas enter the spinal cord by the same route, and there is cross-talk between the two pathways within the spinal cord, with afferents from different sources sometimes synapsing onto the same secondary fibres (e.g. heart attack and left shoulder)
What happens to the secondary fibres in this pathway?
decussate in their segment of origin and ascend the spinal cord in the anterolateral system on the contralateral side
What are the 5 main pathways by which the fibres ascend in the spinal cord?
Spinothalamic tract Spinoreticular tract Spinomesencephalic tract Spinohypothalamic tract Cervicothalamic tract
What is the spinothalamic tract divided into?
Can be divided into the lateral (neospinothalamic) and medial (paleospinothalamic) tracts
Describe the neospinothalamic tract
Contains Aδ fibres
Decussate through the anterior white commissure
Terminate in the ventroposterolateral (VPL) nucleus of the thalamus
VPL then relays neurons to SI and SII, responsible for detecting first pain
Describe paleospinothalamic tract
C fibres
Decussate through anterior white commissure
Small portion of fibres terminate in intralaminar nuclei of thalamus (centromedian and parafascicular nuclei) → go to cingulate gyrus and anterior insular cortex → associated with the emotional aspects of pain
Most C fibres terminate in brainstem reticular nuclei, PAG, deep layers of superior colliculus and parabrachial nucleus in the pons
Parabrachial nucleus relays information to amygdala and hypothalamus
Draw the anterolateral system
OneNote
What is an important pain inhibitory centre?
PAG - can be stimulated electrically for anaesthesia
Describe projections from the PAG
PAG neurones project mainly to the raphe nuclei of the rostroventral medulla (RVM), notably the nucleus raphe magnus, and serotonergic neurones project into the dorsal horn of the spinal cord where they activate inhibitory opioidergic interneurons
Describe the inhibitory opoidergic interneurons
these interneurons release endogenous opioids, including enkephalins and endorphins, which primarily affect presynaptic release of neurotransmitter (especially glutamate) by primary afferent nociceptive neurones
They do this by binding to opioid receptors which are coupled to Gαi
Reduced cAMP leads to reduced PKC activity which leads to less VGCC phosphorylation, reduced Ca2+ entry and NT release
Describe Melzack and Walls gate control theory
Activation of Aβ fibres (touch) with non-noxious stimuli results in activation of inhibitory interneurons in the dorsal horn leading to inhibition of pain signals transmitted via C fibres, as illustrated below
Draw from OneNote
This may the reason why rubbing an injured area provides temporary relief
What does the spinoreticular tract do?
TO reticular formation - alertness and arousal in response to painful stimuli
What does the spinotectal tract to?
To tectum - orients eyes and head towards stimuli
Where does the spinomesencephalic tract go?
PAG
what does the PAG recieve input from?
The PAG gets inputs from the limbic system, hypothalamus, amygdala and cortex (insula), allowing
emotional states to modulate anti-nociception
What other group of neurons may be inhibitory to pain?
Neurones in the locus coeruleus (LC) and the nucleus raphe magnus (NRM) in the medulla, which use noradrenaline and 5-HT respectively, descend through the dorsal funiculus to send axons into the dorsal horn; here they release endogenous opioid peptides (enkephalins and endorphins, primarily dynorphin, derived from large precursor molecules), which reduce transmission from nociceptors into lamina I dorsal horn cells by: Presynaptic inhibition Stimulating postsynaptic receptors that open K + channels, causes hyperpolarisation of lamina I cells Stimulating lamina II enkephalinergic and GABAergic inhibitory interneurones that hyperpolarise the lamina I cells by opening K + channels or closing Ca 2+ channels THIS IS THE DESCENDING PAIN MODULATORY SYSTEM
Why is the DPMS important?
Maintains central sensitisation
Aberrant activity identified across a range of pain conditions, eg. chronic neuropathic pain
Gabapentin modulation
Presence relates to extent of ‘neuropathic’-like pain features in OA patients
WHat do primary nocicpetive afferents release?
Glutamate and peptides such as substance B and CGRP which act to prolong effets of glutamate
Discuss commons areas felt during referred pain
Heart – pain felt in neck, left arm, chest, back (angina) during myocardial ischaemia/infarction
Foregut – pain fibres travel to spinal cord level T8, pain referred to epigastric region (just below
intersection of ribs)
Midgut – pain fibres travel to spinal cord level T10, pain referred to periumbilical region (eg.
appendicitis)
Hindgut – pain fibres travel to spinal cord level L1, pain referred to suprapubic area/hypogastric
region
What are the cranial nerve-associated pains?
Trigeminal neuralgia and migraine
How do LAs block pain?
- Block action potential conduction along axons by reversibly blocking voltage-gated Na + channels (enter
channel and prevent ion flow through it) – prevents the initiation and propagation of action potentials,
hence prevents conveyance of sensory and motor information and so results in loss of pain sensation
(general anaesthetics render patient unconscious and oblivious to pain) - Neurons with small diameters show the greatest sensitivity to block by local anaesthetics: myelinated
Aδ and unmyelinated C fibres carrying pain information are most sensitive, though larger fibres
carrying other sensory information and motor fibres are commonly also blocked (sequence of block:
pain first, then general sensory, then motor last) - They’re usually weak bases: pKA (50% charged, 50% uncharged) usually between 8-9 (BH + ↔ B + H + )
- Only the non-ionised form (B) diffuses through the membrane to reach the axoplasm:
♥ The anaesthetic has to have a positive charge to enter and block (cationic) Na + channels, however
the ionised (+ve) form can only enter from the cytosolic side – so it must either be introduced into
the cytosol or diffuse through the membrane via the hydrophobic pathway in the non-ionised
form, before accepting a H + ion and entering the Na + channel.
What does opoid receptor activation lead to?
a) Inhibition of adenylyl cyclase, reducing cAMP and so blocking intracellular signalling cascades
b) Inhibition of voltage-gated Ca 2+ channels, which decreases transmitter release (substance P,
CGRP, glutamate)
c) Increased K + conductance, which leads to hyperpolarisation and decreased cell excitability
What else may be used to treat pain?
Anxiolytics
Describe sumatriptan
Sumatriptan is structurally similar to 5-HT, and is a 5-HT receptor agonist, specifically activating 5-HTRs
present on cranial and basilar arteries, causing vasoconstriction of these dilated arteries and so
relieving pain of headache/migraine
