Pain Mechanisms Flashcards
What are nociceptors?
Translate noxious stimulus into electrical signals which are sequentially passed through peripheral nerves to brain stem
Perception of pain
1st order neurons that relay information to second order neurons in the CNS via chemical synaptic transmission
Pseudounipolar
What is pain?
An unpleasant sensory and emotional experience, associated with actual tissue damage or described in terms of such damage
What are the different forms of pain?
Nociceptive pain - adaptive (immediate, protective response, short-lived)
Inflammatory pain - adaptive (assists in healing, persists over days, possibly weeks)
Pathological pain - maladaptive (no physiological purpose, persists over months, years, or even a lifetime)
Describe the 1st order neuron of the nociceptive pathways
Made up of sensory receptor and sensory unit
Cell body located at the DRG (innervation of limbs, trunk, posterior head)
OR
Cranial ganglia (innervation of anterior head)
Describe the 2nd order neuron of the nociceptive pathways
Projection neuron
Cell body location; dorsal horn of spinal cord or brain stem nuclei
Describe the 3rd order neuron of the nociceptive pathway
Projection neuron
Thalamic neuron
Where will the 3rd order neuron of the nociceptive pathway project to?
Cortical areas; primarily the somatosensory cortex
What are the different forms of nociceptive stimulus?
Thermal
Mechanical
Chemical
What 2 phenomena are associated with inflammatory pain?
Hypersensitivity (heightened sensitivity to noxious stimuli)
Allodynia (innocuous stimuli now elicits pain)
What mediates inflammatory pain?
Macrophages
Mast cells
Neutrophils
Granulocyte
How does inflammatory pain assist in healing?
Discourages physical contact from would
Discourages movement
Although adaptive in nature, nonetheless requires reduction in ongoing inflammation e.g. RA
What are the 2 forms of pathological pain?
Neuropathic pain; neural lesion or CNS lesion (haemorrhagic stroke for example)
Dysfunctional pain; no neural lesion, no inflammation however positive pain symptoms
Describe pathological pain
Pain resulting from damage to the peripheral or central nervous systems and from dysfunction of the nervous system (IASP) = present for at least 2-3 months
What are the different subtypes of nociceptors?
Comprise A-delta and C fibres (n.b. not all A-delta and C-fibres are nociceptors)
Transduction begins in free nerve endings; mediated by numerous receptors and channels
Describe A-delta fibres
Mechanical/ thermal nociceptors that are thinly myelinated
Respond to noxious mechanical and thermal stimuli
Mediate first, fast pain
What is the conduction velocity of A-delta fibres?
6-20 m/s
Describe C-fibres
Nociceptors that are unmyelinated
Collectively respond to all noxious stimulus e.g. polymodal
Mediate second, slow pain
What is the conduction velocity of C-fibres?
0.5-2.9 m/s
What is a bar unit in terms of nociceptor activation?
A bar is a unit of pressure whereby one bar corresponds to one atmosphere of pressure
Describe the relationship between pressure and frequency of nociceptor action potentials?
Increase in pressure increases the action potential frequency via nociceptive fibres (spikes/second)
Describe the experimental paradigm, isolated skin nerve stimulation
Recording from an A-delta nociceptor innervating inflamed skin, induced experimentally
Action potential discharge of increasing frequency occurs in response to mechanical stimulation of the skin in the receptive field of the neuron
What is frequency coding?
Rate of action potential discharge correlates with the intensity of applied stimulus
Describe the sub classification of C-fibre; C-MH (mechanical and heat)
Responds to noxious mechanical stimuli, activated by noxious heat (threshold 39-51)
Sensitive to capsaicin
Shows sensitization to repeated stimuli
Contributes to heat pain and location of stimulus
What is capsaicin?
Ingredient of chilli peppers that causes burning sensation
Mimics effect of heat upon C-MH nociceptors
Capsaicin is occasionally used as topically applied analgesic
Excites C-MH by provoking an inward current response by the inward flux of sodium and calcium
Describe the sub-classification of C fibres; C-M fibres
Respond to noxious mechanical stimuli
Insensitive to heat and capsaicin
Describe the sub-classification of C-fibres; C-H
Respond to noxious stimulus heat (threshold 42-48), normally insensitive to mechanical stimulus, sensitive to capsaicin
Mediate heat hyperalgesia, but do not contribute to the precise localization of stimulus
Acquire sensitive to mechanical stimulation in the context of inflammation
Describe the sub-classification of C-fibres; C-MiHi (silent)
Normally insensitive to mechanical and heat stimulus
Acquires sensitivity following sensitization by inflammatory mediators
Sensitive to capsaicin and other algesic, or pro-algesic substances
Describe the sub-class of A-delta fibre; A-MH (type 1)
Requires strong mechanical stimuli for activation
Activated by high noxious heat (>53)
Insensitive to capsaicin
Shows sensitization to prolonged stimulus
Threshold for activation by heat or mechanical stimuli drops in the setting of tissue injury
Describe the sub-class of A-delta fibre; A-MH (type 2)
Respond to noxious mechanical stimuli
Sensitive to noxious heat (43-47)
Sensitive to capsaicin
Shows adaptation rate of action potential discharge gradually declines in the presence of a prolonged stimulus of constant intensity
MEDIATE FIRST PAIN TO HEAT
Describe the sub-class of A-delta fibre; A-M
Respond to mechanical stimuli
Insensitive to heat and capsaicin
Describe the receptors that respond to chemical stimuli within the noxious pathway
ASIC (acid sensing ion channels) - H+
P2X - ATP (released from damaged cells)
P2Y - ATP
B2 receptors - bradykinin
Describe the receptors that are believed to respond to mechanical stimuli within the noxious pathway
Piezo 1 and 2
Describe the ion channels responsible for the response to thermal stimuli
TRP family
TRPA1
TRPC3
TRPV1
TRPV1 is greatly sensitized in inflammation to become active at body temperatures
Describe the peptidergic polymodal nociceptors (subset of C-fibres) afferent action
Transmit nociceptive information (orthodromic) to the CNS via release of glutamate and peptides (substance P, neurokinin A) within the DH
Noxious stimulus in the long term increases spinal excitability contributing to hyperalgesia and allodynia = sensitization
Describe the peptidergic polymodal nociceptors (subset of C-fibres) efferent action
Release of pro-inflammatory mediators (e.g. calcitonin gene related peptides (CGRP) and substance P) from peripheral terminals
NEUROGENIC INFLAMMATTION
Describe the neurotransmission between the primary afferent and the second order neuron in the DH (or spinal nucleus of TG system)
Primary nT is glutamate, produces a fast EPSP; increases neuronal excitability via activation of AMPARs and NMDARs
Peptides (SP and CGRP) also participate (particularly during HFS) causing a slow and prolonged EPSP that facilitates the activation of NMDA receptors via removal of Mg2+
This calcium entry allows for long term potentiation at these nociceptive synapses; sensitization
Where do the primary afferent cell bodies (nociceptive) termniate?
Centrally in the dorsal horn of the spinal cord in the laminae of rexed
Describe where C and A-delta fibres terminate in the laminae of rexed
Mostly in laminae 1 and 2 (C-fibres can send interneurons to laminae 5)
However, A-delta can also terminate in laminae 5
Which what cell will C and A-delta fibres synapse with inside the laminae rexed?
Nociceptive specific cells (NS) within lamiae 1 and 2
What is the role of the wide dynamic range (WDR) cells within lamiae rexed 5
Input from all 3 types of fibres to respond to a wide range of stimulus
Input from A-beta (low intensity, non-noxious mechanical stimulus), A-delta and C fibres
What type of cells respond only to A-beta fibres?
Proprioceptive cells within laminae 3,4 and 5
What tracts within the spinal cord mediate pain?
Spinothalamic - “pain matrix”
Spinoreticular - limbic structures; emotional aspect of pain `
What stimulates visceral afferents?
Nociceptors covering tissues (peritoneum, pleura)
Stretching, twisting, inflammation and ischaemia
Where do visceral afferents run?
Follows sympathetic pathways before entering dorsal horn
Describe the mechanism of referred pain
Some visceral and skin afferents converge upon the same spinothalamic neurons (all cells with a visceral receptive field also have a separate cutaneous separate cutaneous RF)
The brain interprets the nociceptive information arising from the viscera as originating from an area of skin that may be distance from the internal organ
Describe the mechanism of viscerosomatic pain
Occurs when inflammatory exudate from a diseased organ contacts a somatic (body wall) structure e.g. parietal peritoneum
Pathology may present with diffuse visceral pain that progresses to sharp viscerosomatic pain (e.g. appendicitis)
In appendicitis, pain originates as visceral, unspecific, dull pain in the umbilical region
However, when the appendix gets big and starts to rub, it presents as right iliac fossa pain
Describe the spinothalamic tract
Projection neurons originate in lamina 1 (fast fibre A-delta pain) terminate in the poster nucleus of the thalamus
Projection neurons originating in the lamina 5 (WDR) terminate in the posterior and ventroposterior nucleus of thalamus
Pain perception; location and intensity requires simultaneous firing in BOTH pathways
Describe the spinoreticular tract
Largely transmits slow C-fibre pain
Makes extensive connections with the reticular nuclei in the brainstem (PAG) and parabrachial nucleus (PBN)
Involved in the autonomic responses to pain, arousal, emotional responses and fear of pain
Describe the gate control theory of pain very simplicity
Pain evoked by activity in nociceptors (C and A-delta) can be reduced by simultaneous activity in low threshold mechanoreceptors (A-beta fibres)
Innocuous and nociceptive signals conduct to the spinal cord via a beta and C/a-delta fibres respectively and are processed by the substantia gelatinosa
When a-beta fibres activity exceeds that of c/a-delta fibres the spinal gate is CLOSED and synaptic transmission of nociceptive signals to the ascending tracts is supressed (STT, SRT) and ultimately pain is NOT perceived
When C/ A-delta fibre exceed that of A-beta; the spinal gate is OPEN and synaptic transmission of nociceptive signals to the ascending tracts is facilitated and ultimately pain is perceived
Describe the role of the interneuron in the gate control theory
C/A-delta are inhibitory on the inhibitory neuron (disinhibition) therefore increasing activity of pain
Activity in the nociceptive axon alone maximally excites the projection neurone, allowing nociceptive signals to arise to the brain
Balance of activity between a-beta and c/a-delta that confers pain in the end
Describe counter-stimulation analgesia
Sophisticated version of “rubbing it better”
Stimulation of non-nociceptive afferents can activate (directly or indirectly) lamina 2 inhibitory interneurons that supress firing of the projection neuron
A-beta fibres can be activated by high frequency, low intensity electrical stimulation = TENS
Most effective at “near noxious” stimulation intensity, that may activate a-delta fibres that engage supraspinal anti-nociceptive pathways descending from the brainstem
