Physiology and pathophysiology of pain Flashcards
what is pain?
An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage
what are IASP – Key notes on pain?
Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.
Pain and nociception are different phenomena.
Pain cannot be inferred solely from activity in sensory neurons.
Through their life experiences, individuals learn the concept of pain.
A person’s report of an experience as pain should be respected.
Although pain usually serves an adaptive role, it may have adverse effects on function, social and psychological well-being.
Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain
use the example of an individual stepping on glass to describe the difference between nocioception and perception of pain?
So let us imagine that an individual is stepping on a broken glass. Obviously that person will experience pain. The broken glass causes tissue damage. This activates the somatosensory nervous system, which conveys the message to the CNS, which is perceived as pain.
So the process of conveying the message is nociception while the perception of this message is pain.
what is the definition of nociception?
The physiologic process by which noxious stimulation is communicated through the peripheral and central nervous system.
why is pain a subjective experience?
pain is a subjective experience. This perception occurs in the somatosensory cortex.
Most commonly, the experience follows a tissue damage.
However, the brain and spinal are capable of triggering activity leading to perception of pain even without tissue damage.
Some of the common conditions such as fibromyalgia, widespread pain, ME, are examples where pain perception occurs without external tissue damage.
What are the different parts of the pain pathway?
Periphery
Detection
Transmission to spinal cord (first order of neurons)
Spinal cord
Processing
Transmission to brain (thalamus) (second order of neurons)
Brain
Perception, learning, response
Modulation
Descending tracts
[In periphery, the tissue damage is usually detected by the specialized receptors called nociceptors. The created afferent volley gets transmitted to spinal cord. The first set of nerve fibres and nerve cells involved for the first order neurons. In spinal cord, the received impulses gets processed and conveyed to the brain, particularly thalamus. These are called second order neurons. Thalamus acts as the second relay centre and feeds the messages to various centre’s in brain, where the perception, learning and response are processed. This processing involves a modulation component as well, by which the brain either dulls or amplifies the input. These feedback impulses are processed in midbrain and effected via the descending tracts to spinal cord, thereby completing the loop. At each step, with appropriate initial stimuli, the normal capacity of physiologic processing and modulation can be exceeded, making it behave abnormally by continued activity or abnormal processing of other stimuli, leading to chronic pain.]
What is the periphery responsible for in the pain pathway?
Detection
Transmission to spinal cord (first order of neurons)
What is the spinal cord responsible for in the pain pathway?
Processing
Transmission to brain (thalamus) (second order of neurons)
What is the brain responsible for in the pain pathway?
Perception, learning, response
What part of the pain pathway is responsible for modulation?
Descending tracts
What is nociception?
Detection of tissue damage by specialised transducers connected to A-delta and C fibres
Nociception is done by free nerve endings of what fibres?
A-delta fibres
C fibres
when do nociceptors become activated?
The stimuli – thermal, mechanical, or mechanical, when reaches a threshold for noxious range, these receptors gets activated.
For example, when you raise a skin fold on your forearm by pinching, it does not cause pain but the more pressure, mechanical stimuli, you exert, the threshold for noxious ranges reaches, activating these nociceptors
What are the 4 different kinds of nerve fibres?
A alpha
Myelinated
Large diameter
Proprioception, light touch
A beta
Myelinated
Large diameter
Proprioception, light touch
A delta
Lightly myelinated
Medium diameter
Nociception (mechanical, thermal, chemical)
C
Unmyelinated
Small diameter
Nociception (mechanical, thermal, chemical)
Temperature, itch
Are A alpha fibres myelinated or not?
Myelinated
Are A beta fibres myelinated or not?
Myelinated
Are A delta fibres myelinated or not?
Lightly myelinated
Are C fibres myelinated or not?
Unmyelinated
Describe the diameter of A alpha fibres?
Large diameter
Describe the diameter of A beta fibres?
Large diameter
Describe the diameter of A delta fibres?
Medium diameter
Describe the diameter of C fibres?
Small diameter
What are A alpha fibres responsible for?
Proprioception, light touch
What are A beta fibres responsible for?
Proprioception, light touch
What are A delta fibres responsible for?
Nociception (mechanical, thermal, chemical)
What are C fibres responsible for?
Nociception (mechanical, thermal, chemical)
Temperature, itch
What are the 2 different kinds of matter in the spinal cord?
Grey matter (neurons)
White matter (ascending and descending axons)
What can the grey matter of the spinal cord be divided into?
Ventral, lateral and dorsal horn based on location
What divides the grey matter in the spinal cord into layers?
Rexed laminae
How many layers does rexed laminae divide the grey matter of the spinal cord into?
10 layers based on their cytoarchitecture
What are the different types of neurons contained in the rexed laminae of the spinal cord?
Low threshold mechanoreceptive neurons
Located in layer 3 and 4
Receives input from A beta fibres
Nociceptive specific neurons
Located in layer 1 and 2
Receive input from C and A delta fibres
Interneurons
Influence the projection neurons and afferent input
Wide dynamic range (WDR) neurons
Layer 5
Receive input from alpha beta
What layers of rexed laminae contains low threshold mechanoreceptive neurons?
Layer 3 and 4
What layers of rexed laminae contains nociceptive specific neurons?
Layer 1 and 2
what layers of rexed laminae contains wide dynamic range (WDR) neurons?
layer 5
From what fibres to low threshold mechanoreceptive neurons receive input?
Alpha-beta fibres
From what fibres do nociceptive specific neurons receive input?
A-delta and C fibres
From what fibres do wide dynamic range (WDR) neurons receive input?
Alpha-beta
What does WDR neurons stand for?
Wide dynamic range neurons
Describe the process of pain perception?
Primary afferents/1st order neurons
Cell body in dorsal root ganglion
First order neuron
Synapse at spinal cord
A and C nerve fibres conduct pain, A delta being slightly myelinated medium diameter fibres responsible for fast pain, then dull pain is conducted by small diameter slowly conducting C fibres
Spinal dorsal horn
First order synapse
Rexed lamina 2 and 5
Neurons which receive the input
Nociceptive specific
Low threshold mechanoceptive
Wide dynamic range
Axons continue as tracts
Spinothalamic tract
Major ascending tract for nociception
Cell bodies in rexed lamina 1, 2 and 5
2 different types are lateral and ventral STT
Lateral STT terminates in ventroposterior thalamic nuclei which feeds to somatosensory cortex to facilitate the spatial, temporal and intensity discrimination of painful stimuli
Medial thalamus nuclei receives input from ventral STT, projects to cortical regions such as anterior cingulate and insular cortex as well as other parts of limbic system
Since limbic system is associated with behaviours, the firing in medial thalamus affects behavioural state
Anterior cingulate cortex may contribute to affective component of pain experience and modulate the autonomic and motor components of pain
Brain
Thalamus is the second relay station
Contains ventroposterior thalamic nuclei and medial thalamus
Connections
Cortex
Limbic system
Brainstem
Descending pathways
Descending from brain to dorsal horn
Periaqeductal grey
Usually decreases pain signal
Noradrenergic system
Where is the cell body for the primary afferent/1st order neurons in pain reception?
Cell body in dorsal root ganglion
where do the primary afferents end?
rexed lamina 1 and 2
which neurons in the grey matter receive input from lamina 1 and 2?
Nociceptive specific neurons , which are primarily located in layetr 1 and 2.
The deeper layers 5 contains mainly the LTM and WDR neurons. They receive impulses both directly from primary afferents and interconnections. Their axons continue as the tracts to higher centres.
what is the major tract sending impulses to the thalamus?
Spinothalamic tract
where are the cell bodies of the spinothalmic tract located?
primarily in Rexed lamina 1, 2, & 5
what are the different types of spinothalmic tract?
There 2 different types of STT.
Lateral and ventral or neo and paleo STT.
Lateral and anterior?
Where does the lateral spinothalamic tract terminate?
Lateral STT terminates in ventroposterior thalamic nuclei which feeds to somatosensory cortex to facilitate the spatial, temporal and intensity discrimination of painful stimuli
Where does the ventral spinothalamic tract terminate?
Medial thalamus nuclei receives input from ventral STT, projects to cortical regions such as anterior cingulate and insular cortex as well as other parts of limbic system
In addition to STT, three other tracts are know to carry nociceptive information to other parts of the brain, what are they?
Spinoreticular tract (medulla)
Spinomesencephalic tract (brainstem)
Spinohypothalamic tract (hypothalamus)
The firing of the ventral spinal thalamic tract affects behavioural state, why is this?
Medial thalamus nuclei receives input from ventral STT, projects to cortical regions such as anterior cingulate and insular cortex as well as other parts of limbic system
Since limbic system is associated with behaviours, the firing in medial thalamus affects behavioural state
What function does the anteiror cingulate cortex have to the pain experience?
Anterior cingulate cortex may contribute to affective component of pain experience and modulate the autonomic and motor components of pain
What is the second relay station in the perception of pain?
Thalamus
What nuclei does the thalamus contain the relates to pain?
Contains ventroposterior thalamic nuclei and medial thalamus
What connections does the thalamus make as part of the perception of pain?
Cortex
Limbic system
Brainstem
As part of the perception of pain, where are descending pathways from and to?
Descending from brain to dorsal horn
As part of pain perception, what are descending pathways responsible for?
Usually decrease pain signal via the noradrenergic system
What is the primary control centre for descending pain modulation?
Periaqueductal grey
In what cortex of the brain does pain perception occur?
Somatosensory cortex
What does PAG stand for?
Periaquaductal grey
What is the brain matrix?
Connections between different brain centres to perceive brain
what does the thalamus act as?
the second relay station for nociceptive transmission
where does all the different nuclei of thalamus receive input from
spinal cord via STT
what are the relay from the thalamus (third order neurons divided into?
medial and lateral system
which tracts are termed as the lateral system?
The tracts arising from posterior nuclei of thalamus is termed as lateral system
where does the input originate from?
The input originates from superficial layers of Spinal cord particularly lamina 1
how
how do the tracts end in the lateral system of the thalamus?
The tract end in all 3 nuclei- ventral posterior lateral, Ventral posterior medial and ventral posterior inferior nuclei of thalamus
where do the third order neurons from VPLP, VPM and VPI project to?
The third order neurones from these nuclei project into Somatosensory cortex, which serves as the sensory discriminative part of the nociceptive system.
where does the medial part of the thalamic nucleo receive input from?
The medial part of the thalamic nuclei receives input from lamina 5 of the spinal cord and projects into both insula and anterior cingulate cortex
what does the medial system of the thalamus serve as?
This medial system serves as the affective and evaluative component of the pain.
what componenets make up the medial system?
VMpo- Ventromedial nucleus (posterior part)
MDvc – Medial dorsal nucleus (ventrocaudal part)
what does the periaqueductal grey in the midbrain receive?
input from the medial system
Depending on the input, they either want to amplify or dampen the signal
where does rostero ventral medulla have connections to?
spinal dorsal horn projection neurons via the reticulospinal tract
They have a inhibitory tone on these cells. The inhibition is maintained by the so called ‘on’ cells
what influences the on and off cells based on the feedback from medial system?
The PAG
describe the nature of the descending system?
This descending system is called as noradrenergic system as NA acts as the neurotransmitter.
The tone of this system – diffuse noxious inhibitory control can be measured in humans.
what is diffuse noxious inhibitory control?
Diffuse noxious inhibitory controls (DNIC) are a mechanism of endogenous descending pain modulation and are deficient in a large proportion of chronic pain patients. However, the pathways involved remain only partially determined with several cortical and brainstem structures implicated
What is the lateral aspect of the brain matrix composed of?
Lateral aspect is composed of somatosensory cortex and VPM nuclei of thalamus
Involved in sensory discriminative part of nociception
What is the medial aspect of brain matrix composed of?
Medial aspect is composed of amygdala, hippocampus, cingulate cortex, prefrontal cortex which all feedback and forward with brainstem centres for the affective and emotional component as well as descending control of pai
What function does the lateral aspect of brain matrix have in pain perception?
Involved in sensory discriminative part of nociception
What function does the medial aspect of brain matrix have in relation to pain perception?
All feedback and forward with brainstem centres for the affective and emotional component as well as descending control of pain
What is the medical term for the increased perception of pain?
Hyperalgesia
what key channels create the afferent volley based on the stimuli?
This sodium and TRPV1 channel
list some receptors that msy be found on the periphery?
5HT, histamine, bradykinin, tyrosine kinase, purine, acid sensing channel
how does inflammation of the peripjhery lead to sensitisation?
the inflammatory soup - This occurs in response to chemical mediators released by nociceptors and non-neuronal cells (e.g. mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes and fibroblasts) at the site of tissue injury or inflammation becomes responsible for keeping the sodium channels open for longer periods, This process is called sensitisation, so even minor non-painful stimuli becomes painful.
what is hyperalgesia?
It is the leftward shift of the stimulus response curve.
Increased perception of pain or even perception of non-noxious stimuli as noxious stimuli
what is primary hyperalgesia?
Primary hyperalgesia is hyperalgesia at the site of injury
what is secondary hyperalgesia?
hyperalgesia in the surrounding uninjured tissue is termed secondary hyperalgesia
what is allodynia?
Allodynia is defined as “pain due to a stimulus that does not normally provoke pain.
what changes occur in the nociceoptor for allogynia?
Decreased threshold for response
what changes occur in the nociceoptor for hyperalgesia?
Exaggerated response to normal and supranormal stimuli
what changes occur in nocioceptors for? spontaneous pain
Spontaneous activity in nerve fibres
What is spontaneous pain?
Stimulus-evoked pain, where the stimulus goes unrecognized because it is generated by the activities of daily life (both external stimuli and the internal stimuli that are produced by normal physiological processes).
Describe the function of the dorsal root projection neuron?
The neuron which is to send the impulses to the thalamus, gets inut from primary afferents the sodium and calcium channels needs to be opened for its afferent volley to be created. This is influenced by the descending neurons as well as the other interneurons. A variety of transmitters – 5HT, NE, opiates, Cannabinoids receptors all influence the activity.
what is central sesnitization?
It is the response of second order neurons in the CNS to both noxious & non-noxious stimuli
what are the three main componenets of central sensitization?
wind-up
classical
long-term potentiation
Describe the wind-up component of central sensitisation?
Happens only in neurons taking part in the synapses with primary afferent input
Homosynaptic activity dependent, progressively increases the response of the neuron
Manifests over the course of a stimulus and terminates with stimulus
Mechanism is mediated by neurotransmitters substance-P and CGRP
What is the wind-up component of central sensitisation mediated by?
Mechanism is mediated by neurotransmitters substance-P and CGRP
When does the wind-up component of central sensitisation begin and terminate?
Manifests over the course of a stimulus and terminates with stimulus
Describe the classical component of central sensitisation?
Involves opening up of new synapses in dorsal horn, which start to receive input and record the nociception (silent nociceptors)
Heterosynaptic activity dependent plasticity
Immediate onset with appropriate stimuli
Can be maintained even at low levels of ongoing stimuli
Clinical result is secondary hyperalgesia where the surrounding tissue is also painful
What is the clinical result of the classical component of central sensitisation?
Clinical result is secondary hyperalgesia where the surrounding tissue is also painful
Describe long-term potentiation component of central sensitisation?
Involves mainly the activated synapses
Occurs primarily for very intense stimuli
Mechanism involves both AMPA and NMDA receptor activation by glutamate
What neurotransmitter and receptors are involved in the long-term potentiation component of central sensitisation?
Mechanism involves both AMPA and NMDA receptor activation by glutamate
What is the main difference between central and peripheral sensitisation?
Main difference between central and peripheral sensitisation is it happens at the level of the spinal cord and acts in tandem
how can pain be divided?
duration
- acute
- chronic
mechanism
- nociceptive
- neuropathic
- nociplatic
Compare and contrast acute pain and chronic pain in terms of:
physiological/pathological
presence of noxious stimuli
function
nociceptive/neuropathic
What is nociceptive pain?
Sensory experience that occurs when specific peripheral sensory neurons (nociceptors) respond to noxious stimuli
What is nociceptive pain often described as?
Often described as throbbing, aching or stiffness
Decribe the timing of nociceptive pain?
Usually time limited and resolves when damaged tissue heals
Can also be chronic (such as osteoarthritis)
What does nociceptive pain respond to?
Tends to respond to conventional analgesics
Where is the painful region in nociceptive pain?
Painful region localised at site of injury
What is neuropathic pain?
Pain initiated or caused by primary lesion or dysfunction in the somatosensory nervous system
Where is the site of neuropathic pain?
Painful region may not be the same as the site of injury
Pain occurs in neurological territory of the affected structure (nerve, root, spinal cord, brain)
Describe the timing of neuropathic pain?
Almost always a chronic condition (such as postherpetic neuralgia, poststroke pain_
How does neuropathic pain response to convential analgesics?
Responds poorly to conventional analgesics
What are the different components of pain that analgesics act on?
Transduction
Transmission
Perception
Descending modulation
What are some examples of analgesics?
Transduction
NSAIDs
Ice
Rest
LA blocks
Transmission
Nerve blocks
Drugs
Opioids
Anticonvulsants
Surgery
DREZ
Cordotomy
Perception
Education
Cognitive behavioural theory
Distraction
Relaxation
Graded motor imagery
Mirror box therapy
Descending modulation
Placebos
Drugs
Opioids
Antidepressants
Surgery
Spinal cord stimulation
What are some different analgesics for the transduction component of pain?
NSAIDs
Ice
Rest
LA blocks
What are some different analgesics for the transmission component of pain?
Nerve blocks
Drugs
Opioids
Anticonvulsants
Surgery
DREZ
Cordotomy
What are some different analgesics for the perception component of pain?
Education
Cognitive behavioural theory
Distraction
Relaxation
Graded motor imagery
Mirror box therapy
What are some analgesics for the descending modulation component of pain?
Placebos
Drugs
Opioids
Antidepressants
Surgery
Spinal cord stimulation
what is nociplastic pain?
Stimulus Independent
No inflammation / Injury
No structural neuronal damage
Due to central plasticity
Serves no protective or adaptive function
Pathological pain
