Pain physiology Flashcards
Define and classify pain?
Unpleasant sensory and emotional experience associated with harmful stimuli
can be categorised as acute or chronic
acute pain = less than 6 weeks
chronic pain = more than 6 weeks, more complex, often unidentifiable cause.
can also be classified by nature e.g. nociceptive vs neuropathic
what is difference between nociceptive and neuropathic pain?
nociceptive pain occurs from activation of nociceptors which may be somatic (peripheral or deep) or visceral
neuropathic pain comes from disruption of nerve fibres that are part of the pain pathway. usually differs from nociceptive pain by causing burning, electric shocks or paraesthesia and alloydia. can result from either central or peripheral NS
what is the difference between nociception and pain
nociception is the process of noxious stimulus being transduced and transmitted to brain as action potentials
pain is the emotional/sensation felt as a result on cortical interpretation of nocicption.
what is the importance of pain?
Protective role – immediately warns of tissue damage leading to reflex to withdrawing from harmful stimulus
Persisting pain encourages immobilisation to allow for healing.
give a detailed description of the pain pathways from painful stimulus to conscious perception
pain is carried by the spinothalamic tract
- nociceptors are present on nerve terminals of Ad or C fibres - these include a variety of receptors e.g. heat, prostaglandins
- once these are activated, Na influx into the cell, generator potential
- threshold - AP
- AP carried by 1st order neurons and these enter dorsal horn
- synapse with second order (at substantia gelatinosa- lamina 2) - involves AMPA receptors and glutamate NT
- cross to contralateral side
- arried within lateral spinothalamic tract to thalamus
- synapse with 3rd order to cortex for conscious interpretation
Initially sharp pain felt from fast conducting Ad fibres this initiates withdrawal from painful stimulus
Followed by a throbbing dull pain sensation when C fibres have transmitted signal more slowly.
some sensory fibres also sent to other areas e.g. RAS and limbic system
what are nociceptors?
specialised free nerve terminals which contain receptors that detect noxious stimuli
they therefore transduce pain into AP which can be transmitted throughout nervous system
stimuli sensed include…
* thermal = TRPV1 or VR1 - also responds to capsacin
* mechanical and chemical
* internal stimuli of inflammation e.g. serotonin, histamine, H+ and K+. these mediators directly cause nociception. some mediators e.g. prostaglandins, leukotrienes, substance P will lower the threshold potential for pain.
describe the activation of nociceptors
mechanoceptors - distortion of neuron results in gate opening and ion influx
VR1 = thermoreceptors - opens above 42 degrees and lets cations in
generator potential –> ?threshold –> ?AP
what is meant by primary and secondary hyperalgesia ?
hyperalgesia is defined as increased pain from a stimulus that normally provokes pain. now the response is exagerated.
primary hyperalgesia - after injury, there is inflammation and release of mediators e.g. substance P, bradykinin, prostaglandins - these sensitise nociceptors and reduce their threshold for AP generation. occurs via phosphorylation of channels.
secondary hyperalgesia - Secondary hyperalgesia refers to an increased sensitivity to pain in areas surrounding an injury, rather than directly at the site of the injury.by substance P to nearby areas. Also at a higher level within substanstia gelatinosa
what type of nerve fibres carry pain - compare these..
Ad
- myelinated , fast transmission (20ms/)
-short acting pain
- well localised
C
- unmyelinated, small, slow (0.5-2m/s)
- longer lasting pain
- poorly localised
tell me about histamine..
Major amine derived from histidine
produced by mast cells and basophils
responsible for inflammation, vasodilation, increased vascular permeability and direct stimulation of nociceptors
also has a physiological role in the gut - triggers parietal cels.
and also acts a NT
tell me about serotonin
biological amine
derived from typtophan (aa)
involved in neurotransmission, inflammation and vasodilation, gut motility
as a NT involved in emotion, sleep, appeptite, N&V
tell me about substance P
Neuropeptide transmitter acting as both a NT and neuromodulator in the pain pathway.
Involved in transmission of tissue damage to CNS and plays a significant role in pain modulation in dorsal horn and brain.
Binds Neurokinin 1 receptor (GPCR)
also plays a role in inflammation and has a role in control of nausea and vomitting.
describe the gate theory for control of pain?
The gate theory explains how peripheral nerve tranmission of pain to higher centres is ‘gated’ .
this is through ascending and descending pathways via interneurons.
e.g. when C fibres and Ad fibres active secondary interneuron they also send impulses to inhibit inhibitory interneurons to ‘open’ the gate.
conversely non-noxious stimuli e.g. from pressure fibres is activated they activate inhibitory interneurons to inhibit the gate - this is why rubbing it better helps.
finally descending pathways also activate inhibitory interneurons to ‘close’ the gate. The two main pathways include the periaqueductal grey and The locus caeruleus. These use serotonin and NA via complex interneuron connections to close the gate for pain transmission. opioid receptors also involved.
This explains how NA and 5HT3 reuptake inhibitors e.g. tramadol can be used for analgesia.
The degree of gate opening will depend on the intensity and balance of these different inputs.
This is a simplified model
describe the process of transmission of pain at the substantia gelatinosa…
At the substantia gelatinosa the 1st order and 2nd order neurons synapse.
Main transmitters involved = glutamate and substance P - these activate 2nd order neurons and some interneurons
also other transmitters involved e.g. NA, opioid receptors in descending inhibition
substance P –> NK1 receptor
glutamate –> NMDA/ AMPA
what glutamate receptors do you know?
2 types of glutamate receptor
- AMPA - fast ionotrophic
- NMDA - slower, ionotrophic, calcium in too, neuromodulation
- also metabotrophic ones - neuromodulation
describe the role of higher structures in pain transmission
Cortex: Primary and secondary somatosensory cortex - Discrimination of pain in time and space.
Includes a somatotopical arrangement giving a map of the body. Known as sensory homunculus
Frontal lobe - Involved in emotional response
PAG, amygdala and hippocampus - emotional/memory
PAG - Modulation of pain pathways, descending inhibition
Thalamus - integrates and channels pathways
can you tell me about any descending modulators of pain?
2 main areas involved in descending inhibition =
Periaqueductal grey (Pag) in the midbrain (main one)
This recieves inputs from other areas e.g. hypothalamus, amygdala, cortex and from dorsal horn.
its transmitters include endorphins and enkephalins (moP opioid receptors) and serotonin (5Ht1 and 5Ht3 receptors).
Stimulation of PAG gives analgesia
Locus caeruleus (lc).
an important brainstem nucleus - uses NA as NT
what is the role of opioid receptors in pain?
in high conc in PAG and Dorsal column
invovled in descending inhibition of pain transmission
pre-synaptic Gi GPCR - result in K+ efflux and hyperpolarisation
prevents transmission of pain transmission
how can emotion influence pain
Emotion influences pain through descending modulatory pathways…
E.g. anticipation and fear lowers pain threshold and conversely pain is experienced less when in intense cognitively demanding situation – distraction
describe the process of peripheral sensitisation…
inflammation after tissue damage results in release of mediators. these can directly stimulate nociceptors or modulate them by lowering threshold for action potential
this results in sensitisation - hyperalgesia is seen
action potentials down the fibres go to the dorsal column. They ALSO spread to near by areas and release substance P. this results in local inflammation and sensitisation.
now allodynia is seen
zone of primary hyperalgesia is increased.
Explain the mechanism behind central sensitisation…
this is the process whereby the CNS has developed an inappropriately high response to stimulus.
mechnisms include wind up
wind up:
* glutamate and substance P released by C fibre
* activate AMPA and NK1 on post synaptic neuron
* Na enters cells –> AP
* depolarisation primes NMDA receptors - removes Mg block.
* glutamate can activate NMDA - neuromodulation
* also results in allodynia, hyperalgesia and expansion of receptor site (secondary hyperalgesia) .
Prolonged noxious stimulation leads to post-translational and transcriptional changes in dorsal horn synapses e.g. in receptors and ion channels.
what is the difference between clinical and physiological pain?
Physiological pain – normal response - only produces pain when stimulus is high intensity. There is no inflammation.
Clinical pain, also called pathological pain, refers to pain that is chronic or disease-related and goes beyond the normal protective mechanism of pain. lower abnormal threshold
what are the physiological changes seen in pain?
by body system
tachypnoea
tachycardia, high BP
Nausea
urinary retention
anxiety/ agitation
can you tell me about different types of pain
visceral
- poorly localised , dull
- involves more autonomic features, no hyperalgesia/ allodynia features
- referred pain
somatic
* well localised
* sharp or dull
* intensity proportional to tissue damage
neuropathic
* burning, tingling, shoot
* arises from nerve damage
* can result in hyperalgesia, allodynia etc
* may be central (lesion in CNS) or perpheral
what are the mechanisms of neuropathic pain?
can be central e.g. stroke / MS/ tumour
or peripheral e.g. compression or metabolic (diabetes) or autoimmune.
a number of differnet mechanisms
e.g. diabetic - ischaemia causes demyelination and ectopic firing.
overall usually results in ectopic firing
chronic pain - by modulation of substantia gelatinosa
allodynia, secondary hyperalgesia etc
sympathetic NS is involved in modulation but also vasomotor symptoms e.g. sweating, pale, red etc
do you know any examples of neuropathic pain?
trigeminal neuralgia
post hepatic neuralgia
complex regional pain syndrome
diabetic neuropathy
what is complex regional pain syndrome?
chronic pain condition that typically affects one limb after an injury. the pain is prolonged and excessive in comparison to the injury
CRPS type 1 follows injury that didn’t directly damage nerves and type 2 develops after a distinct nerve injury.
Clinical features include pain at rest, allodynia, hyperpathia as well as hypoaesthesia. The affected limb is often held motionless.
Autonomic disturbance is common - oedema, r red, warm and glossy. sweating
describe the pathway for visceral pain…
visceral pain is poorly defined, slower in transmission and more dull.
The nociceptive stimuli usually include ischaemia and distension of internal organs.
Mostly by unmyelinated C fibres
These fibres run along with sympathetic and parasympathetic fibres towards the spinal cord.
The cell bodies of these fibres lie within the dorsal root ganglion - synapse with second order neurons
Some will stimulate second order neruons bilaterally – hence explains the poor localisation of pain.
Carried up via ascending pathways to higher cortical structures.
what is meant by referred pain?
Many second order neurons receive both visceral and somatic inputs
This is termed visceral afferent convergence
The second order neurons cannot distinguish between the two
Hence referred pain occurs when higher cortical areas perceive visceral pain as somatic pain at the spinal level the visceral afferents joined.
This depends on embryological origin e.g. heart visceral pain fibres enter levels C3- T5
what is meant by neuroplasticity?
Neuroplasticity is the ability of neural connections to change through growth and reorganisation and learning.
Neural pathways aren’t fixed - As we practice something, the pathway becomes stronger
Similar concept in pain, the more we process the signals the more we learn to be in pain
This occurs through up regulation of receptors and downstream signalling pathways and new neural connection.
E.g. wind up of NMDA receptors in dorsal horn
define hyperalgesia
painful stimulus becomes more painful
define hyperaesthesia
increased sensitivity to stimulation
define allodynia
painful response to stimulus which would not normally be painful
often a feature of neuropathic pain e.g. trigemninal neuralgia
potentially occurs from re-organisations of neural circuits
define hyperpathia
abnormal response to normally painful stimuli. e.g. radiation, altered sensation. may be positive or negative
define hypoalgesia
reduced sensitivity to painful stimuli
How does pain pathway differ for nociceptive info in face ?
Sensation is relayed via trigeminal nerve
First order neurons (C and Ad) relay action potential to trigeminal nucleus
Synapse to second order - substance P
The trigeminal nucleus has different nuclei within it the spinal one is for pain and temp, main one for proprioception and vibration from face and mouth. The mesencephalic proprioception from jaw
Second order to thalamus
Third order to cortex
how is pain modulated?
number of mechanisms for modulation
one of the main theories is the gate theory
segmental inhibition:
* reduced pain by rubbing the area - inhibition from non pain fibres via inhibitory interneurons
opioids:
* opioid receptors are located throughout CNS but especially in PAG, ventral medulla and spinal cord
* activation by enkephalins and endorphins inhibits pain transmission
* pre - synaptic = hyperpolarise (K+ channels) and less Ca via VG calcium - less transmitter release
* post synaptic = hyperpolarise via K channels
descending inhibition
* from PAG via ralphe nuclei in brainstem to spinal cord
* influence gate at dorsal horn
* activate inhibitory interneuron
* NT = serotonin and NA
how does clonidine reduce pain?
Clonidine inhibits the release of substance P, a neuropeptide that plays a crucial role in the transmission of pain signals.
acts pre-synaptically
