Session 6: Pain Flashcards
What is Pain? What is Nociception? What does stimulus threshold and tolerance mean?
Pain is defined as ‘an unpleasant sensation or emotional experience associated with actual or potential tissue damage’.
Pain can have visceral or somatic origin, and will elicit sensations with not just somatic responses, but also autonomic, endocrine (e.g. stress hormones such as cortisol) and emotional responses.
It is sensory-discriminative + subjective – affective, behavioural processes.
Nociception: non-conscious neural traffic originating with trauma or potential trauma to tissues, going to the brain (and only then we become aware of the pain).
Pain: complex, unpleasant awareness of a sensation (which can be modified with experience, expectation, immediate context etc).
This means that nociception is the sensing of the painful stimulus yet requires transmission to the cortex to allow the specificity of pain to be experienced (i.e. the type of pain, its location etc).
The term stimulus threshold applies to the amount of sensation required to perceive pain (and is universal to everyone – we all have the same types of cells) whereas tolerance is the variable reaction to a painful stimulus; these are two different concepts, as an individuals’ tolerance are heterogeneous due to factors such as environment, emotion, age, ongoing pain or psychological.
It can be described as prickling, burning, aching, stinging, soreness etc
What does the perception of pain indicate? How can the pain pathway be broken down?
The perception of pain indicates that a specific set of nerve fibres – the nociceptive fibres – have been activated. Tissue damage releases substances such as bradykinin, histamine and prostaglandins, which lower the threshold of nociceptive nerve fibres, so that after an injury, normally innocuous stimuli are perceived as painful (allodynia).
Other sensory modalities for example the upper and lower limits of temperature sensation can also be perceived as pain.
Pain Pathway: the pain pathway can be broken down into transduction (activation of nociceptors by a stimulus), transmission (relay of action potentials along pain fibres to the CNS), modulation (affected by other peripheral nerves or CNS mechanisms), and perception (the interpretation by the brain of the sensation as painful).
What is the main pathway? What is the other pathway?
The main pathway is the direct pathway, which is the discriminative pain, yet there is an indirect pathway, which is involved in the affective aspect of pain (i.e. the emotional, endocrine and autonomic effects of pain).
The indirect pathway is a much slower pathway, totalling 85% of all pain fibres, and involves 4 main pathways (with associated functions):
- Spinoreticular (arousal and weakness)
- Spinomesencephalic (activation of descending inhibition and emotional)
- Spinotectal (reflexes of eyes, upper body and head)
- Spinohypothalamic (autonomic and endocrine responses)
However the pain pathway to consider is the direct (fast) pathway that is the pathway in pain perception.
Review the direct and indirect pathways?
What are the two main pain fibres?
the two main pain fibres (peripheral nociceptive fibres):
- Rapidly conducting Aδ(delta) fibres have the stimulus modality of mechanical stimulus and have small receptor fields
- Slowly conduction C fibres are more polymodal and respond to mechanical, thermal and chemical stimulus yet have much larger receptor fields.
What happens in Transduction?
Any tissue damage causes the release of serontonin, bradykinin and prostaglandins which all act to activate the nociceptors. The result is a release of substance P and glutamate (which are the main neurotransmitters for the Aδ and C fibres).
Substance P also acts locally to cause increased vascular permeability and histamine release from mast cells, which in turn activates noiceptor endings and causes redness and increased sensitivity to pain of the affected region.
Transduction essentially involves the detection of a stimulus and changing that into an action potential.
What happens in Transmission?
the Aδ and C fibres allow for the transmission of pain from the periphery to the CNS
A δ fibres are myelinated neurones and consequently have a fast conduction velocity and narrow receptor fields. The pain produced is well localised, sharp pain and the Aδ fibres are those involved in initiating the withdrawal reflex. They have a lower threshold.
C fibres are unmyelinated neurones and consequently have a slower conduction velocity and wider receptor fields. The pain produced is a poorly localised, dull pain and requires a higher threshold to be activated. Generally, visceral pain comes from the C-fibres.
Example: When pricked with a pin, an intense brief pain is experienced (Aδ – phase 1 pain which initiates withdrawal reflexes) and is followed by a dull longer lasting (C fibre, phase 2) pain.
Local anaesthetics e.g. lignocaine inhibit voltage dependent sodium channel activity => stop transmission of action potential.
Where do the A-delta and C fibres synapse in the spinal cord? What happens next? What is required for pain to actually be ‘felt’?
The Aδ and C fibres travel to the CNS where they synapse in the rexed laminae of dorsal horn of the spinal cord. Whilst they enter the laminae I, II and V, only from laminae I and V do they synapse with second-order neurones, as those that enter laminae II (Substantia gelatinosa – SG) will be involved in the modulation of the pain stimulus.
- β (light touch) fibres branches to III, IV and V
- Pain fibres from the face and front of the head enter the trigeminothalamic system. From the back of the head they travel in cervical nerves.
- Spinothalamic tract origin in I, IV to VII
The second order neurones then decussate to the other side of the spinal cord. Pain fibres then run in the lateral spinothalamic tract to reach the thalamus (specifically the ventral posterolateral nucleus of thalamus) allowing for nociception to be detected.
However, in order for the nociceptive sensation to be felt as pain, third order neurones synapse in the thalamus and run to the cerebral cortex, which then results in the sensation of pain. The representation of pain in the cerebral cortex is rather diffuse and is seen mostly in the areas of the cingulate gyrus and sensory and motor association areas.
How can referred pain be experienced due to the direct pain pathway?
Referred Pain can be experienced due to the direct pain pathway.
Visceral fibres converge on second order spinal cord neurones in rexed laminae V, which can be shared by somatic nociceptive fibres. Consequently, pain felt on a visceral organ can be felt as being from somatic nerve fibres. Examples include myocardial infarction visceral pain being perceived as pain from somatic origin in the neck and left arm.
Referred pain arises because of the convergence of nociceptive and cutaneous fibres in the dorsal horn of the spinal cord, so that pain arising in visceral structures, may produce sensations associated with areas of the body surface.
In clinical diagnosis, it is essential to know about the sites to which pain may be referred.
What happens in Modulation?
Modulation: modulation of the pain impulses mean that pain is perceived differently by individuals and it is the gate control theory of pain that allows for this modulation to occur.
The SG is a main part of this inhibition, as it acts negatively on laminae I and V to inhibit the nociceptive impulses.
δ and C-fibres entering laminae I and V synapse to the secondary order neurone to pass the nociceptive impulse up to the thalamus. However, they also act on the SG (lamina II) to inhibit its inhibitory signal on laminae I and V resulting in positive effect on the pain impulse.
Mechanoreceptors, via Aβ-fibres, act positively on the SG to increase its inhibitory effect, meaning that rubbing a damaged area may reduce the pain felt by the individual.
Direct descending inhibitory neurones act to inhibit laminae I and V (directly, and indirectly (via SG)), achieving this by utilising endogenous opioids (e.g. 5-HT and enkephalin) and other neurotransmitters.
Where do these direct descending inhibiting neurones arise?
These descending inhibitory neurones arise from the periaqueductal grey matter (PAG) of the brain, receiving their stimulus from the cortex and thalamus.
- The PAG consists of a collection of cells highly sensitive to endogenous opioid neuropeptides (enkephalins, endorphins, dynorphins, endomorphins) and direct electrical stimulation of this area will have an analgesic effect.
- Opiate receptors: μ (miu), δ (delta), κ (kappa) and noicepetin
Agonist: Morphine, codeine, heron
Antagonist: Naloxone (some studies have shown Naloxone can block the inhibitory effect – internal mechanism switched on=> release of opioid neuropeptides can be activated psychologically?
The PAG stimulates the nucleus raphe magnus, which also receives feedback via the nucleus reticularis paragigantocellularis, sending the inhibitory neurones down to laminae I and V.
NB: the reticular formation includes the locus coeruleus, nucleus raphe magnus and the nucleus reticularis paragigantocellularis (NRPG)
- The pathways can be targeted very effectively by analgesics, providing very good analgesia to patients.*
- Analgesia: inability to perceive pain when tissue damage is occurring*
- Hypnosis, morphine, TENS, natural childbirth techniques and placebos.*
Describe Central Modulation
Central Modulation of Pain: inherent modulatory system via inhibition in spinal cord
- The experience of pain is highly dependent upon the context of the injury, when a severe hurt may be ignored until the immediate cause is removed.
- Descending serotoninergic pathways from the reticular formation are thought to be involved.
- Fibres from the periaqueductal grey matter (PAG) of the midbrain regulate these pathways.
- The descending serotonergic fibres end on cells in the substantia gelatinosa, causing the release of enkephalin, which modulates the activation of the ascending pain pathway. These ideas are incorporated into the gate control theory of pain, which suggests that enkephalin “gates” the input into the anterolateral system.
Describe the Gate Control Theory of Pain
The Gate Control Theory of Pain
Suggests that cutaneous stimuli, as well as projecting into the dorsal columns of the sensory pathway, excite projection neurones (P) of the anterolateral system (the pain pathway) and enkephalinergic neurones in the substantia gelatinosa (SG).
As the enkephalinergic neurones inhibit the pain pathway, normal cutaneous stimulation is not painful.
Following tissue damage, histamine, bradykinin etc stimulate C fibres, which inhibits cells of the substantia gelatinosa leading to activation of the pain pathway.
Descending serotoninergic pathways may now reactivate cells of the substantia gelatinosa partially reimposing the inhibition to modulate the pain.
This theory predicts that rubbing the wound, for example, activates the large cutaneous fibres, which will increase the inhibition on the pain pathway. So if you rub a hurt it will feel less painful.
- Other transmitters:*
- Analgesia in morphine tolerant patients:*
- Baclofen (GABA agonist), anti-depressants, anti-convulsants
- Somatostatin
Potential drug therapies: NDMA receptors, ion channels, neurotrophins (NGF)
What is meant by Perception
The thalamocortical projections carry information on location, intensity, and nature of pain. Primary and association areas, secondary somatosensory cortex
Any emotional response occurs via the limbic system.
Perception aries depending on circumstances and past experiences
Stress response via hyothalamus
Remember: Pain fibres (along with temperature sensation) synapse in the dorsal horn and the ascending fibres cross over at the segmental level to travel to the brain in the anterolateral tract. Most of these fibres join the spinothalamic tract to enter the thalamus on their way to the sensory cortex. On their way some fibres peel off to
- Activate the reticular formation
- Enter the periaqueductal grey matter (PAG) of the mid-brain
What is Congenital Analgesia?
Congenital analgesia:
- Person cannot feel and has never felt physical pain
- E.g. could be due to massive enkephalin release or faulty voltage-gated Na+ channels
- Possible confusion with child abuse at presentation
Describe Compound Nerve Action Potentials
A mixed nerve contains a variety of different nerve fibres, which vary in diameter, myelinated or unmyelinated, or modality.
A compound action potential shows the different nerves present in a mixed cell, by showing the varying conduction speeds and can be done on both motor or sensory mechanisms.
The fastest nerves will appear in the A-wave and will be the large, myelinated neurones whereas those appearing in the C-wave will be the small, unmyelinated neurones, with the B waves being intermediates.
An artefact is commonly seen at the beginning, as the procedure involves placing electrodes at the proximal part of the nerve and measuring the responses in the distal part of the nerve. The responses seen are variable, from a threshold response to a maximal response, depending on the nerves that become involved in the conduction.
These tests can be used to highlight conditions such as multiple sclerosis, where the demyelination of neurones affects their conduction velocities.
Describe (briefly) the normal physiological pain pathway and gate control
Third order neurons relay nociceptive impulses to the cerebral cortex (conveying quality and location) leading to a sensation of pain
Dorsal horn
- A-delta and C fibres enter Lamina I, II and V
- Lamina II (SG) synapses with Laminae I and V – controls output from I and V (‘volume controller’)
- Spinothalamic pathways: afferent information leaves via I and V
Physiological Gate Control:
SG: tonic inhibition of I and V => reducing background stimuli going to the cerebral cortex
If you inhibit the SG, you lose its inhibitory effect => more afferent information goes up the spinal cord
Aβ fibres also impinge on SG => activation of SG => inhibition of I and V (so rubbing a wound => pain goes away)
The same thing happens with thermoreceptors (think effect of a long bath)
What is Wind-Up?
“Wind-up” occurs in persistent activation of pain afferents and result in hyperalgesia and allodynia.
Nerve (neuropathic pain) or tissue damage (nociceptive pain) causes the persistent activation and resultant upregulation of NMDA receptors and increased (excessive) glutamate release, causing excessive second order neurone firing. The result is long-term changes in nociceptive neurones becoming hyperexcitable (respond at lower stimulus – hyperalgesia)
Wind up can lead to receptive field expansion at the peripheral site or allodynia.
Very difficult to treat so clinical treatment focus is on preventing acute pain becoming chronic pain.
Pain sensitisation: noxious stimuli can sensitise the nervous system response to subsequent stimuli. The normal pain response as a function of stimulus intensity is depicted by the curve at the right (of the top figure), where even strong stimuli are not experienced as pain. However, a traumatic injury can shift the curve to the left. Then, noxious stimuli can become more painful (hyperalgesia) and typically painless stimuli are experienced as (allodynia)
Remember the facial expression of pain: furrowed brow, lowered lids, tighten nose, wrinkles, lips tightens
Compare acute pain to chronic pain
Remember the facial expression of pain: furrowed brow, lowered lids, tighten nose, wrinkles, lips tightens
You can treat acute pain by treating underlying problem (e.g. giving good post-operative care after surgery).
Explain how chronic pain phenotype varies. How would you classify chronic pain?
Chronic pain phenotype is different
Changes in the physiology of the spinal cord (central sensitisation) in chronic pain – wind up – repeated stimulation increases spinal processing (NMDA receptors involved)
Changes in functional mapping of the human e.g. phantom pain
With reference to pain there are
- Sex differences ?? (Controversial)
- Racial differences in terms of opiate and pain sensitivity (so need to titrate drug to produce the analgesic response you want in the patient)
- Genetic differences
Chronic pain can be neuropathic, nociceptive or mixed
Describe Nociceptive Pain
Nociceptive Pain: the activation of nociceptors which stimulate the nociceptive signalling along the Aδ and C fibres. Commonly described as a sharp, stabbing pain. A good example is for arthritis, as this will act on the Aδ and C fibres. Long-term activation of these fibres will result in wind-up so many patients will eventually complain of hyperalgesia and allodynia.
Give examples of neuropathic pain
Examples of neuropathic pain include phantom limb pain, where the painful neuropathy resulting from neuroplastic changes in the CNS, or complex regional pain syndrome, where descending nerve fibres impinge on the sympathetic nervous system and results in oedema and chronic pain.
Phantom limb pain: sensation may non-painful (common), pain in the missing limb – painful neuropathy (common)
Phantom limb pain-cortical remapping occurs: strong positive correlation with severity of pain (amount of afferent stimulation)
So for some patients, stroking lip produces a painful missing hand sensation as the part of the somatosensory cortex encoding the hand has decreases and the part encoding the lips has increased.
Describe Cancer Pain
2 main causes
- The disease (invasion – neuropathic, visceral, nociceptive, inflammatory)
- The treatment (drugs, procedures)
How do opioids work and describe their side effects
Opioids such as morphine, codeine or fentanyl, act on MOP, DOP, and KOP receptors to cause analgesia.
These receptors are GPCRs so act by closing VOCC, opening potassium channels to hyperpolarise the membrane, and inhibiting cAMP formation, thus overall inhibiting neurotransmitter release.
However, the side effects of opioids include respiratory depression, nausea and vomiting, antitussive (suppress coughing), constipation, itching and euphoria.
The MOP, DOP and KOP receptors are found centrally (such as cortex, thalamus and hypothalamus, PAG, NRM and LC, brainstem and the spinal cord) and peripherally (such as nociceptive afferents (inflammation), vas deferens, heart and myenteric plexus).
The opioid receptors are present so that endogenously released opioids (endorphins (MOP), enkephalins (DOP) and dynorphins (KOP)) can act on them for setting pain thresholds.
Remember: SG inhibition is driven by endogenous opioids.
NB: acupuncture raises the spinal levels of endogenous opioids
MOP is a major clinical target
Receptor for morphine
Analgesia (supraspinal especially PAG and spinal). Importance of combined spinal/supraspinal administration.
Respiratory depression.
Inhibition of GI transit-constipation euphoria and dependence.
