5.1: Neural Basis of Pain and Analgesia Flashcards
Define Nociception and Pain
What is the relationship between these?
Nociception: non-conscious neural traffic in response to (potential) trauma.
Pain: an unpleasant sensory and emotional experience associated with actual or potential tissue damage.
Nociception leads to pain BUT pain isn’t only nociception
How can pain be good and bad?
Pain can be good: stops us from hurting ourself (eg. putting hand on something hot)
Pain is bad because it is unpleasant to live with (eg. chronic pain can be extremely debilitating)
List 4 other factors, in additon to nociception, that can lead to pain
1) Cognitive set: attention, distraction, catastrophising
2) Mood: depression, anxiety
3) Context: pain beliefs, placebo, expectation
4) Chemical and structure: neurodegeration, metabolic
Which gender and age group is most commonly affected by chronic pain?
Women and elderly
List 3 things chronic pain is associated with
1) increased mortality
2) worsening mental health
3) social deprivation
What parts of the brain are responsible for the following?
a) perception of pain
b) fear
c) memories
d) planning and reaction
a) somatosensory cortex
b) amygdala
c) hippocampus
d) prefrontal cortex
What type of nerves are pain nociceptors?
Give 3 stimuli they are sensitive to
They are free nerve endings
Sensitive to mechanical, thermal and/or chemical stimulation
What kind of channels do pain nociceptors contain?
Name five factors that may potentially trigger these channels
TRP channels- cation channels (resemble voltage gated K+ channels but more unspecific)
Triggered by:
- Inflammation
- Injury
- Injury to CNS
- Nerve invasion (i.e cancer)
- Abnormal activity (i.e chronic regional pain syndrome)
What is complex regional pain syndrome (CRPS)
A condition that causes severe pain which won’t go away
Eg. a minor injury such as a sprained ankle, where pain persists even after the injury has healed. This is because of abnormal healing processes
What are the spinothalamic tracts responsible for?
Pain, temperature and crude touch
Define the sensation of crude touch
Being able to sense the feeling of touch without being able to localize where you were touched
What 2 fibre types transmit pain?
Compare these fibres
Pain is transmitted via Aδ and C fibres
Aδ fibres are myelinated and transmit fast, sharp and well localized pain
C fibres are unmyelinated and transmit slow, diffuse and dull pain
Describe the sensation of visceral organ pain and state 2 reasons why
Visceral/organ pain is diffuse and poorly localised
1) Organs have relatively few pain sensors
2) Enter the spinal cord at many levels, leading to potential crossing over of signals. This which is what results in ‘referred pain’
Give 3 examples of reffered pain
1) Appendix pain: reffered from peri-umbilical area to RLQ
2) Flank pain from the kidney and/or radiating down the lower abdomen from the ureter
3) MI: pain presents in the upper chest, left arm, neck and lower jaw
What theroy describes how the spinal cord modulates pain?
The gate theory of pain: suggests that stimulation of non-nociceptive receptors can inhibit transmission of nociceptive information in the dorsal horn.
Explain the Gate theory of pain (use the example of stubbing toe)
1) Painful stimuli (eg. stubbing toe) will stimulate first order nociceptor C fibres and Aδ fibres
2) These will synaps with the second order fibres in the substantia gelatinosa of the dorsal horn and carry the signal to the brain via the spinothalamic tract (perception of pain)
3) If we rub the area, we stimulate touch/pressure fibres
4) The touch pathway neurons activate an inhibitory interneuron which reduces ascending pain signals from the C fibres and Aδ fibres
5) This therefore reduces the sensation of pain
Name two ways the CNS can modulate pain
1) Endogenous opioids in brain and spinal cord
2) Central modulation/ descending signals from the brain
What is central modulation of pain?
Involves descending analgesia producing pathways from the brain stem to the spinal cord
Explain the pathway and mechanism of central modulation of pain
Periaqueductal grey matter (PAG) in midbrain ➞ through rostroventromedial medulla (RVM) ➞ into spinal cord
(receiving inputs from hippocampus, PFC, amygdala etc… as part of regulatory process)
down spinal cord to dorsal horn ➞ releases Serotonin & NA which stimulate interneurons to release Enkephalins, beta-endorphins and/or dynorphin
These bind opioid receptors ➞ inhibitory effect on synapses b/w 1st and 2nd order neurones of nociceptive pathways
Explain why we encourage patients with chronic pain (ie. Trigeminal neuralgia) to exercise?
Targeting the central modulation of pain! Excersise releases endorphins which can bind to the opioid receptors and help relieve pain
Give 3 substances which bind opioid receptors
Give 2 substances which bind non-opioid receptors
Opioid: Enkephalins, beta-endorphins, dynorphin
Non-opioid: Serotonin and noradrenaline
Define chronic pain and list 3 influential factors?
Any pain that lasts for more that 3 months past the normal healing time for an injury or disease
Has extensive psychological, social and economical factors
List 3 broad catagories that may cause chronic pain and give 2 examples of each
1) Nociceptive/inflammatory
- Osteoarthritis and Rheumatoid arthritis
- Post-op pain
2) Neuropathic
- Trigeminal neuralgia
- Nerve injuries/ neuropathies
3) Idiopathic
- Fibromyalgia
- Irritable bowel disorders
List 2 reasons we may have increased sensitisation to pain
1) increased activity of nociceptors
2) lower threshold of nociceptors
Hyperalgesia and Allodynia are both examples of sensitisation, define and expalin each of these
Hyperalgesia: Increased pain from a stimulus that normally provokes pain due to an increased response at a normal threshold
- Eg. a stimulus that would normally be perceived as slightly painful is perceived as significantly more so
Allodynia: Pain due to a stimulus that does not normally provoke pain due to increased excitability of neurons in the dorsal horn of the spinal cord (CNS)
- Eg. perception of pain from something that is normally an innocuous stimulus (such as a feather)
What is central sensitisation and what does this lead to?
Increased excitability of neurons in the dorsal horn of the spinal cord (CNS)
Leads to allodynia: perception of pain from something that is normally an innocuous stimulus
Compare nociceptive vs neuropathic pain
Nociceptive pain is pain elicited by an INTACT nervous system
- Pain pathways is acting normally, it is an actual stimulus affecting the nerve endings
Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system.
- Can occur anywhere along the pain pathway
Why can neuropathic pain be difficult to treat?
What 2 things commonly occur alongside neuropathic pain
Cannot be explained by a single disease process or specific location of damage
Neuropathic pain commonly occurs alongside hyperalgesia and allodynia
Name 4 examples of neuropathic pain
- cancer
- phantom limb
- diabetes (diabetic neuropathy)
- MS
- spinal injury
- postherpetic neuralgia
What causes postherpetic neuralgia and what is it?
Most common complication of shingles, it’s a condition affecting the nerve fibres on the skin which causes burning and pain lasting long after the shingles have disappeared
Name 2 potential causes of neuropathic pain for each of the following locations:
a) thalamic/cortical level
b) brainstem
c) spinal level
d) peripheral level
a) Infarctions, tumors, MS
b) Infarctions (Wallenberg’s syndrome), tumors, MS
c) spinal cord injuries, MS
d) diabetic neuropathies, peripheral trauma, plexus avulsion, herpes zoster
What is Wallenberg’s syndrome?
When an infarction or stroke occurs in the lateral medulla (part of the brainstem)
Pathophysiology of neuropathic pain:
After a peripheral nerve injury sensitization occurs, give 6 things this can lead to:
1) decreased threshold of the nociceptor to activation
2) Increased receptive field of nociceptors
3) Allodynia and/or Hyperalgesia
4) Prolonged post stimulus sensations – hyperpathia
5) Emergence of spontaneous activity/increased excitability
6) Damaged peripheral nerves can develop abnormal Na+ channels which fire dysfunctionally and demonstrate different depolarisation properties
Give 3 symptoms of neuropathic pain
1) Shooting and burning
2) Tingling and numbness
3) Unpredictable
Give 2 treatments of neuropathic pain and explain the MoA of these
Amitriptyline: Tricycline which is an antidepressant
Duloxetine: NA/ Serotonin re-uptake inhibitor
Both of these increase the amount of Serotonin and NA that is available in the dorsal horn. This activates the inhibitory interneurons thus reducing the pain signals sent up the spinothalamic tract
(Non-pharmacological treatments must also be considered: eg psychological therapies)
Explain the pathophysiology of chronic pain
Tissue injury (nociceptive) or nerve damage (neuropathic) causes persistent activation of pain pathway leading to:
Excess Glutamate release ➞ excess excitation of NMDA receptor ➞ excess 2nd order neurone firing ➞ ‘wind up’
Wind up results in long term hyper-excitability of 2nd order nociceptive neurones (respond at lower stimulus intensity) ➞ hyperalgesia & allodynia
Injury can also cause receptive field expansion at peripheral site
Explain how wind up leads to receptive field expansion at the peripheral site
There is a certain amount of cross-over at the dorsal horn, so there is link between the second order neurones.
Normally a first order neurone will predominantly link to one second order neurone. However, with wind up stronger links form between first order neurones synapsing with two or three second order neurones
This causes expansion of the receptive field, making the location of pain perceived more diffuse
Pain relief is multifactoral, not simply pain reduction
Give 4 other considerations we must make when treating pain
Context, cognition, mood, personality
Give 5 types of analgesia
- Paracetamol
- NSAIDS
- Opioids
- Adjuvants
- Placebo
Compare paracetamol vs NSAIDS
Both are COX enzyme inhibitors which block the formation of prostaglandins (trigger pain pathways at nerve endings) and thromboxane from arachidonic acids.
Paracetamol:
- Main action is in the CNS
- Has an analgesic and anti-pyretic effect (reduce temperature)
NSAIDS:
- Main action is in the PNS
- Has an analgesic, anti-pyretic AND anti-inflammatory effect
Give 3 examples of an NSAID
Ibuprofen, naproxen and aspirin
What is an Adjuvant?
Give an example
Adjuvants are drugs that have few or no pharmacological effects by themselves, but may increase the efficacy or potency of other drugs when given at the same time.
Eg. patients with arthritis may be given pain relief meds alongside corticosteriods (to reduce inflammation)
Give 2 examples of the following analgesia:
- Non-opioids
- Weak opioids
- Strong opioids
Non-opioid: Paracetamol, NSAIDs
Weak opioids: Codeine, Tramadol
Strong opioids: Morphine, diamorphine, fentanyl, alfentanyl
Give 4 examples of an adjuvant
Give 4 examples of non-pharmacological analgesia
Adjuvants: Antidepressants, anticonvulsants, steroids, muscle relaxants, bisphosphonates, radiotherapy, nitrous oxide
Non-pharmacological: TENS, CBT, meditation, acupuncture, massage, hypnosis
What 3 receptors do exogenous opioids bind and how does it work as an analgesia
Exogenous opioids interact with specific receptors:
- μ (mu)
- δ (delta)
- ƙ (kappa)
This has an inhibitory effect on pain pathways and also has an central effect of creating a feeling of euphoria, which helps the patients short-term dealing with pain (this is a side effect)
Give 4 side effects of exogenous opioids
Euphoria, sedation, respiratory depression, tolerance, miosis, nausea and vomiting, cough suppression, constipation, dependence, addiction
Compare codeine vs morphine
Briefly explain how morphine works
Codeine: partial/weak mu-opioid receptor agonist
Morphine: full agonist at mu-opioid receptors in the CNS
- Binds receptors in CNS involved in transmission and modulation of pain and dampens nerve signals transmitting pain
What ‘effect’ demonstrates the higher brain functions and the complexity of pain in an individual
Give 2 examples of studies demostrating this effect
The placebo effect
Numerous studies:
- Students and stimulants vs sedatives
- Alcohol vs non-alcohol
- Post-operative pain
