Pain

What is pain?

an unpleasant sensory or emotional experience associated with actual or perceived tissue damage

What is congenital insensitivity to pain and why is it dangerous?

• condition where cannot feel pain though sensation of touch usually normal

• continue to do things that causes injury which could cause infections etc

What does congenital insensitivity to pain teach us about pain?

• pain is a learned response

• pain and touch are different

What are nociceptors?

sensory receptors that respond to dangerously intense stimuli

What are the 3 main types of nociceptors?

• A delta mechanosesnsitive nociceptors

• A delta mechanothermal nociceptors

• C fibre polymodal receptors

What are 2 features of nociceptors?

• high thresholds of stimulation

• large receptive fields making fine localisation difficult

What is perception of pain from A delta fibres like?

sharp, brief, better localised

What is perception of pain from C fibres like?

duller, poorly localised, longer lasting with burning quality

Can you separate the 2 fibres to look at them indiividually?

yes - selectively blocked pharmacologically and so stimulated separately

What experiement shows separate activation of specialised nociceptors and thermoreceptor rather than a greater discharge from neurons responding to normal stimuli?

Smith and Lewin 2009

• place hand under lamp and increase temp gradually

• thermoreceptor activity gradually increasaes then plateaus

• nociceptor only active once temp becomes noxious

• at this point thermoreceptors are already at max rate

• indicates that nociception is not overstimulation of receptor but just different neurons responding differently

Who did this experiment?

Smith and Lewin 2009

What are the 3 ascending pathways within pain?

• spinothalamic tract

  • important in localisation of painful or thermal stimuli

• spinoreticular

  • motivational/affective aspects of pain

  • level of attention

• spinomesencephalic

  • important in activating descending modulation (PAG)

  • orientation towards stimulus

  • escape behaviours and aversive memory

Apart from the skin where can nociceptors also be found?

in the internal organs though alarm signals less easy to pinpoint resulting in pain being perceived in wrong body location

What does the ‘convergence projection theory’ of referred pain suggest?

Ruch, 1949

What is brown sequared hemiplegia?

condition which causes loss of motor function and numbness to touch on same side as injury but loss of pain sensation on opposite side

What causes brown squared hemiplegia?

lateral hemisection of spinal cord eg injury or tumour

What does brown squared hemiplegia show?

sensations of touch and pain are carried by different anatomical routes

What is hyperalgesia?

increased sensitivity to pain from a stimulus that normally causes pain

Why might hyperalgesia happen?

following injury polymodal C fibres do not adapt to stimuli so become sensitised to pain and normal touch (allodynia)

Better:

• C fibres do not adapt to stimuli they can become sensitised to pain by mediators released by injured tissue that can diffusse to non-injured areas and activate nociceptors

What is allodynia?

pain caused by a stimulus that does not normally provoke pain

What does hyperalgesia involve?

• sensitisation of peripheral nociceptive nerve terminals

• central facilitation of transmission at the level of the dorsal horn and thalamus

  • neuroplasticity - ‘wind up’

What is central sensitisation or wind up phenomenon?

• spinal neurons subject to repeat or high-intensity nociceptive impulses

• become progressively and increasingly excitable sometimes even after stimulus removed

• alteration of strength in circuitry

What can central sensitisation lead to?

non responsive or chronic pain

• facilitates pain transmission particularly in extended pain states

What is the biological mechanisms behind wind up?

• occurs in dorsal horn and thalamus

• repetitive stimulation, C fibres fire repetitively

• leads to substance P release which acts on NK1 receptors

• causes slow depolarisation

• NMDA receptors on postsynaptic neurones only open is glutamate binds and depolarisation occurs tomove Mg block

• opening NMDA causes influx of Ca

• activates calmodulin kinase and protein kinase C

• makes/inserts new AMPA receptors

• increases sensitivty to glutamate

• hyperexcitability of nociceptive neurones after severe or persistent injury

What is an NMDA antagonist that can reduce wind upin animals but not translated well into human drugs?

ketamine

What are pain medications for inflammatory pain? (3)

• NSAIDS eg aspirin

  • COX 1 and 2 inhibitors, reduce prostglandin synthesis

• local anaesthetics eg lidocaine

  • block voltage gated Na+ channels

• opiates eg morphine

  • cause hyperpolarisation through binding to u receptors and subsequent opening of K+ channels/closure of Ca++ channels

Couple examples of alternative pain medications and therapies for longer lasting pain?

• acupuncture

• CBT

• deep brain stimulation

How does acupuncture work?

• look at particular nodes with highest conc of adenosine receptors

• adenosine release and binds to A1R

• causes analgesia = pain relief

Two example of experiemnts testing pain relief from acupuncture?

• acupuncture with A1R agonist = no analgesia

• acupuncture and adenosine degradation inhibitors = prolonged analgesia

What is transcutaneous electrical nerve stimulation?

• delivery of a mild electric current through patches to skin

• creates electrical impulses in A beta fibres that are believed to reduce sensation of pain

How might TENS reduce pain?

• production of natural endorphins?

• gating of pain transduction?

How does the gate theory of pain work?

Melzack and Wall (1965)

• A beta fibre stimulates an inhibitory interneuron that causes IPSP on to the pain projection neuron and reduces firing

  • why rubbing may make better

• no anatomical evidence but may be to do with different speeds of nerve fibres

Who argued slightly differently for gate theory of pain (lots of controversy)?

Inui et al, 2006

• suggested this is all by cortical mechanism with minimal spinal involvement

Why may the perception of pain be different in different circumstances?

• different environmental circumstances affect pain perception

• eg soldier with battle wound

  • reward system from being able to continue may overcome pain

• why pain of same injury may feel different in training vs competition

• may be descending modulation from the PAG

What is likely to be the main control of pain?

natural opioids???

What are opioids doing - descending modulation? (2)

• modulating the PAG

  • conditioned to not be affected as much by pain

• blocking periphery sensation and also at dorsal horn

What are the mechanisms behing allodynia?

remodelling of the spinal cord circuitry at the first synapse (perhaps descending modulation and gate control theory)

What is deep brain stimulation used for and how does it work?

• treat chronic nerve pain

• targets PAG, thalamus, cingulate cortex

• electrodes implanted into brain which send electrical current

What is the nocebo effect?

• predictions about how painful a stimulus is likely to be exerts a dominant effect on what we perceive

• descending facilitation of pain through the periaqueductal grey rather than the inhibition

Investigation with nocebo effect?

Yoshida et al (2013)

• participants were shown a group of pain ratings from a thermal stimulus by other people before they were then exposed to that stimulus

• the pain rating of each participant was recorded beforehand to make sure that individual differences in pain tolerance does not affect ratings produced

• found that the group pain ratings correlated with the subjective pain ratings given by the participants afterwards

• when the group ratings showed high variability there was also an increase in pain ratings from the participants which implies that uncertainty of what will be received can increase sensitivity and perception of the stimulus

• if pain was simply overstimulation of the touch receptors, then it could be assumed that uncertainty would play no role in how pain is received as pain would instead correlate with just the intensity of the stimulus

Examples of circumstances which may close the gate to pain?

• mechanosensitive stimulation

• emotional support

• distraction

• acupuncture

• placebo

Example of circumstaces which open the gate to pain?

• depression and anxiety

• learned safety signals

• uncertainty

What is phantom limb pain?

occurs when nerves that would normally innervate the missing limb are abnormally stimulated and cause the perception of pain (limb twisted, contracted etc)

Potential reasons for phantom limb pain? (70% experience)

• damage to nociceptor endings

• cortical reorganisation (Schone 2025 argues not this)

  • feeling of pain without touch suggests pain could be caused by separate receptors and more controlled by brain and higher processing

What therapy is there for phantom limb pain?

• mirror box therapy

  • tricks brain and alleviates pain

  • aware what’s happening but still works

Difference between nociception and perception of pain summary?

What 2 things show interactions between pain and touch pathway?

• gate theory

• allodynia

What 2 things demonstrate the independent use of two different systems (dorsal vs anterolateral)?

• Brown Sequard syndrome

• congenital insensitivity to pain

Is pain simply overstimulation of the touch receptors essay plan?

• different neurons respond differently

  • lamp experiment

• injury and unique situations

  • Brown sequard hemiplegia

  • CIP - Stefan Betz

    • outlined by Cox (2017) he could put hand in boiling water but would shudder at a cold wind

  • phantom limb pain

• pain is subjective

  • nocebo effect