What is the definition of pain?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
A subjective experience that can be experienced independently of tissue damage
What are the 4 different classes of pain? Categorise them into 2 major types
Adaptive and Protective
- Nociceptive pain
- Inflammatory pain
Maladaptive and pathological
- Neuropathic pain
- Functional pain syndromes
Pain is divided into four distinct stages. Name and describe these stages?
Transduction = detection of noxious stimuli
Transmission = electrical signals through afferent neurons through the peripheral and then the central nervous systems
Perception = processing of the information into sensory and discriminative and emotional and aversive responses
Modulation = we infer that there is some kind of descending pathway that modifies the ascending pathway in some way because nociception doesn't always lead to pain.
What are some examples of noxious stimuli that are sensed in the transduction stage?
All dected through different types of fibre
You can only percieve pain if you are conscious. What can be inferred by this fact about the pain pathway?
That sensory detection of pain (nociception) can occur independently of the sensation of pain
Describe the afferent pathway of the pain information (electrical information) from the nociceptor to the cortex
- Nociceptors in the skin detect the stimuli and relay information through the afferent neuron to the dorsal horn of the spinal cord
- Two tracts carry the information up to the lateral thalamus and limbic centres
- These then relay information up to the cortex for processing of emotional/aversive and sensory/discriminatory information.
Describe nociceptor neurons
They are specialised afferent sensory nerve cells that respond to high levels of stimuli (high threshold).
They have peripheral bodies, cell body neurons (DRG) and central processes to the spinal cord.
Stimulation by noxious stimuli to a nociceptor sensory neuron will illicit what rmajor esponses? 
- Pain sensation
- Autonomic responses (like sweating, flight or fight, etc)
- The withdrawal reflex
What is the main evolutionary reason for nociception?
Nociception is an adaptive, high threshold pain receptor that gives an early warning system (protection)
Eg. Some people have defects in Na channels in these nociceptive neurons and thus are unable to conduct information through them. These people constantly suffer damaged tissues due to inability to experience pain.
Describe the nerve fibres of nociceptors (what are they called)
- They are free nerve endings
- They have fine axons
- Have no specialised transducers
- They respond/fire to their stimuli with more intensity the longer the stimuli is applied (sometimes long after it is gone)
What is the difference between the two nociception fibres: Aδ fibres and the C fibres?
C fibres are unmyelinated and are very thin (<1.5um). This means that they conduct information quite slowly (< 3m/s)
Aδ fibres are myelinated and are also thin (1.5-4um). They conduct information with medium-fast speed (3-30m/s - which is slower than touch but faster than C-fibres)
Through what afferent system will migraines and tooth and jaw pains transmit through?
The trigeminal afferent system (through the trigeminal ganglion)
What types of pain do the dorsal root afferent fibres relay?
Somatic (skin, muscular and bone)
Visceral (non-somatic organs)
Nociceptors have high thresholds, what is meant by this?
They only fire in response to potentially damaging stimuli. It takes a lot of force or stimulus to activate an action potential within them
(eg. heat nociceptors only fire at temperatures >43 degrees which is damaging to the skin).
What is meant by first and second pain in terms of nociception?
Because of the different speeds of conduction of the Aδ fibres (faster) and the C fibres (slower) there is a resultant separation in the two information sets.
The brain will interpret the first pain as sharp and localised folled by a later pain that is dull and throbbing.
C fibres continue to fibre once the external stimulus has gone away (tonically fire), why would they do this?
Especially if there has been damage to the tissue.
Different tissue have different mixtures and ratios of the receptors. Describe the distribution of the fibres in response to noxious heat in the hand (hairy vs. glabrous)
Hairy skin (the back of the hand) has both a type II Aδ and C-fibres meaning that the hand feels both a sharp and a slow, burning feeling in response to heat.
Glabrous skin (palm) only has the C-fibres and thus will not experience the sharp pain before the burning kicks in.
What part of the dorsal horn do nociceptors predominatly project to?
Predominantly to the peripheral layers of the dorsal horn (particularly to laminae I-V)
C-fibres to laminae I-III
Aδ fibres to laminae IV and V
The C fibres are never deeper than the Aδ fibres
(note that Ab fibres are for mechanoreceptors)
At what level does pain decussate?
At the same level the input arrived in the spinal cord (segmental)
After the nociceptor axons enter the spinal cord, what happens to them from there?
Nociceptive dorsal afferents enter the dorsal horn and then synapse with second order neurons (in the peripheral the dorsal laminae) and these second order neurons decussate to the ventral horn and send axons up and down the spinal cord through the spinothalamic/anteriorlateral tract.
Describe the major difference between the path of mechanoreception axon fibres and nociceptor fibres in the brainstem
They both enter at the dorsal horn but the nociceptor fibres synapse early and decussate while the mechanoreceptors don't have the major synapse and move ipsilaterally through the dorsal columns.
Describe the spino-nociceptive reflex
This is the ability to move the limb as a defensive reflex (withdrawal) can occur purely through a spinal reflex (no higher input).
Thus noxious nociceptive stimuli can drive a circuit that will move the limb (protective reflex) without involvement of the brain or brainstem
NOCICEPTION CAN OCCUR INDEPENDENTLY OF PAIN
What are the two tracts that carry nociceptive information to the brain from the periphery? What is the major difference between them?
- The Spino-brachial tract: carries information from Ad and C fibres to the limbic system which relays info to the frontal cortex for emotional and aversive responses
- The Lateral spino-thalamic tract: carries information from Ab fibres to the lateral thalamus which relays to the frontal cortex for sensory and discriminatory information about the pain.
What is the difference between nociceptive pain and inflammatory pain?
Inflammatory pain is nociceptive pain that has worsened or is different as a result of tissue damage.
What about tissue damage causes the difference between nociceptive pain and inflammatory pain?
The recruitment of inflammatory cells and cytokines in the body.
These interact with the nociceptors (nerve endings) = leading to spontaneous pain (ongoing) that is not dependent on an external stimulus and pain
It also causes hypersensitivity = an ampification of a signal.
What is the evolutionary advantage of having inflammatory pain?
To promote repair (tenderness) and limitation of tissue damage: create protective behavioural responses
Inflammed or damaged tissues release a wide array of inflammatory mediators. What are the main ways they impact pain?
They can target receptors or ion channels on the nocicpetive nerve terminal.
- They can act on receptors (activate 2nd messenger pathways) to cause further activation of the neuron
- Others that act on ion channels changing electrical properties of the channel to make them more receptive to stimuli (hyperalgesia)
How does the TRPV1 receptor respond to a noxious stimuli to cause inflammatory pain? (Eg. Capsaicin)
Capsaicin targets an internal binding site on this ion channel (permeable to Na and Ca - positive cation channel, depolarising channel) - TRPV1 is a transducer.
Binding of capsaicin/acid/heat (the stimuli) to the TRPV1 receptor causes the opening and/or sensitisation of the channel
(decrease activation threshold).
Following inflammation: this channel is continusouly active whereas normally it would only be active with high levels of heat, etc
Inflammatory pain often causes sensitisation of the nociceptor fibres. What is meant by this?
What are the 2 levels at which sensitisation can occur?
They amplify the pain signal
- Sensitisation of the nerve terminal (primary)
- Sensitisation of the central pathway (secondary)
Define allodynia and hyperalgeisa
Hyperalgesia means an increased response to a painful stimulus.
Allodynia means a painful response to a normally innocuous stimulus.
Describe peripheral vs. central sensitisation
Periphal (primary sensory nociceptors) by inflammatory cells acting on the terminals changing their threshold and can cause short term modifications in the sensory neurons.
If the activity is ongoing, central parts of the pathway undergo central sensitisation in either the spinal cord or the brain: allodynia and hyperalgesia
What is secondary hyperalgesia?
Central sensitisation in the spinal cord (projections of sensory terminals running up and down spinal levels) cause hyperalgesia in sensory neurons that are not damaged
ie. expansion/radiation of the area that feels painful
What is maladaptive pain?
What types of experiences are felt?
A low threshold pain that respresents a disease state of the nervous system.
It doesn't necessarily have a physical stimuli that causes the pain
- Spontaneous pain (absence of stimuli)
- Pain hypersensitivity
What is neuropathic pain?
Pain caused by a neuropathic lesion: damage to the neural somatosensory pathway eg. peripheral nerve damage or spinal cord/brain damage involveing the pathway (eg. stroke/MS)
What is dysfunctional pain?
Pain where there is no obvious tissue pathology indentifiable other than the pain itself
Eg. migraine, fibromyalgia, pelvic pain (functional pain syndrome)
What initiates neuropathic pain?
Initiated by damage to the nerves:
The responses (and thus pain itself) can be due to
- reorganisation of the nociceptors
- cut endings can start generating electrical signals without any simuli
- neuronal cell death
- most changes occur in the spinal cord itself, causing pain.
Since we have defined that nociception is not pain (they are independent entities). To what section of the brain do nociception signals relay to, in order to be processed as pain?
There is no one particular area of the brain that generates pain - There is a distrubuted network involving different parts of cortex and brainstem.
The cingulate, insular and somatosensory cortices have an important role
What is meant by spinal control of modulation?
Ascending pathway to the brain and then a descending pathway that is able to modulate and block the transmission of that sensory information = feedback system that controls how much pain it is percieving
provides negative feedback control by modulating nociceptive transmission in spinal cord
The brainstem has been found to be involved in feedback to the spinal cord, what are the two major areas of the brainstem involved in this mechanism?
Describe this descending pathway
- Periqueductal gray (PAG)
- Rostral ventral medulla (RVG)
The pathway modulates the transmission of pain through the dorsal horn up to the brain - through signals via descending noradrenergic inhibitory neurons
What evidence exists for these PAG and RVM and descending modulating pathways existing?
Drug induced analgesia
Elicit pain relief when injected into these areas to mimic the normal activity of the descending pathway that modulates the transmission of pain through the dorsal horn up to the brain
Give some examples of centrally acting analgesic drugs that act on the descending, modulating pathway
- opioids (morphine)
- NSAIDs (non-steroidal antiinflammatory drugs)
- anticonvulsants (gabapentin,pregabalin)
- TCAs (tricyclic antidepressants)
- SNRIs (serotonin-noradrenaline reuptake inhibitors)
- α2-adrenergic agonists (clonidine)
- cannabinoids (marijuana)
Describe the top down psychological modulation of pain
Humans have a system where fear or certain stimuli (not physical) can instigate a powerful array of psychological processes that can activate the descending pathway to cause hypoalgesia or hyperalgesia
(placebo and nocebo)
What are the main cortical areas involved in the psychological modulation of pain?