Definition
The most widely accepted definition of pain is from the International Association of the Study of Pain (IASP):
“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”
As we can see, there can perhaps be thought of as 2 domains:
“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”
As we can see, there can perhaps be thought of as 2 domains:
- Nociception - the ‘physical’ or ‘sensory’ component
- Emotive - the unpleasantness of it
Nociception
This is the “the neural processes of encoding and processing noxious stimuli”.
This can be considered as the sensory modality for ‘tissue damage’.
There is a clear physical pathway that can be considered for this.
A nociceptor is an organ adapted for detection of a noxious stimuli and for processing this stimuli for CNS interpretation. These stimuli are generally heralds of actual or potential tissue damage and are wide ranging in their diversity.
A nociceptor is effectively a free nerve ending that, when triggered by the appropriate noxious stimuli, produces an action potential. This action potential is propagated to higher neural centres where the signal can be processed appropriately.
The nociceptive fibres themselves are of two types.
When someone is exposed to a noxious stimuli there is first a very quick sharp pain, causing a rapid withdrawal reflex, protecting against further damage. This is mediated by the fast A delta fibres.
This is followed by a slower onset ache-type pain that can persist for a significant time, despite removal of the body from the source of injury. This is mediated by the slow C fibres. This will promote a protective response to the injured area, limiting further damage, and encouraging avoidance of similar scenarios.
There are a number of potential triggers of nociceptors:
There are a number of different receptors that these triggers exert their action at, which include the relevant receptors of the neurotransmitters listed above.
Others include:
It is important to note that there is some overlap between the modality of the triggers of pain and what we would call normal sensation e.g. temperature, pressure.
The threshold for the trigger of the nociceptor is usually higher than for the normal sensation in that modality.
However, there is the potential for significant modulation of this, as can be clearly seen with sunburn when a normally painless sensation e.g. touch, becomes painful.
Indeed, there is significant interaction between the components of the pain pathways that can have a big impact on the final result.
The action potential of the nociceptor is similar to other nerves, although there are a few differences.
Cation influx, primarily sodium, results in depolarisation, with K+ efflux leading to repolarisation.
The primary nociceptors do have some specific ion channels, such as the tetrodotoxin resistant family, which may provide a target for analgesic agents.
This can be considered as the sensory modality for ‘tissue damage’.
There is a clear physical pathway that can be considered for this.
- Nociceptor
- 1st order neuron - periphery to spinal cord
- 2nd order neuron - dorsal horn to thalamus
- 3rd order neuron - thalamus to higher structures e.g. primary somatosensory cortex
A nociceptor is an organ adapted for detection of a noxious stimuli and for processing this stimuli for CNS interpretation. These stimuli are generally heralds of actual or potential tissue damage and are wide ranging in their diversity.
A nociceptor is effectively a free nerve ending that, when triggered by the appropriate noxious stimuli, produces an action potential. This action potential is propagated to higher neural centres where the signal can be processed appropriately.
The nociceptive fibres themselves are of two types.
- Fast fibres - A delta nerve fibre subtype. These are of a large diameter and myelinated, producing faster conduction speed.
- Slow fibres - C nerve fibre subtype. These are of a smaller diameter and unmyelinated, hence transmit action potentials at a slower rate. They are more widespread than the A delta type and innervate visceral structures as well.
When someone is exposed to a noxious stimuli there is first a very quick sharp pain, causing a rapid withdrawal reflex, protecting against further damage. This is mediated by the fast A delta fibres.
This is followed by a slower onset ache-type pain that can persist for a significant time, despite removal of the body from the source of injury. This is mediated by the slow C fibres. This will promote a protective response to the injured area, limiting further damage, and encouraging avoidance of similar scenarios.
There are a number of potential triggers of nociceptors:
- Temperature
- Pressure
- Chemical
- Potassium,
- Hydrogen,
- Serotonin,
- Histamine,
- Bradykinin,
- ATP,
- Glutamate
- Potassium,
There are a number of different receptors that these triggers exert their action at, which include the relevant receptors of the neurotransmitters listed above.
Others include:
- Vanilloid receptor-related TRP channels (TRPV)
- Acid-sensing ion channel (ASIC)
It is important to note that there is some overlap between the modality of the triggers of pain and what we would call normal sensation e.g. temperature, pressure.
The threshold for the trigger of the nociceptor is usually higher than for the normal sensation in that modality.
However, there is the potential for significant modulation of this, as can be clearly seen with sunburn when a normally painless sensation e.g. touch, becomes painful.
Indeed, there is significant interaction between the components of the pain pathways that can have a big impact on the final result.
The action potential of the nociceptor is similar to other nerves, although there are a few differences.
Cation influx, primarily sodium, results in depolarisation, with K+ efflux leading to repolarisation.
The primary nociceptors do have some specific ion channels, such as the tetrodotoxin resistant family, which may provide a target for analgesic agents.
Pain Pathways
This is a good video introduction of the pathways: https://www.youtube.com/watch?v=fUKlpuz2VTs
This video goes on to explore a few more features of the pain pathways: https://www.youtube.com/watch?v=5c8maFAhqIc
Activation of the nociceptor (once a threshold is reached) will cause an action potential.
This will propagate down the nociceptive fibre.
These action potentials terminate in the dorsal horn of the spinal cord, where they synapse onto second order neurons.
For nociceptors this is primarily in laminae I, II, and V.
Lamina II is also known as the substantia gelatinosa, and is an important site for modulation of the upgoing signals.
It is mainly type C nociceptive fibres that synapse here, and connection to second order neurons (in laminae I and V) is frequently via interneurons.
These interneurons play an important role in the subsequent modulation of ascending signals.
Type Ad fibres primarily synapse directly onto second order neurons in laminae I and V.
This video goes on to explore a few more features of the pain pathways: https://www.youtube.com/watch?v=5c8maFAhqIc
Activation of the nociceptor (once a threshold is reached) will cause an action potential.
This will propagate down the nociceptive fibre.
These action potentials terminate in the dorsal horn of the spinal cord, where they synapse onto second order neurons.
For nociceptors this is primarily in laminae I, II, and V.
Lamina II is also known as the substantia gelatinosa, and is an important site for modulation of the upgoing signals.
It is mainly type C nociceptive fibres that synapse here, and connection to second order neurons (in laminae I and V) is frequently via interneurons.
These interneurons play an important role in the subsequent modulation of ascending signals.
Type Ad fibres primarily synapse directly onto second order neurons in laminae I and V.
Lamina II is also known as the substantia gelatinosa, and is an important site for modulation of the upgoing signals.
It is mainly type C nociceptive fibres that synapse here, and connection to second order neurons (in laminae I and V) is frequently via interneurons.
These interneurons play an important role in the subsequent modulation of ascending signals.
Type Ad fibres primarily synapse directly onto second order neurons in laminae I and V.
Visceral nociceptive fibres synapse onto a greater number of second order neurons, and hence the more diffuse nature of the pain experienced.
There is also some crossover with somatic pathways, which may explain the phenomenon of referred pain.
The activation of the second order neuron is achieved by a number of neurotransmitters and receptors.
There are also a number of other receptors in this area that may be modulatory on the signals.
Activation of the primary neuron results in some complex changes at the dorsal horn synapse.
Glutamate via AMPA receptors results in Na+ influx into the postsynaptic membrane.
Neurokinin receptors lead to secondary messenger systems being activated.
Prolonged activation leads to displacement of the Mg2+ ion from the NMDA receptor, allowing it to be activated by glutamate.
This results in a more prolonged activation, due to sustained influx of Ca2+.
With ongoing activated, this can lead to a number of intracellular changes that increase sensitisation to nociceptive impulses.
It is mainly type C nociceptive fibres that synapse here, and connection to second order neurons (in laminae I and V) is frequently via interneurons.
These interneurons play an important role in the subsequent modulation of ascending signals.
Type Ad fibres primarily synapse directly onto second order neurons in laminae I and V.
Visceral nociceptive fibres synapse onto a greater number of second order neurons, and hence the more diffuse nature of the pain experienced.
There is also some crossover with somatic pathways, which may explain the phenomenon of referred pain.
The activation of the second order neuron is achieved by a number of neurotransmitters and receptors.
- Glutamate
- NMDA
- AMPA
- Kainite
- Metabotropic
- Substance P
- Neurokinin receptor
- Neurokinin A
- Neurokinin receptor
There are also a number of other receptors in this area that may be modulatory on the signals.
- Opioid
- GABA
- 5HT
- Adrenoreceptors
- Cannabinoid
Activation of the primary neuron results in some complex changes at the dorsal horn synapse.
Glutamate via AMPA receptors results in Na+ influx into the postsynaptic membrane.
Neurokinin receptors lead to secondary messenger systems being activated.
Prolonged activation leads to displacement of the Mg2+ ion from the NMDA receptor, allowing it to be activated by glutamate.
This results in a more prolonged activation, due to sustained influx of Ca2+.
With ongoing activated, this can lead to a number of intracellular changes that increase sensitisation to nociceptive impulses.
Activation of the second order neuron results in propagation of an action potential in the usual fashion.
These fibres primarily cross to the contralateral side and travel up to the brain in the spinothalamic tract, in the anterolateral spinal cord.
A significant number of fibres also ascend on the ipsilateral side.
All these ascending fibres subsequently synapse onto a number of third order neurons in the thalamus:
There are additional important pathways:
These project to brainstem and midbrain structures and are involved in aspects such and descending modulatory pathways, the ANS responses to pain and the arousal component.
The more medial pathways of the spinothalamic tract also have projections to some of these areas.
Important projections include to the:
The pain pathways can be helpfully considered based on their evolutionary development.
The older pathways focused more on the behavioural and emotive nature of pain, and thus have more diffuse connections in the brain.
These tend to be more medial in anatomical location (much like the more ancient cerebral structure are deeper).
In contrast, the development of a more discriminatory analysis of nociception in more evolutionary modern.
These pathways occupy a more lateral spinal cord location and are less diffuse in their connections.
These fibres primarily cross to the contralateral side and travel up to the brain in the spinothalamic tract, in the anterolateral spinal cord.
A significant number of fibres also ascend on the ipsilateral side.
All these ascending fibres subsequently synapse onto a number of third order neurons in the thalamus:
- Lateral thalamus - project to the somatosensory cortex and thus provide the spatial and temporal representation of pain
- Medial thalamus - more involved in transmitting the emotive component of pain
There are additional important pathways:
- Spinoreticular tract
- Spinomesencephalic tract
These project to brainstem and midbrain structures and are involved in aspects such and descending modulatory pathways, the ANS responses to pain and the arousal component.
The more medial pathways of the spinothalamic tract also have projections to some of these areas.
Important projections include to the:
- Hypothalamus
- Periaqueductal grey matter
- Reticular formation
The pain pathways can be helpfully considered based on their evolutionary development.
The older pathways focused more on the behavioural and emotive nature of pain, and thus have more diffuse connections in the brain.
These tend to be more medial in anatomical location (much like the more ancient cerebral structure are deeper).
In contrast, the development of a more discriminatory analysis of nociception in more evolutionary modern.
These pathways occupy a more lateral spinal cord location and are less diffuse in their connections.
Cerebral Connections
There are a number of important cerebral connections for these pathways once they reach the brain.
This is complex and not fully understood, but it seems that this processing is where nociception starts to become pain.
Key structures include:
As with other modalities of sensation, the thalamus is a key relay station for pain signals.
Many second order neurons terminate here, synapsing into third order neurons with subsequent projections.
The key thalamic nuclei are:
As noted already, there can be thought of as being some degree of structural (and evolutionary) distinction of the affective and discriminative components of pain.
The medial thalamic projections go on to project to the evolutionary older parts of the brain which play a greater role in the affective aspect of pain:
The more modern evolutionary parts of the brain take on more of the discriminative interpretation of pain.
The lateral thalamic nuclei project the the somatosensory cortex.
As with other sensory modalities, the different parts of the body are mapped as a homunculus on the cortical surface.
This is complex and not fully understood, but it seems that this processing is where nociception starts to become pain.
Key structures include:
- Thalamus
- Somatosensory cortex
- Insula
- Prefrontal cortex
- Anterior cingulate cortex
- Amygdala
- Hippocampus
As with other modalities of sensation, the thalamus is a key relay station for pain signals.
Many second order neurons terminate here, synapsing into third order neurons with subsequent projections.
The key thalamic nuclei are:
- Lateral ventral posterolateral nuclei
- Medial midline group
As noted already, there can be thought of as being some degree of structural (and evolutionary) distinction of the affective and discriminative components of pain.
The medial thalamic projections go on to project to the evolutionary older parts of the brain which play a greater role in the affective aspect of pain:
- Limbic system
- Anterior cingulate cortex
The more modern evolutionary parts of the brain take on more of the discriminative interpretation of pain.
The lateral thalamic nuclei project the the somatosensory cortex.
As with other sensory modalities, the different parts of the body are mapped as a homunculus on the cortical surface.
Descending Pathways
These represent part of the negative feedback loop of the pain pathways.
There are a few key anatomical areas involved in mediating these pathways:
In general, the role of the descending pathways is to reduce transmission of the nociceptive signal at the dorsal horn level i.e. to impair stimulation of the 2nd order neuron.
The PAG is a region around the aqueduct between the 3rd and 4th ventricles in the brain.
This area has multiple inputs, including:
This subsequently has neurons which project down to the dorsal horn of the spinal cord.
These neurons primarily release noradrenaline and 5HT, and do it is postulated that some analgesics have their mechanism of action by affecting these neurotransmitters.
There are a significant number of opioid receptors in this pathway, and a significant component of the medical opioid analgesia may arise from stimulating this pathway.
There are a few key anatomical areas involved in mediating these pathways:
- Periaqueductal grey (PAG) matter
- Nucleus raphe magnus (NRM)
In general, the role of the descending pathways is to reduce transmission of the nociceptive signal at the dorsal horn level i.e. to impair stimulation of the 2nd order neuron.
The PAG is a region around the aqueduct between the 3rd and 4th ventricles in the brain.
This area has multiple inputs, including:
- Ascending pain pathways
- Frontal lobe
- Amygdala
- Hypothalamus
This subsequently has neurons which project down to the dorsal horn of the spinal cord.
These neurons primarily release noradrenaline and 5HT, and do it is postulated that some analgesics have their mechanism of action by affecting these neurotransmitters.
There are a significant number of opioid receptors in this pathway, and a significant component of the medical opioid analgesia may arise from stimulating this pathway.
Peripheral Sensitisation
Pain is quite different from many of the other senses.
Whilst many of these demonstrate desensitisation after prolonged exposure, pain actually demonstrates this opposite.
This makes evolutionary sense, allowing protection of the self by withdrawal from noxious stimuli, and protection of an injured site during healing.
As noted above, the components of the pain pathway can undergo modulation at many levels.
The changes peripherally at the nociceptor are worth considering first.
A number of chemical mediators can act on the nociceptor to lower its excitation threshold (i.e. the degree of stimulation it needs to trigger an action potential).
These include:
Many substances arise from damaged cells, mast cells and activated platelets, much of these arising as part of the inflammation that occurs in response to injury.
They act by sensitising nociceptors in the local and surrounding area.
The result is that the nociceptors have a lower threshold for activation.
Previously non painful stimuli to the site of injury and surrounding area e.g. touch, moderate temperature, may now be perceived as painful.
This results in primary hyperalgesia.
The mechanisms for this are alteration of the ion channels and receptors on the nociceptors, lowering their threshold for activation.
There may also be increased gene expression, and upregulation of the relevant receptor proteins.
An example is the phosphorylation of sodium channels that occur in response to inflammation, lowering their triggering threshold.
Capsaicin (from chillies) has its effect through the Vanilloid receptor-related TRP channels (TRPV), acting as a ligand at these receptors and lowering their threshold for activation (this is why chillies taste hot as they lower the threshold for stimulation)
It is important to note there is also the opposing analgesic process that occur naturally at a peripheral site.
A key mechanism is the opioid receptor.
These are produced in the dorsal root ganglion of nociceptor fibres in response to tissue damage and pass down the axon to the periphery.
They are then incorporated into the membranes and are acted on by endogenous opioid peptides which are produced by a range of inflammatory cells e.g. macrophages.
Whilst many of these demonstrate desensitisation after prolonged exposure, pain actually demonstrates this opposite.
This makes evolutionary sense, allowing protection of the self by withdrawal from noxious stimuli, and protection of an injured site during healing.
As noted above, the components of the pain pathway can undergo modulation at many levels.
The changes peripherally at the nociceptor are worth considering first.
A number of chemical mediators can act on the nociceptor to lower its excitation threshold (i.e. the degree of stimulation it needs to trigger an action potential).
These include:
- Histamine
- Bradykinins
- Prostaglandins
- Leukotrienes
- Serotonin
- Substance P
- Glutamate
Many substances arise from damaged cells, mast cells and activated platelets, much of these arising as part of the inflammation that occurs in response to injury.
They act by sensitising nociceptors in the local and surrounding area.
The result is that the nociceptors have a lower threshold for activation.
Previously non painful stimuli to the site of injury and surrounding area e.g. touch, moderate temperature, may now be perceived as painful.
This results in primary hyperalgesia.
The mechanisms for this are alteration of the ion channels and receptors on the nociceptors, lowering their threshold for activation.
There may also be increased gene expression, and upregulation of the relevant receptor proteins.
An example is the phosphorylation of sodium channels that occur in response to inflammation, lowering their triggering threshold.
Capsaicin (from chillies) has its effect through the Vanilloid receptor-related TRP channels (TRPV), acting as a ligand at these receptors and lowering their threshold for activation (this is why chillies taste hot as they lower the threshold for stimulation)
It is important to note there is also the opposing analgesic process that occur naturally at a peripheral site.
A key mechanism is the opioid receptor.
These are produced in the dorsal root ganglion of nociceptor fibres in response to tissue damage and pass down the axon to the periphery.
They are then incorporated into the membranes and are acted on by endogenous opioid peptides which are produced by a range of inflammatory cells e.g. macrophages.
Central Sensitisation
This refers to the changes that result in sensitisation to nociceptive impulses at a central level, particularly at the level of the dorsal horn.
A number of important mechanisms have been described:
Windup
This refers the the effect of prolonged stimulation of the second order neuron at the dorsal horn.
This can lead to activation of NMDA receptors and lead to more prolonged second neuron stimulation due to their prolonged action.
Increased excitatory input
Here, prolonged excitatory stimulation of nociceptors (particularly type C fibres) lead to ‘recruitment’ of wide dynamic range (WDR) neurons in the dorsal horn.
These are essential neurons of different sensory modalities, but whose action potentials can be summated towards a second order nociceptive impulse.
This produces the phenomenon of secondary hyperalgesia.
Decreased inhibitory input
This simply refers to the decrease impact of normal inhibitory mechanisms at the dorsal horn (both pre and post synaptically) as a result of the inflammatory response.
Classical sensitisation
This refers to the gene-expression response to inflammation that is similar as at the periphery.
Inflammatory mediators lead to upregulation of certain genes, increased production of certain membrane proteins and this increased sensitivity to afferent inputs.
A number of important mechanisms have been described:
- Windup
- Increased excitatory input
- Decreased inhibitory input
- Classical central sensitisation
Windup
This refers the the effect of prolonged stimulation of the second order neuron at the dorsal horn.
This can lead to activation of NMDA receptors and lead to more prolonged second neuron stimulation due to their prolonged action.
Increased excitatory input
Here, prolonged excitatory stimulation of nociceptors (particularly type C fibres) lead to ‘recruitment’ of wide dynamic range (WDR) neurons in the dorsal horn.
These are essential neurons of different sensory modalities, but whose action potentials can be summated towards a second order nociceptive impulse.
This produces the phenomenon of secondary hyperalgesia.
Decreased inhibitory input
This simply refers to the decrease impact of normal inhibitory mechanisms at the dorsal horn (both pre and post synaptically) as a result of the inflammatory response.
Classical sensitisation
This refers to the gene-expression response to inflammation that is similar as at the periphery.
Inflammatory mediators lead to upregulation of certain genes, increased production of certain membrane proteins and this increased sensitivity to afferent inputs.
Physiological Response
As can be appreciated, there is a clear physiological response to pain, as well as a psychological one.
This primarily is one of arousal and sympathetic ANS activity.
Some of these can have significant implications e.g. risk of coronary events.
This primarily is one of arousal and sympathetic ANS activity.
- CVS
- Tachycardia
- Hypertension
- Peripheral vasoconstriction
- Tachycardia
- Resp
- Tachypnoea
- Tachypnoea
- GI
- Reduced gastric emptying
- Nausea
- Reduced gastric emptying
- GU
- Urinary retention
- Urinary retention
- Sweating
Some of these can have significant implications e.g. risk of coronary events.
Modulation
As already noted, there is significant modulation of this pain pathway.
As well as the different forms of sensitisation, there are mechanisms that reduce the transmission of nociceptive impulses.
These would seem to play a role of creating an overall negative feedback on the pain system.
Gate Control Theory
It has been recognised that additional sensory input at the site of an injury can modulate pain.
We routinely rub ourselves when we have sustained a knock.
Melzack and Wall have gone on to describe the gate control theory of pain.
They postulate that the stimulation of large sensory afferent fibres (A alpha and beta) such as through rubbing, results in activation of inhibitory interneurons which block the onward transmission of C fibre nociceptive fibres.
This ‘gate’ can be appreciated as being a point where incoming signals are modulated in the dorsal horn of the spinal cord.
There are a number of pro-nociceptive and anti-nociceptive signals that feed into this ‘gate’ and the balance of these factors play an impact.
A number of neurotransmitters have an modulatory action.
These act at a number of pre and postsynaptic receptors:
The descending pathways from the PAG and NRM have neurons which project to the dorsal horn, with noradrenaline and 5HT being important neurotransmitters.
As well as the different forms of sensitisation, there are mechanisms that reduce the transmission of nociceptive impulses.
These would seem to play a role of creating an overall negative feedback on the pain system.
Gate Control Theory
It has been recognised that additional sensory input at the site of an injury can modulate pain.
We routinely rub ourselves when we have sustained a knock.
Melzack and Wall have gone on to describe the gate control theory of pain.
They postulate that the stimulation of large sensory afferent fibres (A alpha and beta) such as through rubbing, results in activation of inhibitory interneurons which block the onward transmission of C fibre nociceptive fibres.
This ‘gate’ can be appreciated as being a point where incoming signals are modulated in the dorsal horn of the spinal cord.
There are a number of pro-nociceptive and anti-nociceptive signals that feed into this ‘gate’ and the balance of these factors play an impact.
A number of neurotransmitters have an modulatory action.
These act at a number of pre and postsynaptic receptors:
- Opioid - endorphins, enkephalins, dynorphins
- GABA
- Glycine
- 5HT
- Adrenoreceptors
- Cannabinoid
The descending pathways from the PAG and NRM have neurons which project to the dorsal horn, with noradrenaline and 5HT being important neurotransmitters.
Links & References
- Power, I. Pain - Peripheral and central mechanisms. e-LFH. 2012.
- Hasudungan, A. Nociceptors - an introduction to pain. 2013. Youtube. https://www.youtube.com/watch?v=fUKlpuz2VTs
- Hasudungan, A. PAIN! Physiology - the ascending pain pathway, descending pathway and substantia gelatinosa. 2018. Youtube. https://www.youtube.com/watch?v=5c8maFAhqIc
- Power, I. Kam, P. Principles of physiology for the anaesthetist (2nd ed). 2008. Hodder Arnold.
- Williams, L. Anatomy of the ascending pain pathway. e-LFH. 2014.
- Williams, L. Physiology of pain transmission. e-LFH.
- Williams, L. Modulation and plasticity in the nociceptive system. e-LFH.
