Brain cells and pain

Complex regional pain syndrome (CRPS) - occurring after healing of a wrist fracture

 

Neuron classification: Morphology

  • The different types of neuron can be classified based on morphology

  • Classification in terms of number of neuronal processes (bits that stick out from the cell)

  • Classification in terms of length of the neuronal processes

  • Golgi I neurons: long axons

  • Golgi II neurons: shorter axons project locally

 

What are neurons for?

Three major purposes:

  1. Sensations - afferent neurons: to gather and send information from the senses such as touch, smell, sight etc. (sent towards CNS)

  2. Integration - interneurons: to process all information gathered, thus allowing us to take action

  3. Action - motor neurons: to send appropriate signals to effectors (through activation of skeletal muscles or glands)

Muscles (cardiac, smooth and skeletal)

Glands

 

Neuron classification: function

Function classification based on whether conveying messages towards, within or away from the central nervous system

  1. Towards: sensory neurons (bipolar, unipolar)

  2. Within: interneurons (multipolar, short or long)

  3. Away: motor neurons (multipolar; long)

 

 

Pain-

= an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage

(International Association for the Study of Pain 2020)

 

Dimensions of pain:

  • Sensory: type of stimulus, intensity, location

  • Affective: unpleasantness, emotions

  • Cognitive: attention, memory, expectation, imagination

 

 

What neurons are for:

  1. Sensation - e.g. signalling danger through pain

"nociceptors" - Descartes 1662

  1. Integration - sensory, emotional and cognitive

--->

  1. Action - e.g. withdrawal reflex

 

Sensory/integrative aspects: from receptors to spinal cord to the brain

 

Peripheral sensory neurons

  • Contain receptors (either cellular e.g. vision; or molecular e.g. pain nociceptors)

  • Translate receptor codes to neural codes

  • Transmit information to CNS

 

 

Pain sensors (nociceptors) are free nerve endings

 

Capsaicin and TRP-V1

  • TRP-V1 is polymodal

  • Capsaicin makes TRP-V1 more sensitive to heat and vice versa

  • Capsaicin binds to receptors in your mouth (TRP-V1 receptors) - with spicy food

  • Capsaicin polarises the membrane making it more likely for an action potential to be generated

 

Labelled line theory of pain

Core ideas:

  • Posits that specific neurons, or "lines" are dedicated to transmitting specific types of sensory information - e.g. temperature, pressure or a specific type of pain)

  • One-to-one mapping between the activated neuron and the perceived sensation (if you activate the heat neurone you get a heat sensation etc)

Caveats:

  • Many neurons are polymodal (that is, respond to more than one stimulus modality)

  • The theory ignores neuronal integration (cross-talk) in the spine/brain

 

Supporting evidence: different peripheral nerve fibre types

 

 

Supporting evidence: First and second pain - C vs A

A-delta fibres (First pain)

  • "labelled line" for initial, sharp and localised pain sensation

  • Myelinated, for faster signal transmission

  • e.g. immediate sensation from chili peppers (sharp spiciness)

C-fibres (Second pain)

  • "labelled line" for dull, aching, more diffuse pain that follows the initial sharp pain

  • Unmyelinated, resulting in slower transmission

  • e.g. lingering, diffuse burn from spicy food

  • Spinal neurons-

     

    Nociceptive pathway in the spinal cord

     

     

    Spinal interneurons and theories of pain-

    Labelled line theory/specificity theory:

    • Specialised nociceptive neurons for pain vs non-pain inputs (mirroring that in periphery

    • Issues: does not account for many pain phenomena

    Population coding theory:

    • Co-activation of a number of unspecialised neurons (e.g. Wide-Dynamic Range - WDR) result in pain

    • Accounts for spatial summation of pain

    Combinatorial coding theory:

    • Central sensitisation: A-beta activation (normally for touch) results in pain

    • Gate-control: different neuronal fibre types (e.g. A-beta touch and A-delta pain fibres) can interfere to reduce pain

    • Lateral inhibition: Cross-talk inhibition can refine spatial localisation of pain

     

    Population coding theory of pain

    • Co-activation of number of unspecialised neurons (e.g. Wide-Dynamic Range - WDR) result in pain

    • The recruitment of larger numbers of WDR neurons is associated with increasing intensities of pain

    Wide Dynamic Range (WDR) interneurons:

    • WDR neurons are so-called because they respond to both noxious (nociceptive) and non-noxious (e.g. touch) inputs

    • The relationship between WDR neurons and pain may be due to the fact that WDR neurons have large receptive fields

    • WDR neurons also selectively expand their receptive fields in response to nociceptive input

     

    Spinal integration: Population coding

    WDR neurons respond to both noxious and non-noxious stimuli - so how do they encode pain specifically? - by population coding

    • WDR neurons have large receptive fields (provides a mechanism for spatial summation of pain)

    • Increasingly intense noxious inputs increase the size of the receptive fields, which means more WDR neurons are activated by more intense stimuli (green to yellow to red in the figure)

    • Hence, noxious stimulus intensity can be encoded by progressive recruitment of increasing numbers of WDR neurons

     

    Evidence: WDR population coding

    Greater area of activation in spinal cord with increasing stimulus intensity:

    • “Progressive increases in noxious stimulus intensity applied to the distal hindpaw produced progressive increases in spinal cord activation… Low stimulus intensities (45°C) activated the segment L4 … as noxious stimulus intensities increased (49°C), activation extended from L2 to L5… innocuous brushing produced minimal recruitment of activation, restricted to L4.”

    • Original article: Coghill, R.C. et al. (1993) The roles of spatial recruitment and discharge frequency in spinal cord coding of pain: a combined electrophysiological and imaging investigation. Pain 53, 295–309

    Evidence: WDR receptive fields

    • “Dynamic expansion of receptive fields of nociceptive neurons may represent a key factor for neuron recruitment. Relatively brief (20s) barrages of C-fibre input can evoke nearly 400% increases in receptive field sizes of nociceptive neurons in the rat dorsal horn, a portion of which project supraspinally.”

    • Original article: Cook, A.J. et al. (1987) Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input. Nature 325, 151–153

     

    Spatial summation

    • Large receptive fields of WDR neurons support spatial summation, since:

      • the same neuron can respond to stimuli at 2 different locations.

      • this means a greater likelihood of a WDR neuron reaching the threshold for generating action potentials

    • Can occur even when stimuli are separated by ~40 cm in humans.

    • But, maximal at 5- and 10-cm separation distances (smaller distances summate less – due to lateral inhibition)

     

    Combinatorial coding theory of spinal interneurons

    • Central sensitization: A-beta activation (normally for touch) results in pain due to spinal “cross-talk”

    • Gate-control: Different neuronal fibre types (e.g. A-beta touch and A-delta pain fibres) can interfere to reduce pain.

    • Lateral inhibition: Cross-talk inhibition can refine spatial localization of pain.

     

     

    Question: why does rubbing an injury relieve pain?

    When you get hurt – and it’s not a serious injury – you instinctively start to rub the affected area or start shaking it vigorously.

    Which theories are relevant to understanding this phenomenon?

    Which types of interneurons do you think might be involved?

    • Type of neuron (morphology)

    • Location and anatomy

    • Direction and function

    • Neurotransmitters

     

    Spinal integration: sensitisation to touch

    Injecting capsaicin into the skin causes increased sensitivity to pain

    1. In the "primary zone" of application:

    • Peripheral sensitisation

    • Activates nerve endings (e.g. C-nociceptors

    • Even light pressure and harmless heat causes pain

    1. In the "secondary zone"

    • Central sensitisation

    • Light tone now causes pain, similar to certain neuropathic chronic pain conditions

    • Affects the spinal cord neurons, making the central nervous system more sensitive

     

    Spinal integration: Gate control

    Gate control theory of Pain: Role for Substantia Gelatinosa (SG) interneurons

     

    • Non-painful sensory inputs close the “gates” to a painful input, reducing the pain.

    • Substantia Gelatinosa (SG) neurons of the dorsal horn are inhibitory.

    • C-fibres (responsible for pain) inhibit SG neurons

    • Ab-fibres (responsible for touch) excite SG neurons.

    • Hence, the SG acts as a gate and determine whether pain is encoded within WDR neurons that eventually transmit information to the brain.

     

    Spinal integration: lateral inhibition

    • How is it that people can discriminate the location of a painful stimulus so accurately? Due to lateral inhibition.

    • Spatial perception is “sharpened” due to an inhibitory integration process

    • Also explains the nonlinearity of spatial summation of pain, i.e. stimuli that are close together summate less than those further apart (up to about 20cm)

     

    Question: why does rubbing an injury relieve pain?

    When you get hurt – and it’s not a serious injury – you instinctively start to rub the affected area or start shaking it vigorously.

    Which theories are relevant to understanding this phenomenon?

    Which types of interneurons do you think might be involved?

    • Type of neuron (morphology)

    • Location and anatomy

    • Direction and function

    • Neurotransmitters

     

  • Brain neurons

    Why are brain interneurons interesting?

    What do they do?

    • Receive ascending input (from the spine)

    • Integrate spinal input with existing sensory, affective and cognitive information in the brain – important for the multidimensional perception of pain.

    • Initiate deliberative motor responses/behaviours.

    • Modulate spinal nociception (including the extent of the spinal reflex) depending on cognitive/emotional context

     

    Main features-

    • Different anatomical regions have different functions (e.g. sensory, affective, cognitive)

    • Both short (local processing) and long (e.g. descending modulation) axon types

    • Multiple neurotransmitters (e.g. NMDA, GABA, opioid, serotonin)

     

    Relevant theories and phenomena

    • Pain neuromatrix theory

    • Descending modulation

    • Central sensitisation (similar to spinal mechanisms)

    Predictive coding theory (see research lecture

     

    Pain pathways-

    The spinothalamic tract, (anterolateral system)

    • 3rd neuron: thalamus (ventrobasal complex) --> cerebral cortex

    • 2nd neuron: grey-matter --> thalamus, crossing in anterior part of spinal cord

    • 1st neuron: spinal ganglion --> grey matter of the spinal cord

     

    Pain neuromatrix theory

    • Subjective pain is generated by a neural network (the "neuromatrix“)

    • The neuromatrix integrates sensory, emotional, and cognitive inputs/processes

    • Accounts for the multidimensional experience of pain

     

    Attention modulates spatial summation

    • "When participants were instructed to provide one overall rating of two noxious stimuli (typically used in studies of spatial summation), substantial spatial summation of pain was detected. However, when participants were instructed to divide their attention and provide separate ratings of each of the simultaneous stimuli, spatial summation of pain was abolished.”

     

    Attention modulates spinal nociception

    • Neuronal responses to painful stimulation in the dorsal horn were significantly reduced under high working memory load (“2-back” task) compared to low working memory load (“1-back” task).

    • Reductions of spinal responses correlated with the “distraction from pain” effect: reduced pain perception by distraction.

    • Likely to involve both opioidergic and nonopioidergic mechanisms – an opioid antagonist did not completely block the anti-nociceptive effect of distraction.

    • Regions of the anterior cingulate cortex (ACC) have direct projections to laminae V–VII (including WDR neurons) - may provide attentional information to spinal neurons.

     

    Descending nociceptive control is opioid mediated

    • How much analgesia to apply? Periaqueductal gray matter (PAG)

    • Execution: Rostroventromedial medulla (RVM), dorsolateral pontine tegment

     

    Evidence?

    • Electrical stimulation of PAG/RVM causes suppression of behavioral response to pain (Reynolds, 1969)

    • Microinjections of morphine – m-opioid receptor agonist has the same antinociceptive effect

    • um (DLPT)

    Descending control as predictive coding

    • Predictive coding is the dominant theory of CNS sensory encoding.

    • CNS processing is bi-directional.

    • Descending information codes for predictions about sensory inputs.

    • Ascending information codes for prediction errors, i.e. the discrepancy between predictions and actual input.

    • This allows for more efficient sensory encoding in the CNS.

    • Actions are also related to predictions (preceding sensory input) and prediction errors (after sensory input)