Pain pathways

This chapter tries to address Section K3(i) of the 2023 CICM Primary Syllabus, which expects the exam candidate to "describe the physiology of pain, including peripheral nociception, conduction, receptors, mediators and pathways, spinal cord modulation and central processing of pain". The need to spell out the exact steps in a pain pathway has come up several times, which makes it something of a priority. For example:

  • Question 9 from the first paper of 2023 ("detected and modulated")
  • Question 12 from the second paper of 2019 (mainly nociception)
  • Question 1 from the first paper of 2014 (also motor withdrawal reflexes)
  • Question 22 from the second paper of 2013 (whole pain pathway)

In summary, the path of transmission for nociceptive information from peripheral nerves is as follows:

  • From the nociceptor, along a pain fibre
    • 20 m/s along a myelinated Aδ fibre
    • 2m/s along an unmyelinated C fibre
  • Past the body of the neuron, which lies in the dorsal root ganglion
  • Into the spinal cord via the dorsal root
  • Up (or down) the tract of Lissauer
  • Into the dorsal horn grey matter
  • Here, the primary afferents synapse with dorsal horn neurons, which:
    • Are arranged into discrete laminae which correspond to different spatial and functional groups
    • Are influenced by excitatory and inhibitory interneurons the activity of which is regulated by descending projections from the brain
  • Dorsal horn neurons then send projections across midline to the contralateral spinal cord, where their fibres form the ascending spinothalamic tract
  • The spinothalamic tract fibres synapse with tertiary neurons in the thalamus
    • The thalmus is responsible for sensory mapping and cortical representation of the geographical position of the pain information, and it also regulates some of the affective response to pain
  • They also project to multiple other higher centres:
    • Nucleus of the solitary tract and caudal ventrolateral medulla (cardiovascular response to pain)
    • Periaqueductal grey matter (descending regulation of pain signals)
    • Lateral parabrachial area (emotional and affective response to pain)

In terms of something to read from the world of official literature, Almeida et al (2003) is by far the easiest recommendation. Additionally, Todd (2010) offers a good description of what happens at the level of the dorsal horn.

Peripheral afferent pain fibres

After the terminal nociceptor is stimulated, it transduces the stimulus into an action potential which then propagates up the peripheral pain fibre. These fibres can be classified in a number of different ways:

  • By the thing they are innervating (i.e. cutaneous, visceral, etc)
  • By their conduction velocity (i.e. indirectly by whether or not they are myelinated)
  • By neurochemical phenotype (i.e. whether or not they produce peptides at their endings)
  • By their response characteristics (i.e. whether they require a high or low intensity stimulus, and by what kind of stimulus they require, i.e. thermal, mechanical or chemical)

There are two main types of fibre here, with distinct roles to play:

  • Large myelinated Aδ fibres: 
    • Rapid action potential propagation (20 m/s) facilitates acute withdrawal responses
    • Modality-specific information (eg. specifically heat, or specifically temperature)
    • Type I Aδ fibres usually connect high threshold mechanoreceptors that only respond to high-intensity mechanical stimuli
    • Type II Aδ fibres connect high threshold thermoreceptors which respond mainly to extremes of heat and cold 
  • Thin unmyelinated C fibres (2 m/s)
    • Polymodal information, i.e. the terminal branches of these nerve endings could be triggered by anything - mechanical, heat, chemical changes, etc

The cell bodies for these sensory neurons are in the dorsal root ganglion. The action potential travels past this ganglion and enters the spinal cord via the dorsal root.

Dorsal horn neurons

Sensory nerve fibres travel up or down the spinal cord via the tract of Lissauer before synapsing with the dorsal horn neurons. Most of these primary afferents secrete glutamate as their main neurotransmitter. The precise position of these afferent fibres is carefully laid out into a laminar architecture, which is occasionally referred to as the laminae of Rexed because they were first described by Brer Rexed in 1952. The original drawings were actually somewhat underwhelming and so here is a much better image from Todd (2010) which illustrates that each subtype of fibre has a discrete destination in this layered structure:

architecture of Rexed laminae from Todd et al (2010)

In case you don;t have time to read the entirety of the original Rexed paper or its modern successors (eg. Harding et al, 2020), this organisation (layer and what terminates there) can be summarised as follows:

  • Lamina I: Aδ fibres, mixture of noxious and innocuous tactile and cold information
  • Lamina II: C-fibres, mainly mechanosensor pain and temperature
  • Lamina III: Aδ fibers corresponding to low-threshold mechanosensation
  • Lamina IV, V and VI: proprioceptive and touch information (unrelated to pain)

The college answer to Question 12 from the second paper of 2019 also calls for "a description of the various substances involved in pain" including substance P, and so this would be as good a time as any to mention this curious neuropeptide. In short, Substance P specifically seems to be present at every level of the pain signalling pathways, where it acts as a neurotransmitter and a neuromodulator. Snijdelaar et al (2012) describes it in some detail, which is to say in way too much detail for an ICU exam candidate. To summarise:

  • Primary afferent terminals of pain sensory neurons contain substance P in their synaptic vesicles (i.e. it is a co-transmitter with glutamate)
  • The outer laminae (Lamina I and II) are the areas with most densely expressed substance P (these areas correspond to pain sensation). 
  • Substance P seems to act as both a neurotransmitter and as a neuromodulator; it has its own set of metabotropic receptors (neurokinin receptors, of which substance P seems selective for the NK1 subtype).
  • Binding these receptors increases cAMP and has indirect effects on calcium and potassium currents, which can be broadly described as "excitatory" (i.e. it gives rise to calcium influx and that usually results in membrane depolarisation, neurotransmitter release, etc). 
  • It is released only if the noxious stimulus is both prolonged and of a high intensity
  • The effects of it are prolonged and delayed, i.e. its maximum effect on neurotransmission is seen some 20-40 seconds delayed, and lasts for about 30-90 seconds, ie. it outlasts the pain stimulus.
  • It appears to have the effect of sensitizing the dorsal horn neurons to input (both excitatory and inhibitory)

Descending inhibition and interneurons

At the dorsal horn, a layer of filtering and processing is applied. The dorsal horn grey matter is full of excitatory and inhibitory (glutamate and GABA) interneurons which can amplify or dampen the signal before passing it to higher CNS structures. Moreover, there are descending tracts that add central regulation. Todd (2010) mentions three systems which send their descending projections to the dorsal horn:

  • Serotonergic neurons from the raphe nucleus
  • Noradrenergic neurons from the locus coeruleus
  • GABAergicneurons axons from the rostral ventromedial medulla

The inhibitory interneurons use GABA or glycine as their neurotransmitter, and receive descending input from these higher CNS systems. It is thought that their function forms the basis of central sensitization and "pain gating" that are discussed elsewhere.

Ascending pain pathways in the spinal cord

Dorsal horn neurons  send projections across midline to the contralateral spinal cord, where their fibres form the ascending spinothalamic tract. To borrow an image from the chapter on major white matter tracts, here's an illustration of this structure:

Lateral spinothalamic tract

Though the thalamus is singled out in this diagram, in fact dorsal horn neurons send ascending projections all over the place, most notably to:

  • Nucleus of the solitary tract which regulates the reflex tachycardia associated with pain
  • Caudal ventrolateral medulla which also regulates the cardiovascular response to pain
  • Periaqueductal grey matter which is one of the central sites of action of analgesics, and which regulates descending inhibition of pain signals
  • Lateral parabrachial area which then connects to the hypothalamus and amygdala to integrate the emotional and affective response to pain
  • Thalamus which maps the pain sensation spatially and is also probably responsible for some of the affective responses to pain

 

References

Almeida, Tatiana F., Suely Roizenblatt, and Sergio Tufik. "Afferent pain pathways: a neuroanatomical review.Brain research 1000.1-2 (2004): 40-56.

Todd, Andrew J. "Neuronal circuitry for pain processing in the dorsal horn." Nature Reviews Neuroscience 11.12 (2010): 823-836.

Rexed, Bror. "The cytoarchitectonic organization of the spinal cord in the cat." Journal of Comparative Neurology 96.3 (1952): 415-495.

Snijdelaar, Dirk G., et al. "Substance P." European Journal of Pain 4.2 (2000): 121-135.

Harding, Erika K., Samuel Wanchi Fung, and Robert P. Bonin. "Insights into spinal dorsal horn circuit function and dysfunction using optical approaches." Frontiers in Neural Circuits 14 (2020): 31.