1. Pain pathway
Y Tang

2. IASP definition
“Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

3. Pain The pain experience has two dimensions:
1. Sensory/discriminative - allowing us to locate tissue damage
2. Affective/aversive - ‘unpleasant’ and ‘emotional’ in the IASP definition. Avoid stimuli that can damage tissue.

4. Pain pathway

5. Ascending pain pathway
Those responsible for pain are called anterolateral system (also relays crude touch and temperature).
Dorsal column-medial lemniscal pathway mainly fine touch, vibration and position.
Somatosensory to cerebellum mainly for proprioception.

6. Anterolateral system Contains at least 2 pathways:
Spinothalamic (a.k.a. direct/neospinothalamic) –pain/temp/crude touch.
Spinoreticular (a.k.a. indirect/paleospinothalamic) –’suffering pathway’/arousal in response to nociception.
Spinomesencephalic –pain modulation.
Spinotectal –initiating eye movement to painful stimuli.
Spinohypothalamic - autonomic and reflex responses to nociception.

7. Anterolateral system
Peripheral receptor – nerve ending of Aδ and C-fibres, detect stimulus. Signal carried by:
1st order neuron – from periphery to spinal cord. Cell body in dorsal root ganglion, may travel up or down in ipsilateral spinal cord for several segments in the dorsolateral fasciculus (Lissauer tract), and then turn deeply to end in the dorsal horn. Then synapse with:

8. Anterolateral system
2nd order neuron – cell body in dorsal horn. Decussates in anterior white commisure to the contralateral cord. Axons of spinothalamic tract ascend all the way to terminate in the thalamus. The other two tracts terminate at brainstem levels. Then synapse with:
3rd order neuron – cell body in thalamus, ascend ipsilaterally to project to somatosensory cortex.

9. Ascending pathway. See handout.

10. Peripheral receptor (Nociceptor)
Nerve endings of Aδ and C-fibres (80%)
Polymodal –mechanical, thermal, chemical.
Responds to high threshold stimuli.

11. First order neuron Fibre Aδ (myelinated) C (unmyelinated) Diameter
Speed of conduction
5-15 m/s
0.5-2 m/s
Type of pain
‘fast’ sharp, pinprick, noxious heat
well-localised, short-term.
‘slow’ dull ache, burning sensation, diffuse, persistent.
Distribution
Skin, muscle, joint
Most tissues

12. First order neuron Aδ primary afferents terminate in laminae I and V.
C primary afferents terminate in lamina II (substantia gelatinosa) and III.
Some 1st order neuron synapse with interneuron (95% dorsal horn neurones are interneurons-associated with reflex motor activity).
Axon of interneurons synapse with 2nd order neurons in laminae V-VIII

13. Second order neurons Cell bodies in dorsal horn of spinal cord.
Direct –spinothalamic
Indirect –spinomesencephalic, spinotectal, spinohypothalamic.

14. 2nd order neuron:Spinothalamic tract
Aδ fibres.
15% nociceptive fibers from spinal cord terminate directly in thalamus via spinothalamic tract.
Consists of 2 anatomically distinct tracts; lateral (sharp pain and temp) and anterior spinothalamic tract (crude touch). Recent studies show all tracts in anterolateral system transmit nociceptive signals.
Projections to ventral posterior lateral nucleus of thalamus (also ventral posterior inferior and intralaminar nuclei).
Also has collaterals to reticular formation.

15. 2nd order neuron: Spinoreticular tract
C fibres.
Some fibers decussate to contralateral side via anterior commisure, many ascend ipsilaterally.
Transmit nociceptive, thermal, crude touch signals from spinal cord to thalamus indirectly by forming multiple synapses in the reticular formation prior to their thalamic projections.
Some second order neurons bypass reticular formation and relay sensory input from C fibres directly to intralaminar nuclei of thalamus.
Reticular formation sends signals not only to thalamus but to hypothalamus (autonomic and reflex response), and the limbic system (mediate emotional component of nociception).

16. 2nd order neuron: spinomesencephalic tract
Fibres terminate in periaqueductal grey matter and the midbrain raphe nuclei, both which give rise to fibres that modulate nociceptive transmission (‘descending pain-inhibiting system’).
Some other fibres terminate in parabrachial nucleus, which then sends fibres to amygdala (component of limbic system associated with processing of emotions).

17. 2nd order neuron: spinotectal tract
Terminate in deep layers of superior colliculus.
For turning upper body, head and eyes in the direction of painful stimulus.

18. 2nd order neuron: spinohypothalamic tract
Ascend to hypothalamus.
Associated with autonomic and reflex responses to nociception (e.g. endocrine and cardiovascular).

19. 3rd order neurons –spinothalamic tract
Cell bodies in thalamus.
ventral posterior lateral, ventral posterior inferior and intralaminar thalamic nuclei.
Ventral posterior lateral nucleus gives fibres to posterior limb of internal capsule and corona radiata. Terminate in primary somatosensory cortex S-I (postcentral gyrus). Also sends fibres to secondary somatosensory cortex S-II.

20. 3rd order neurons –spinothalamic tract
Ventral posterior inferior nucleus projects mostly to S-II but some to S-I.
Intralaminar nuclei projects to striatum (ie caudatae nucleus and putamen), S-I and S-II, cingulate gyrus and prefrontal cortex.
(Most nociception relaying fibres arriving at intralaminar nuclei transmit nociceptive information relayed there from reticular formation (have multiple synapses before arriving)).

21. 3rd order neurons –spinoreticular tracts
Signals transmitted from reticular formation to intralaminar nuclei of thalamus, hypothalamus, limbic system.
Hypothalamus-autonomic and reflex.
Limbic-emotional/’suffering’.

22. Pain to face and head Trigeminal nerve 3 branches:
Ophthalmic (V1) –scalp and forehead, upper eyelid, conjunctiva, cornea, nose, nasal mucosa, frontal sinus, meninges.
Maxillary (V2) –lower eyelid, cheeks, nares, upper lip, upper teeth/gums, nasal mucosa, palate and roof of pharynx, maxillary/ethmoid/sphenoid sinuses, meninges.
Mandibular (V3) – lower lip, lower teeth and gums, chin, and jaw (except angle), parts of external ear and meninges, mouth (not taste).
* V1 and V2 pure sensory, V3 mixed sensory and motor.

23. Pain to face and head
1st order neuron carried by trigeminal nerve (cell body in Trigeminal/ Gasserian ganglion) enter pons, descend to medulla forming the spinal trigeminal tract and synapse in spinal trigeminal nucleus (caudal part) 2nd order neurons cross midline and ascend as trigeminothalamic tract  VPM thalamus  3rd order neurons to sensory cortex

24. Pain pathway

25. Primary somatosensory cortex S-I
Postcentral gyrus of parietal lobe
Brodmann’s areas 3a,3b,1,2.
Processing of pain localisation, intensity, quality, and sensory integration at conscious level.
Also sends signals to secondary somatosensory cortex.

26. Sensory homunculus
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27. Secondary somatosensory cortex S-II
At parietal operculum, ceiling of lateral sulcus.
Brodmann’s area 43.
Function in memory of sensory input and sensory integration.

28. Other brain areas related to pain
From electroencephalography (EEG), functional MRI (fMRI), magnetoencephalography (MEG), positron emission tomography (PET).
Anterior cingulate cortex (ACC), anterior insular cortex, supplemental area of motor cortex.
ACC and anterior insular cortices connected to limbic cortex.

29. Visceral pain
Visceral organs themselves have no pain receptors. Pain receptors embedded in walls of arteries serving these organs.
Diffuse, poorly localised, ‘referred’ to another somatic structure.
Nociceptive signals follow same pathway as signals from somatic structures.
Receptors: free nerve endings or Pacinian corpuscles.
First order neurons: C, Aδ or Aβ fibres.
Respond to stretching, or ischaemia.
Second order neurons: spinothalamic and spinoreticular tract.

30. Modulation of nociception
Gate control theory of pain
Impulses flow from periphery to brain through a ‘gate’ at spinal level.
Site at substantia gelatinosa (lamina II) where pain is modulated.
Small nerve fibers (C fibres) and large nerve fibers (Aβ fibres) synapse with: projection cells, which go up the spinothalamic tract to the brain, and inhibitory interneurons within the dorsal horn.

31. Gate control theory

32. Descending pathway Not as well understood as ascending one.
Originate at cortex, thalamus and brainstem (Periaqueductal grey; raphe nuclei and locus coeruleus).
Relay stations in brainstem.
Main neurotransmitters: noradrenaline, serotonin and endogenous opioids (enkephalin, beta-endorphin and dynorphin).

33. Descending pathway

34. Descending pathway
PAG –main descending inhibitory control on the ‘gate’ mechanism in the dorsal horn. Has abundance opioid receptors and peptides. Connections with:
Nucleus raphe nucleus (serotonergic)  inhibitory interneurones.
Locus coeruleus (Noradrenergic)  dorsal horn.

35. Pain pathway examples

36. Pain pathway in labour Stage 1 labour (pain poorly localised)
Due to uterine (visceral) contractions and stretching cervix.
Sensation carried by mainly C-fibres  inferior, middle and superior hypogastric
plexus  travel with sympathetic chain associated with dorsal rami of T10-L1 spinal nerves referred visceral pain.

37. Pain pathway in labour 2nd stage labour (pain sharp)
direct pressure by the presenting part on vagina and perineum
Stimulation of pudendal nerve (S2-4).
Aδ fibres carry impulse via pudendal nerve (S2-4)  spinothalamic tract  somatosensory cortex.

38. Pain pathway in labour
Other pain sensitive structures in the pelvis are also involved, i.e. the adnexi, the pelvic parietal peritoneum, bladder, urethra, rectum and the roots of the lumbar plexus.
Therefore L2 to S5 must  also be blocked. There is an overlap and pain relief is not a simple matter of blocking T10 to L1 for the first stage and S2, 3, 4 for the second stage of labour.

39. Caesarean section
Higher block level (T4) due to peritoneal manipulation.

40. Pain pathway cornea
Cornea  long ciliary nerves (also has sympathetic fibres) and short ciliary nerves (also has parasympathetic fibres +/- sympathetic)nasociliary nerve ophthalmic division trigeminal nerve (V1) (cell body in Trigeminal/ Gasserian ganglion) enter pons, descend to medulla forming the spinal trigeminal tract and synapse in spinal trigeminal nucleus (caudal part) 2nd order neurons cross midline and ascend as trigeminothalamic tract  VPM thalamus  3rd order neurons to sensory cortex
*note sensory to conjunctiva:lacrimal branch V1 , vision:optic nerve.

41. Pain pathway -Cornea
Taken from Grey’s Anatomy.