1. Pain systems
Domina Petric, MD

2. Nociception
Nociception is perception of pain (modality of somatic sensation).
There is affective component of pain which is very important.
Secondary affect phenomenon exmplains how the impact of chronic pain affects the emotional life.
Psychosocial context is very important in understanding pain: it has significant impact in modulating the experience of pain.

3. Pain Free nerve endings of pheripheral axon is the receptor for pain.
Cell body of first order neuron is in the dorsal root ganglion.
Central process of first order axon synapses with the second order neuron in the dorsal horn of the spinal cord.

4. Receptors, fibres
Free nerve endings are receptors for sensation of pain.
Free nerve endings distribute broadly within the tissues: large receptive fields.
Pain fibres are Aδ fibres and C fibres (unmyelinated).
Aδ fibres include axons that are sensitive to mechanical stimulation that can lead to nociception.
There is also a type of Aδ fibre that is sensitive to both mechanical energy and thermal energy when there is a risk for tissue damage.
Conduction velocity of C fibres is smaller than the Aδ fibres.

5. Receptors, fibres
C fibres are polymodal: respond to multiple modalities of energy or chemical conditions that can potentially cause damage to tissue (mechanical, thermal, chemical stimuli).

6. Sensory transduction in nociceptors
Channels in nociceptors belong to the transient receptor potential family of ion channels.
TRP channels may be sensitive to heat or cold or protons in accidic conditions.
TRP channels have modulatory sites for organic compounds (capsaicin).
When TRP channels open, cations like sodium and calcium ions can influx into the cell.
If there is potential above the treshold, we call it action potential.

7. Dorsal horn of the spinal cord
Substantia gelatinosa (lamina 2 of the dorsal horn): second order neuron for processing pain.
C fibres terminate superficially in the marginal zone (lamina 1) and in the substantia gelatinosa (lamina 2).
Aδ fibres terminate more deeply (laminae 5 and 6)

8. Two categories of pain sensation
Sharp shooting pain
Throbbing pain
Also called first pain that subsides in a matter of seconds.
Aδ fibres give rise to projections that go directly to the thalamus (ventral posterior complex) after the laminae 5 and 6.
Signals go to somatosensory cortex in postcentral gyrus.
Localisation of nociception!
Also called second pain that evolves more slowly and persist for longer period of time.
C fibres give rise to projections (after the laminae 1 and 2) that go into the brainstem and some of the fibres go to the thalamus (synapse in medial nuclei of the thalamus).
Emotion and cognition about nociception (ventral and medial parts of the forebrain or limbic system)!

9. Second pain pathway First pain: spinothalamic tract
Anterior cingulate cortex, insular cortex
Somatosensory cortex (S1, S2)
Reticular formation, superior colliculus, periaqueductal gray, hypothalamus, amygdala
Ventral posterior lateral thalamic nucleus
Midline thalamic nuclei
Cross midline
Crossing midline
Second order neuron: laminae 5 and 6
Second order neuron: laminae 1 and 2 Aδ C

10. Reticular formation and periaqueductal gray matter
multiple small nuclei
level of arousal and attention
modulation of cognition and responses to pain
Periaqueductal gray matter:
top down or the feedback modulation of pain transmission in the dorsal horn of the spinal cord

11. Insular and anterior cingulate cortex
Insular cortex: processing emotional signals, building an image of the body that is especially informed about the internal state.
Anterior cingulate cortex: participates in prefrontal cortical networks that are involved in evaluating the significance of the consequence of our actions.

12. Hyperalgesia Enchanced sensitivity to mechanosensory stimulation.
Tissue damage causes tissue inflammation and immune response.
Immune mediators have impact on the nociceptors (free nerve endings): bradykinins, ATP, prostaglandins, histamin, hydrogen ions...
Immune mediators can increase currents that flow through TRP channels of the nociceptors: there is an increase of sensitivity of free nerve endings.
Allodynia: stimulus is perceived as painfull, although there is no tissue damage.

13. Wind up phenomenon
When there is repeated activation of nociceptors, it leads to sustained depolarisation of that neuron.

14. Descending pathways that modulate pain
Somatic sensory cortex
Anterolateral
system
Amygdala
Hypothalamus
Periaqueductal gray
Parabrachial nucleus
Medullary reticular formation
Locus coeruleus
Raphe nuclei
Dorsal horn of spinal cord

15. Descending pathways that modulate pain
Periaqueductal grey is a key node in a network that allows for the feedback modulation of pain.
Locus coeruleus releases norephinephrine in the dorsal root of the spinal cord and raphe nuclei release serotonin.

16. Gate theory of pain (feed forward modulation of nociception)
Activation of, for example, mechanoreceptors can, because of competition with stimulated nociceptors, inhibit nociceptors.

17. Chronic pain
Nociceptive chronic pain results from ongoing stimulation of nociceptors.
Involves both first and second pain.
Chronic pain syndrome is chronic pain with no known nociceptive etiology.
Dysregulation of feedback descending systems?

18. Neuropathic pain
Abnormal activity in nociceptive pathway unrelated to the presence of a nociceptive stimulus.
Mechanisms:
nerve compression
abnormal somatic sensation
sustained senzitisation of neurons in nociceptive pathway
abnormal activity in sympathetic outflow to viscera
maladaptive plasticity in higher centers (phantom sensation)

19. Pain and temperature pathways
II.

20. Two pairs of somatosensory pathways
Post-cranial body: posterior part of the head and body below the head
Dorsal column medial lemniscal system: mechanical stimuli
Anterolateral system: pain and temperature
Face and anterior portion of the head
Pathway through the principal sensory trigeminal complex nucleus: mechanical stimuli
Pathways through the spinal trigeminal complex nucleus: pain and temperature

21. Anterolateral system

22. Second pain pathway First pain: spinothalamic tract
Anterior cingulate cortex, insular cortex
Somatosensory cortex (S1, S2)
Reticular formation, superior colliculus, periaqueductal gray, hypothalamus, amygdala
Ventral posterior lateral thalamic nucleus
Midline thalamic nuclei
Cross the midline
Cross the midline
Second order neuron: laminae 5 and 6
Second order neuron: laminae 1 and 2 Aδ C

23. Spinothalamic tract
Second order neurons cross the midline in the ventral white commissure of the spinal cord and enter the anterolateral white matter of the spinal cord.

24. Trigeminothalamic tract: pain and temperature from face
First order neuron is in the trigeminal ganglion and sends axons that are descending in the spinal trigeminal tract (afferent axons).
Those axons synapse in the spinal nucleus of the trigeminal complex.
From the spinal nucleus neuron grows an axon that enters the lateral tegmentum of the brainstem and ascends.
Third order neuron is in the ventral posterior medial thalamic nucleus.

25. Trigeminothalamic tract: pain and temperature from the face
Somatosensory cortex
Third order neuron: ventral posterior medial thalamic nucleus
First order neuron: trigeminal ganglion
Axons ascend the lateral tegmentum
Spinal trigeminal tract:
descending afferent
first order axons
Axons cross the midline
Second order neuron: spinal nucleus of trigeminal complex

26. Dissociated sensory loss
Loss of pain and temperature on the one side of the body and loss of mechanosensation on the other side of the body when there is one-sided lesion of the spinal cord.

27. Dorsal column visceral pain pathway
Visceral pain is derived from Aδ fibres and C fibres that are innervating the viscera.
Their axons then join the anterolateral pathway.
There is an additional pathway that runs in dorsal columns.
From dorsal columns axons after crossing midline go via the medial lemniscus to the ventral posterior thalamic nuclear complex and then to the insular cortex.
Insular cortex serves as a somatosensory cortex for the viscera.

28. Literature
Leonard E. White, PhD, Duke University