Pain systems Domina Petric, MD

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.

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.

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.

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).

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.

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)

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)!

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

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

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.

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.

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

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

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.

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

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?

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)

Pain and temperature pathways II.

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

Anterolateral system

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

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.

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.

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

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.

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.

Literature https://www.coursera.org/learn/medical-neuroscience: Leonard E. White, PhD, Duke University