F2- Nociceptors and Pain

Nociceptors and Pain Pathways

• Nociceptors are nerve cell endings that detect pain. They originate in dorsal root ganglia (or trigeminal ganglion) and have one axon extending to the periphery and another to the spinal cord/brainstem.
• Nociceptors' axons conduct pain signals slowly, either lightly myelinated (Aδ fibers, 5-30 m/s) or unmyelinated (C fibers, <2 m/s).
• Two main types of pain are perceived: sharp first pain (Aδ fibers) and delayed, diffuse second pain (C fibers).
• Type I Aδ fibers respond to intense mechanical/chemical stimuli but have high heat thresholds, while Type II Aδ fibers have low heat thresholds but high mechanical thresholds.
• C fibers are polymodal, responding to thermal, mechanical, and chemical stimuli. Subsets are specialized for heat or chemical stimuli.
• Nociceptive threshold for heat is around 43°C (110°F).
• TRPV1 (vanilloid receptor) is a transient receptor potential channel, sensitive to noxious heat and found in both Aδ and C fibers; activated by sodium and calcium influx triggering action potentials. Mechanoreceptors less understood, but include other TRP family members (TRPV4), Piezo2, ASICs.

Central Pain Pathways

• Pain pathways begin in dorsal root ganglia. Central axons enter the dorsal roots of the spinal cord.
• Nociceptive axons branch into ascending and descending collaterals in Lissauer's tract, then dorsal horn grey matter.
• Axons in the dorsal horn contact second-order neurons in Rexed's laminae I, II, and V.
• Laminae I and V neurons project to brainstem/thalamus.
• C fibers terminate exclusively in laminae I and II, while Aδ fibers terminate in laminae I and V.
• Wide-dynamic-range (WDR) neurons in lamina V receive nociceptive and non-nociceptive input (potential for referred pain).
• Second-order neurons cross the midline (anterolateral/ventrolateral quadrant) to brainstem.
• Anterolateral system conveys pain and temperature info.

Parallel Pain Pathways

• Spinothalamic tract (anterolateral system part) mediates pain's sensory-discriminative aspects: location, intensity, quality.
• Information from laminae I and V-VII relayed to VPL nucleus, and then to primary/secondary somatosensory cortex.
• Spinoreticular and spinomesencephalic tracts convey pain's affective-motivational aspects (unpleasantness, fear, autonomic response).
• These tracts project to the reticular formation, periaqueductal gray, superior colliculus, and parabrachial nucleus.
• Parabrachial nucleus relays second pain to amygdala, hypothalamus, and medial thalamic nuclei.
• Medial thalamic nuclei project to anterior cingulate cortex and insula, which contribute to affective/motivational pain aspects.
• Pain matrix: interconnected areas like somatosensory cortex, insula, amygdala, and anterior cingulate cortex, active during pain experience. Stimulus intensity mainly affects somatosensory cortex, while unpleasantness mainly affects cingulate cortex.

Pain and Temperature Pathways for the Face

• Pain/temperature from the face originates from neurons in the trigeminal ganglion and cranial nerves VII, IX, and X.
• Trigeminal fibers enter the pons, descend to medulla, forming spinal trigeminal tract.
• Fibers terminate in pars interpolaris and pars caudalis of spinal trigeminal nucleus.
• Second-order neurons cross the midline to brainstem/thalamic targets.
• Discriminative aspects of facial pain mediated by contralateral VPM nucleus (trigeminothalamic tract) projections to primary/secondary somatosensory cortex.
• Affective aspects mediated by connections to reticular formation, parabrachial nucleus, and medial thalamic nuclei projecting to cingulate/insular cortex.

Nociception - Thalamic Nuclei and Primary Somatosensory Cortex

• VPL nucleus receives spinothalamic pathway info from body, VPM receives trigeminothalamic pathway info from face.
• Medial thalamic nuclei (central lateral and intralaminar complex) process affective/motivational aspects of nociception.
• Primary somatosensory cortex receives info from lateral nuclear group, but cingulate and insular cortices more active with nociceptive stimuli.

Pain Modulation

• Descending pain-modulating pathways project to dorsal horn, regulating pain signals. Periaqueductal gray (PAG) is a crucial area.
• Cingulate and insular cortices modulate pain via descending pathways to PAG.
• Animal studies show PAG stimulation elicits analgesia without impacting other senses. PAG connections inhibit projection neurons in laminae I and V (spinothalamic pathway) and laminae I, II, and V (other pain pathways), especially in the Locus Coeruleus (noradrenergic) and Nucleus Raphe Magnus (serotonergic) regions.

Peripheral Regulation of Pain Perception (Gate Control Theory)

• Wall and Melzack's gate control theory describes peripheral modulation.
• Projection neuron in spinal cord receives inputs from C fibers (exciting) and inhibitory interneurons.
• A-beta fibers inhibit the interneuron, reducing the projection neuron firing rate.

C-Tactile Afferents

• Recent discovery of a class of C fibers that transmit gentle touch.
• C-tactile fibers are low-threshold mechanoreceptors in hairy skin. Likely associated with positive autonomic responses and project to posterior insula.
• May play a role in pain modulation.

Social Pain

• Cingulate and insular cortices process social pain (visual pain observation).
• Area activation is similar to actual pain experience.
• Anterior cingulate cortex processes emotional state, insular cortex processes internal body state.

Insular Cortex in Pain

• Insular cortex topographically organizes nociceptive information, from posterior (foot) to anterior (face).
• Represents ascending sympathetic and parasympathetic system afferents, integrating nociceptive with arousal/autonomic responses.

Social Touch & Social Pain

• Study by Keysers demonstrates mirroring of somatosensory sensations between people.
• Observing another person feeling touch activates somatosensory areas in observer, similar to actual touch, overlapping in SII/VP.
• Common activation areas in pain and pain observation (anterior insula, middle cingulate cortex).
• Anterior insula and anterior cingulate cortex thought to mediate pain empathy.