In one breath
Pain is an unpleasant sensory and emotional experience tied to actual or threatened tissue damage, and it is detected by nociceptors, which are free nerve endings. Thin myelinated Aδ fibers carry the sharp, well-localized fast pain at 10–30 m/s; unmyelinated C fibers carry the dull, diffuse slow pain at 0.5–2 m/s. In the dorsal horn, Aδ fibers end in laminae I and V and C fibers in lamina II.
Builds on: Sensory receptors and their classification · Afferent fibers, dorsal root and spinal laminae · Leads to: Pain pathways and perception · Visceral and referred pain · Endogenous pain control and gate control theory
General concepts
- Pain is usually the first sign of disease, and its purpose is protective.
- Almost everyone knows it, and a painful experience, whether from injury or punishment, stays in the memory.
- People call it throbbing, burning, piercing, aching or lacerating, yet the exact feeling is hard to put into words.
Definition
The IASP (International Association for the Study of Pain) definition, in its key words:
- an unpleasant experience,
- both sensory and emotional,
- linked to actual or potential tissue damage,
- or described in terms of such damage.
- Worth knowing, though not in your pages: IASP reworded it in 2020, so that the experience is linked with, or resembles one linked with, actual or potential tissue damage. Your book gives the older wording, which is what the examiner expects.
Nociceptive stimuli
- A noxious (nociceptive) stimulus is one that damages tissue or threatens to. The sensation it produces is nociception.
- What counts as noxious differs from tissue to tissue:
- Skin: pricking, cutting, crushing, burning, freezing
- Gut: inflamed mucosa, distension or spasm of its smooth muscle, pull on the mesentery
- Skeletal muscle: ischemia, necrosis, hemorrhage, an injected irritant, injury to its connective-tissue sheath
- Heart muscle: ischemia or inflammation
- Joints: inflamed synovium, hypertonic saline on the synovium, stretched or torn ligaments
- Blood vessels: a needle through the wall, inflammation, thrombotic or embolic block, the excessive pulsation of migraine
- Brain: traction on the cerebral arteries or the meninges
- Nerves: compression of a nerve root or sensory ganglion; a lesion inside a nerve hurts through the nerve sheath
Types of pain
Fast pain and slow pain
- One painful stimulus gives two waves: first a sharp, well-localized pain, then a dull, diffuse one.
- The first is fast (first) pain, carried by Aδ fibers. The second is slow (second) pain, carried by C fibers. The full comparison is at the end of this page.
Other contrasts
| Pair | First kind | Second kind |
|---|---|---|
| Superficial vs deep | skin, subcutis; usually fast | bone, muscle, connective tissue; usually slow (C fibers) |
| Somatic vs visceral | from somatic structures | from viscera |
| Peripheral vs central | receptors or nerves stimulated directly (neuralgia) | central pain fibers stimulated (below a cord transection) |
- Visceral pain has a page of its own: Visceral and referred pain.
Physiologic and pathologic pain
- Physiologic pain is acute pain. It starts suddenly and fades as the tissue heals or is treated. It is the “good” pain, because it protects.
- Pathologic pain is chronic pain. It persists after the injury has healed or been treated, and it usually does not yield to ordinary anti-inflammatory analgesics. It is the “bad” pain, and it comes in two kinds:
- Neuropathic: from nerve damage, as in long-standing diabetes, ischemia or toxins.
- Inflammatory: from inflammatory disease such as rheumatoid arthritis. It usually comes with hyperalgesia and allodynia (Specific pain syndromes).
Nociceptors
- Pain receptors are nociceptors, and they are free nerve endings.
- They are found in most tissues. The neural tissue of the brain has none, but the brain’s coverings are rich in them.
- Three broad groups:
| Nociceptor | Fiber | Fires to |
|---|---|---|
| Aδ mechanical | Aδ (thin, myelinated) | intense mechanical stimuli only |
| Polymodal C | C (fine, unmyelinated) | intense mechanical, chemical, hot and cold stimuli |
| Others | Aδ or C | extreme heat or cold; strong mechanical force |
Aδ mechanical nociceptors
- Endings of Aδ fibers: small myelinated axons about 1–5 µm across, conducting at 10–30 m/s.
- They fire only to intense mechanical stimuli, not to heat or chemicals.
- They carry fast pain.
Polymodal C-fiber nociceptors
- Endings of C fibers: fine unmyelinated axons about 0.3–1.2 µm across, conducting at 0.5–2 m/s.
- Polymodal (your book also says multimodal), because strong mechanical, chemical and thermal stimuli, hot or cold, all fire them.
- In practice they respond mostly to heat (skin at 45°C or more) and to chemicals applied locally.
- They carry slow pain.
Micrometres, not millimetres
Nerve fibers are measured in µm. If your copy prints the fiber sizes as “1–5 mm” and “0.3–1.2 mm”, read them as µm.
Other nociceptors
- Thermal nociceptors: Aδ and C endings that fire to extreme cold (below 5°C) or extreme heat (above 45°C).
- Aδ fibers that respond to heat, and C fibers that respond only to strong mechanical stimuli (these are not polymodal).
- Three receptors for thermal pain have been cloned: CMR1, VR-1 and VRL-1.
- VR-1 and VRL-1 are the vanilloid receptors for painful heat. Your book names them after the vanillins, a family of pain-producing compounds that includes capsaicin.
Vanilloid receptors
| Receptor | Found on | Fires to |
|---|---|---|
| VR-1 | C-fiber endings | capsaicin; heat above 43°C; change in pH |
| VRL-1 | C fibers | heat above 50°C, but not capsaicin |
- So C-fiber endings seem to carry several receptor types for different stimuli. Or there may be several separate C-fiber systems.
The TRP family of ion channels
- CMR1, VR-1 and VRL-1 all belong to the transient receptor potential (TRP) family of excitatory ion channels.
- VR-1 has a binding site for PIP₂. The less PIP₂ is bound, the more sensitive this heat nociceptor becomes.
- How these receptors work is not yet fully understood. (The “not” has dropped out of your book’s sentence.)
- A skin receptor can depolarize in three ways: its K⁺ channels close (less K⁺ leaves), its Na⁺ channels open (Na⁺ enters), or its Na⁺–K⁺ pump is inhibited.
- Cool receptors depolarize by Ca²⁺ influx.
Menthol, not methanol
CMR1 is the cold- and menthol-sensitive receptor 1. Menthol is the cooling compound of mint; your book prints “methanol”, which is a different substance.
- Worth knowing, though not in your pages: VR-1 is now called TRPV1, VRL-1 TRPV2 and CMR1 TRPM8. Chilli feels hot and mint feels cool because capsaicin and menthol open these same channels. The compound family is properly called the vanilloids; vanillin itself is the flavour of vanilla.
Where pain fibers end in the spinal cord
- Cell bodies: the dorsal root ganglion (DRG). The fibers enter the cord through the dorsal horn.
- Pain fibers from the head go instead to the nucleus of the trigeminal nerve, the medulla’s version of the dorsal horn (Trigeminal pathway and trigeminal neuralgia).
- Inside the dorsal root, pain fibers run in its most lateral part.
- In the dorsal horn: Aδ fibers → laminae I and V; C fibers → lamina II.
- Ascending pain fibers run in the lateral funiculus (lateral fasciculus). The thinnest ones, the C fibers, form their own bundle, Lissauer’s tract, which also carries a few deep-sensory and propriospinal fibers.
- Worth knowing, though not in your pages: lamina II is the substantia gelatinosa, the site of the “gate” in gate control theory. In Lissauer’s tract (the dorsolateral fasciculus), entering fibers run up or down a few segments before they enter the grey matter.
Draw it: where pain fibers end in the dorsal horn
- Draw one half of a spinal cord section. Divide the dorsal horn into laminae: I as a thin cap at the tip, II just under it, then III–IV, and V at the neck of the horn.
- Bring in a dorsal root from its ganglion, with the pain fibers at its lateral edge, passing through Lissauer’s tract at the tip of the horn.
- End an Aδ fiber in laminae I and V, and a C fiber in lamina II. Label each with its speed.
- From the dorsal horn, draw a second-order axon crossing to the opposite anterolateral white matter and turning up as the spinothalamic tract.
Specificity of nociceptors
Three theories set out to explain what makes a stimulus painful:
| Theory | Claim |
|---|---|
| Specificity | pain is its own modality, with its own receptors and pathway |
| Overstimulation | any afferent ending, driven hard enough, signals pain, by various pathways |
| Pattern | a particular pattern of receptor firing is read as pain |
- Your book’s verdict: specificity theory explains pain, and its receptors and pathways are specific.
Dermatomal distribution of pain fibers
- Somatic pain fibers follow the body’s sensory map of dermatomes (Afferent fibers, dorsal root and spinal laminae), which helps a physician find the level of a lesion.
- Deep structures are also supplied segment by segment, but their pattern does not fully match the skin map:
| Segments | Main supply |
|---|---|
| T1–T4 | thoracic organs (heart, lungs) |
| T6–T8 | upper abdominal organs |
| T10–L2 | lower abdominal viscera |
Localization
- Sharp pain localizes better than dull pain. It keeps its dermatomal representation and its somatotopic map in the CNS.
- Pain in general localizes less well than other sensations. Pain endings are sparse (low innervation density), and pain pathways branch more than any other sensory pathway.
- Visceral pain localizes worst of all. Viscera have few receptors and a poor cortical map (Visceral and referred pain).
- Worth knowing, though not in your pages: nociceptors adapt very little, so pain lasts as long as the damaging stimulus does, and ongoing damage can make them more sensitive still.
Fast and slow pain compared
| Feature | Fast pain | Slow pain |
|---|---|---|
| Other name | first pain | second pain |
| Feels | sharp, well localized | dull, diffuse |
| Fiber | Aδ, thin myelinated | C, unmyelinated |
| Diameter | 1–5 µm | 0.3–1.2 µm |
| Speed | 10–30 m/s | 0.5–2 m/s |
| Nociceptor | Aδ mechanical | polymodal C |
| Dorsal horn | laminae I and V | lamina II |
| Pathway | neospinothalamic | paleospinothalamic |
| Thalamus | VPL (specific) | intralaminar, midline (non-specific) |
| Role | where, what kind, how strong | arousal, emotion, autonomic |
| Usual source | superficial (skin) | deep tissues, viscera |
- Worth knowing, though not in your pages: fast pain is felt within about 0.1 s of the stimulus, while slow pain begins after 1 s or more and builds over seconds to minutes. Guyton splits the transmitters: Aδ endings release glutamate, and C endings release glutamate and substance P.
Exam-answer skeleton: "Fast and slow pain" (short note)
- Define pain (IASP), and describe the two waves that follow one stimulus.
- The fibers: Aδ vs C, with diameters and conduction speeds, and the nociceptor each one ends in.
- Where they end in the dorsal horn (laminae I and V vs lamina II), with the diagram.
- The pathways: neo- vs paleospinothalamic, with their thalamic nuclei and cortical targets (Pain pathways and perception).
- The functions: localization and intensity for fast pain; arousal, emotion and autonomic effects for slow pain; why slow pain is poorly localized.
- Superficial pain is mostly fast; deep and visceral pain are mostly slow.
- Close with the comparison table.
Asked in exams
- Fast and slow pain: Mar 2024, 5 marks