Show the model answerAttempt it first — that is what makes it stick
The pathway from the finger
What earns the marks
| Receptor | Free nerve endings; transduction to action potentials |
|---|---|
| Fibres | Aδ first pain, C second pain, in the digital nerves |
| First-order neurone | Cell body in the dorsal root ganglion, C6 to C8; synapse in the dorsal horn |
| Second-order neurone | Crosses; contralateral spinothalamic tract to the thalamus |
| Third-order neurone | Thalamus to somatosensory cortex |
Read the question: “Briefly outline” is a limit. One line per neurone and a labelled diagram answer it; the remaining two sentences of the question, a definition and a mechanism, are where the detail belongs.
The ascending pathway, in three neurons
Read it from the bottom. The first-order neuron has its cell body in the dorsal root ganglion, outside the cord, and synapses in the dorsal horn. The second-order neuron starts in the dorsal horn, crosses in the cord and ascends on the opposite side. At the brainstem the projection divides: the lateral, neospinothalamic route relays in the ventral posterolateral nucleus (VPL) and reaches the primary somatosensory cortex, which is where and how intense; the medial, paleospinothalamic route passes through the reticular formation and periaqueductal grey to the intralaminar nuclei and on to the cingulate and insula, which is how unpleasant. The third-order neuron runs from thalamus to cortex. From the face the plan is the same, with the first-order cell body in the trigeminal ganglion, the second in the spinal trigeminal nucleus and the third in the ventral posteromedial nucleus.
| Step | Structure | Detail |
|---|---|---|
| Transduction | Nociceptors in the skin of the finger | Free nerve endings. Noxious heat, pressure or chemicals open TRPV1, ASIC and P2X3 channels; the generator potential fires action potentials through voltage-gated Na⁺ channels |
| Fibres | Digital nerves, branches of the median, ulnar and radial nerves | Aδ, thinly myelinated, 12 to 30 m/s: sharp, localised first pain. C, unmyelinated, 0.5 to 2 m/s: dull, burning second pain |
| First-order neurone | Cell body in the dorsal root ganglion: C6 for the thumb, C7 for the middle three fingers, C8 for the little finger | Enters the cervical cord by the dorsal root, runs 2 to 3 segments in Lissauer's tract, and synapses in the dorsal horn: Aδ in laminae I and V, C in lamina II. Glutamate and substance P |
| Second-order neurone | Cell body in the dorsal horn | Crosses in the ventral white commissure within one or two segments, and ascends in the contralateral anterolateral quadrant as the spinothalamic tract |
| Third-order neurone | Cell body in the thalamus | Ventral posterolateral nucleus, through the internal capsule, to the primary and secondary somatosensory cortex of the opposite hemisphere: where and how intense. Medial projections to the cingulate and insula: how unpleasant |
In the dorsal horn, Aδ input also initiates the rapid withdrawal of the finger through a spinal reflex, and the difference in conduction velocity is why a sharp pain is felt first and a dull ache follows it.
What is primary hyperalgesia?
What earns the marks
| Hyperalgesia | Increased pain from a stimulus that normally hurts: a leftward shift of the stimulus-response curve |
|---|---|
| Primary | At the site of injury, from sensitisation of the nociceptors there |
| Features | Lower threshold, more pain above threshold, spontaneous pain; to heat and to mechanical stimuli |
| The contrast | Secondary hyperalgesia: uninjured tissue around the injury, central, mechanical only |
Read the question: “What is” asks for the definition and what marks it out. Primary hyperalgesia is peripheral and extends to heat; secondary hyperalgesia is central and mechanical only. Without that contrast, “primary” has not been explained.
| Primary hyperalgesia | Secondary hyperalgesia | |
|---|---|---|
| Where | The injured tissue | The uninjured tissue around it |
| Where the change is | The nociceptor terminal: peripheral sensitisation | The dorsal horn: central sensitisation |
| More pain from | Heat and mechanical stimuli | Mechanical stimuli only |
| How it shows | Lower pain threshold; more pain from stimuli above threshold; spontaneous pain | Allodynia and tenderness to touch |
Two zones around an injury, and what sensitisation does to the response
A. Primary hyperalgesia is in the injured tissue and is peripheral; secondary hyperalgesia is in the uninjured tissue around it and is central. The discriminator is heat: the primary zone is more sensitive to thermal and mechanical stimuli, the secondary zone to mechanical stimuli only. B. Sensitisation moves the stimulus-response curve left and up. Left is a lower threshold, so a stimulus that was not painful now is (allodynia); up is more pain from a stimulus that already was (hyperalgesia). The axes are deliberately unnumbered: the sources give the direction of the shift, not a scale.
The mechanisms by which primary hyperalgesia develops
What earns the marks
| The mediators | Released from damaged cells, mast cells, platelets and immune cells, or made at the site |
|---|---|
| Activation against sensitisation | Some make the terminal fire; others lower its threshold |
| The cellular mechanism | G-protein-coupled receptors, second messengers and kinases phosphorylate TRPV1 and Na⁺ channels |
| What changes in the nociceptor | Lower threshold, greater discharge, spontaneous discharge |
| Recruitment | Silent nociceptors become responsive |
| Spread | Neurogenic inflammation: substance P, CGRP and neurokinin A released from the terminals |
| Gene expression | Nerve growth factor, through trkA, increases synthesis of neuropeptides and ion channels |
Read the question: The mechanism asked for is peripheral. Wind-up, the NMDA receptor and central sensitisation explain secondary hyperalgesia; here they are worth a sentence of contrast at most.
How injury sensitises the nociceptor
The inflammatory soup
Acting on the terminal
Activation and sensitisation are different actions
| Activate: make the terminal fire | Sensitise: lower its threshold |
|---|---|
| Potassium | Prostaglandins |
| Serotonin | Leukotrienes |
| Bradykinin | Substance P |
| Hydrogen ion | Noradrenaline |
| Histamine | Neurokinin A and B |
| ATP and adenosine | Calcitonin gene-related peptide |
| Nitric oxide |
- Bradykinin does both, through its B2 receptor.
- Prostaglandins, mainly PGE2, sensitise rather than stimulate: through EP receptors they phosphorylate Na⁺ channels and TRPV1, so the terminal responds to mechanical, chemical and thermal stimuli it previously ignored. This is why an NSAID acts on the hyperalgesia of inflammation rather than on the stimulus itself.
Mechanisms that sustain it
| Mechanism | How | Effect |
|---|---|---|
| Channels already present are modified | Phosphorylation through second messengers and kinases | Lower threshold and greater discharge of the nociceptors already active |
| More afferents are recruited | Silent nociceptors, unresponsive in normal tissue, respond once it is inflamed | More fibres firing, as well as each fibre firing more |
| Mediators amplify one another | Cytokines from immune cells release other mediators: interleukin-1β and interleukin-6 release prostaglandins; tumour necrosis factor α and interleukin-1β stimulate nerve growth factor production | The soup keeps itself going while inflammation lasts |
| Gene expression changes | Nerve growth factor, from fibroblasts, Schwann cells and keratinocytes, acts through trkA and alters gene transcription | More neuropeptides (neurokinins and CGRP) and ion channels are made. Receptors and channels on the nociceptor, TRPV1 and Nav1.8 among them, adapt in ways that lower its firing threshold |
| Resolution | Inflammation settles as the tissue heals | Peripheral sensitisation diminishes and nociceptors return to their resting threshold |
Primary hyperalgesia is protective: it helps prevent tissue that is already damaged from being damaged further. It becomes a problem when the inflammation does not resolve and the sensitised periphery keeps driving the dorsal horn.