Show the model answerAttempt it first — that is what makes it stick
(a) The immediate local tissue response 4 marks
The scenario gives the frame: the wound becomes increasingly painful. Part (a) is the local response that makes that happen, from the first mediators to the first action potential, and then what turns the signal up over the hour.
What earns the marks4 marks
| Answered as pain | The responses that generate and amplify the pain signal, not bleeding and clotting |
|---|---|
| Mediators | K⁺, H⁺, ATP, bradykinin, serotonin, histamine released; prostaglandins, cytokines and NGF made at the site |
| Transduction | Mediators open channels on nociceptor terminals: a generator potential |
| Sensory nerve action potential | Threshold, Na⁺ influx, K⁺ efflux, all-or-none, frequency coding, propagation |
| Peripheral sensitisation | Lower threshold, faster and spontaneous firing, silent nociceptors recruited: primary hyperalgesia |
| Neurogenic inflammation | Axon reflex releases substance P and CGRP: vasodilatation, oedema, spreading sensitisation |
Commonly lost: Answers built on vasoconstriction and haemostasis earned nothing: the stem says the wound becomes increasingly painful, and (a) had to be answered in relation to pain.
1 · Within seconds: what the injured tissue releases
| Mediator | Source | Action on the nociceptor terminal |
|---|---|---|
| Potassium | Released from damaged cells | Depolarises the terminal directly: activates |
| Hydrogen ion | Injured, ischaemic tissue | Opens ASIC and TRPV1: activates, and sensitises |
| ATP | Released from damaged cells | Opens P2X3: activates |
| Bradykinin | Generated in injured tissue | B2 receptor: a potent algesic that both activates and sensitises |
| Serotonin | Platelets | 5-HT3: depolarises C and A fibres; activates |
| Histamine | Mast cells | Activates |
| Prostaglandins | Made from membrane arachidonic acid by cyclo-oxygenase | Sensitise rather than activate: lower the threshold for everything else |
| Cytokines, IL-1β and TNF-α | Immune cells drawn to the site | Hyperalgesic; stimulate prostaglandin and nerve growth factor production |
| Nerve growth factor | Fibroblasts, Schwann cells, keratinocytes | trkA receptor: increases neuropeptide and ion channel synthesis over hours |
2 · Transduction, and the sensory nerve action potential
From mediator to action potential in the nociceptor
The action potential
Commonly lost: Even among relevant answers, many gave too little physiological detail of the sensory nerve action potential: threshold, the ionic events and propagation each carry marks.
3 · Over the next hour: why it hurts more
| Change at the nociceptor | Mechanism | Consequence |
|---|---|---|
| Activation threshold falls | Mediators act through G-protein-coupled receptors and kinases that phosphorylate the terminal's ion channels; prostaglandins are the classic sensitisers | Stimuli that were not painful now are |
| Faster discharge when activated | Same | The same stimulus sends more impulses |
| Spontaneous discharge | Same | Pain at rest, without a stimulus |
| Silent nociceptors wake | Unresponsive in normal tissue, responsive once it is inflamed | More afferents firing, not only each one firing more |
| Gene expression changes | Nerve growth factor through trkA | More neuropeptides and channels over hours |
The result is primary hyperalgesia, confined to the injured tissue: greater pain from mechanical and thermal stimuli at the wound. That is the physiological answer to the stem’s “increasingly painful”.
4 · Neurogenic inflammation: the nerve inflames its own territory
- An impulse in one branch of a nociceptor runs centrally and antidromically into the fibre’s other branches: the axon reflex.
- Those terminals release substance P, neurokinin A and CGRP: vasodilatation, plasma extravasation and oedema, and mast cell degranulation.
- Histamine from mast cells and serotonin from platelets then activate and sensitise neighbouring nociceptors, so tenderness spreads beyond the first terminals.
- Visible at the skin as the triple response: a red reaction (capillary dilatation), a wheal (increased permeability) and a spreading flare (arteriolar dilatation through the axon reflex, lost if the skin’s sensory nerves have degenerated).
(b) Pain transmission after the local response 3.5 marks
What earns the marks3.5 marks
| The right terms | First-, second- and third-order neurones, each placed correctly |
|---|---|
| First-order neurone | Aδ and C fibres; cell body in the dorsal root ganglion; synapse in the dorsal horn |
| The dorsal horn synapse | Laminae I and V (Aδ), II (C); glutamate and substance P |
| Second-order neurone | Crosses in the anterior white commissure within one or two segments; contralateral spinothalamic tract |
| Third-order neurone | Thalamus to cortex: VPL to somatosensory cortex; medial nuclei to cingulate and insula |
Commonly lost: Answers were expected to use first-, second- and third-order neurones, and the dorsal horn was confused with the dorsal root ganglion.
Commonly lost: Describing the reflex arc instead of the ascending pathway earned nothing, and nor did repeating the local tissue response from (a).
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.
| Order | Cell body | Course | Ends in |
|---|---|---|---|
| First | Dorsal root ganglion, outside the cord | Pseudounipolar. Aδ (thinly myelinated, 12 to 30 m/s, sharp first pain) and C (unmyelinated, 0.5 to 2 m/s, dull second pain). Enters through the dorsal root and divides in Lissauer's tract over 2 to 3 segments | Dorsal horn: Aδ to laminae I and V, C to lamina II (substantia gelatinosa). Releases glutamate (AMPA, NMDA) and substance P (NK1) |
| Second | Dorsal horn, inside the cord | Nociceptive-specific or wide dynamic range neurone. Axon crosses in the anterior white commissure within one or two segments and ascends in the contralateral anterolateral quadrant; 85 to 90% of spinothalamic cells project contralaterally | Thalamus: ventral posterolateral nucleus (lateral route) and intralaminar nuclei (medial route), with collaterals to the reticular formation and periaqueductal grey |
| Third | Thalamus | Thalamocortical projection | Primary and secondary somatosensory cortex from VPL; anterior cingulate and insula from the medial route |
| Neospinothalamic (lateral) | Paleospinothalamic (medial) | |
|---|---|---|
| Main input | Aδ, lamina I | C, laminae II and III relayed to V |
| Relay | Ventral posterolateral nucleus | Reticular formation, periaqueductal grey, intralaminar nuclei |
| Destination | Somatosensory cortex | Anterior cingulate, insula, limbic structures |
| Serves | Where, and how intense | How unpleasant; arousal and the autonomic response |
For a hand the whole route is spinal. The same three orders apply to the face 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.
(c) The central mechanism that modulates transmission 2.5 marks
What earns the marks2.5 marks
| Higher centres | Anterior cingulate and prefrontal cortex, hypothalamus and amygdala drive the periaqueductal grey |
|---|---|
| Brainstem structures | Periaqueductal grey; rostral ventromedial medulla with nucleus raphe magnus (serotonin); locus coeruleus (noradrenaline) |
| Route | Dorsolateral funiculus to the dorsal horn, laminae I and II |
| Spinal mechanism | Presynaptic reduction of transmitter release, and postsynaptic or direct inhibition of the projection neurone |
| Transmitters | Endogenous opioids, serotonin, noradrenaline through α2 receptors |
Commonly lost: Many answered with gate control theory instead of the descending inhibitory pathways the question asks for.
Descending inhibition, from higher centres to the synapse
Brainstem relays
The spinal mechanism
Commonly lost: Most did not state how inhibition happens at the spinal level: presynaptic reduction of release, and postsynaptic or direct inhibition of the neurone.
| Transmitter | From | Acts at the dorsal horn through |
|---|---|---|
| Endogenous opioids | Periaqueductal grey; enkephalin interneurones in the dorsal horn | µ and δ receptors, Gi/Go: less cAMP, closed Ca²⁺ channels, open K⁺ channels. About 75% of dorsal horn opioid receptors are presynaptic |
| Serotonin | Nucleus raphe magnus, rostral ventromedial medulla | Inhibits transmission, in part by exciting enkephalin interneurones |
| Noradrenaline | Locus coeruleus | α2 adrenoceptors, presynaptic and postsynaptic; synergistic with opioids |
| GABA and glycine | Local dorsal horn interneurones | Tonic inhibition; GABA-A mainly postsynaptic, GABA-B mainly presynaptic |
- Stimulating the periaqueductal grey produces profound analgesia that naloxone reverses: the endogenous opioids are part of the circuit.
- The system works in both directions: the rostral ventromedial medulla also holds cells that facilitate transmission.
- Gate control is segmental modulation in the dorsal horn, not the central mechanism asked for; if it appears at all it is one line.