Show the model answerAttempt it first — that is what makes it stick
How pain is perceived
What earns the marks
| Transduction | Nociceptor free endings; mediators and noxious stimuli open channels; action potentials |
|---|---|
| Transmission | Aδ first pain and C second pain to the dorsal horn |
| The three neurones | Dorsal root ganglion; dorsal horn, crossing to the spinothalamic tract; thalamus to cortex |
| Two streams | Lateral: where and how intense. Medial: how unpleasant |
| Perception | A distributed network, the pain matrix, not a single centre; each area's contribution |
Read the question: The verb is perceived. An answer that stops at the spinothalamic tract has described transmission. The marks for perception are in what the cortex does with the signal: the sensory and the emotional components, and where each is made.
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 | Where | What happens |
|---|---|---|
| Transduction | Nociceptor: free nerve endings in skin, muscle, joints and viscera | Noxious heat, pressure or chemicals, and mediators from injured tissue (K⁺, H⁺, ATP, bradykinin, serotonin), open TRPV1, ASIC and P2X3 channels. The generator potential fires action potentials through voltage-gated Na⁺ channels such as Nav1.8 |
| Transmission | Aδ and C fibres; cell body in the dorsal root ganglion | Aδ, thinly myelinated, 12 to 30 m/s: sharp, localised first pain. C, unmyelinated, 0.5 to 2 m/s: dull, diffuse second pain |
| First synapse | Dorsal horn: Aδ to laminae I and V, C to lamina II | Glutamate on AMPA and NMDA receptors, substance P on NK1, onto nociceptive-specific and wide dynamic range neurones. This is the first place the signal is modulated |
| Ascent | Second-order neurone | Crosses in the ventral white commissure within one or two segments and ascends in the contralateral anterolateral quadrant |
| Lateral stream | Neospinothalamic: ventral posterolateral thalamus to primary and secondary somatosensory cortex | The sensory-discriminative component: where the stimulus is, how intense, how long |
| Medial stream | Paleospinothalamic, spinoreticular and spinolimbic: reticular formation, periaqueductal grey, intralaminar thalamus, hypothalamus and amygdala | The motivational-affective component: unpleasantness, arousal, the autonomic response. Reticular activation also starts descending inhibition |
The cortex: a network, not a centre
Functional imaging during acute pain shows a set of areas active together, the pain matrix. Broadly, the somatosensory cortices make the sensory-discriminative component and the limbic and paralimbic areas the affective one.
| Area | Contribution |
|---|---|
| Primary somatosensory cortex | Localisation |
| Secondary somatosensory cortex | Intensity, and spatial appreciation |
| Insula | Intensity, and the pain-related autonomic response |
| Anterior cingulate cortex | Response selection, attention, affect, appraisal |
| Prefrontal cortex | Affect, emotion, memory, modulation |
The two components can be separated. Damage to the prefrontal cortex reduces the ability to judge how severe a pain is, and cingulotomy reduces its emotional component. The anterior cingulate and prefrontal cortex also project back to the periaqueductal grey, which is how perception reaches back down to modulate its own input.
How the perception of pain can be modulated, with examples
What earns the marks
| Segmental: the gate | Aβ input excites an inhibitory interneurone in the substantia gelatinosa. Example: rubbing, TENS |
|---|---|
| How inhibition works | Presynaptic (less transmitter released) and postsynaptic (hyperpolarisation) |
| Descending | PAG to rostral ventromedial medulla (serotonin) and locus coeruleus (noradrenaline), to the dorsal horn. Example: PAG stimulation, morphine |
| Endogenous opioids | Enkephalin, β-endorphin, dynorphin. Example: stress-induced analgesia |
| Higher centres | Attention, expectation, mood. Example: placebo analgesia |
| Upward modulation | Peripheral and central sensitisation. Example: sunburn; wind-up |
| Drugs at each level | NSAIDs, local anaesthetics, opioids, α2 agonists, ketamine, tricyclics |
Read the question: “With examples” is half the instruction. Every mechanism named should carry one: rubbing an injury for the gate, stress-induced analgesia for the descending opioid system, placebo for expectation, sunburn for sensitisation.
Read the question: Modulation works in both directions. Hyperalgesia after injury is perception turned up, and the brainstem nuclei that inhibit transmission also contain cells that facilitate it. An answer that treats modulation as analgesia alone is incomplete.
1. At the first synapse: the gate
The gate, drawn as a circuit
Solid lines excite (+); dashed lines inhibit (−). Both afferents excite the projection neuron directly. The difference is what each does to the inhibitory interneuron in the substantia gelatinosa: the large Aβ fibre excites it, so touch closes the gate; the small C fibre inhibits it, so a noxious input removes the brake and opens the gate twice over. Descending fibres close it from above, by exciting the interneuron and by inhibiting the projection neuron directly.
Melzack and Wall (1965) proposed that transmission from the primary afferent to the projection neurone is gated by inhibitory interneurones in the substantia gelatinosa, and that the gate’s position is set by the balance of large- and small-fibre input.
| Input | Effect on the inhibitory interneurone | Gate | Example |
|---|---|---|---|
| Aβ: touch, pressure, vibration | Excites it | Closes | Rubbing a bumped elbow; transcutaneous electrical nerve stimulation; spinal cord stimulation |
| Aδ and C: nociceptive | Inhibits it | Opens | The noxious input itself |
| Descending fibres | Excite it, and inhibit the projection neurone directly | Closes | The route by which descending control, below, acts on the gate |
Two places to inhibit the same synapse
2. From the brainstem: descending control
The descending pathway, from higher centres to the dorsal horn
Brainstem relays
- Example: electrical stimulation of the periaqueductal grey produces profound analgesia, and naloxone reverses it, so endogenous opioids are part of the circuit.
- Two directions: in the rostral ventromedial medulla, off cells inhibit dorsal horn transmission and on cells facilitate it. Descending control can turn perception up as well as down.
3. The endogenous opioids
| Peptide | Endogenous agonist at |
|---|---|
| Enkephalins | δ |
| β-endorphin | µ |
| Dynorphins | κ |
All act through Gi/Go-coupled receptors: adenylyl cyclase is inhibited, voltage-gated Ca²⁺ channels close, and inwardly rectifying K⁺ channels open. The effect is the same cell-level inhibition wherever the receptor is, in the periaqueductal grey, the dorsal horn, or on peripheral terminals in inflamed tissue.
4. From higher centres: stress, attention and expectation
| Influence | Example | Mechanism |
|---|---|---|
| Stress | Soldiers wounded in battle often feel little pain until the fighting is over | Stress-induced analgesia. β-endorphin shares its precursor with ACTH; mice unable to make β-endorphin lose naloxone-reversible stress-induced analgesia |
| Expectation | Placebo analgesia | Acts on the same brain regions as an opioid, presumably by releasing endogenous opioids |
| Attention, anxiety, mood | The same injury hurts differently in different people and circumstances | Cortical and limbic projections to the periaqueductal grey set the descending system |
5. Turning perception up: sensitisation
| Level | Example | Mechanism |
|---|---|---|
| Peripheral | Sunburnt skin is more sensitive to pain than normal skin: primary hyperalgesia | Mediators such as prostaglandins and bradykinin lower the nociceptor's threshold; silent nociceptors are recruited |
| Central | Tenderness in uninjured skin around a wound: secondary hyperalgesia and allodynia | Repeated C-fibre input removes the Mg²⁺ block of the NMDA receptor: wind-up, lower threshold and larger receptive fields in the dorsal horn |
| Descending facilitation | On cells of the rostral ventromedial medulla | Firing just before a withdrawal response, they facilitate dorsal horn transmission |
6. Drugs and techniques, each acting at a named step
| Step modulated | Example |
|---|---|
| Peripheral sensitisation by prostaglandins | NSAIDs |
| Transduction and conduction through Na⁺ channels | Local anaesthetics |
| Presynaptic and postsynaptic inhibition in the dorsal horn; the periaqueductal grey | Opioids |
| Spinal α2 adrenoceptors, the target of descending noradrenaline | Clonidine, dexmedetomidine |
| The NMDA receptor behind wind-up | Ketamine |
| Descending serotonin and noradrenaline | Tricyclic antidepressants such as amitriptyline |
| Large-fibre input at the gate | Transcutaneous electrical nerve stimulation |