Block 6 · CNS · CNS12 · Rev 1.1 · Updated Oct 23, 2026
CNS12 · Neuroscience · Study Guide
Pain Pathways
Learning objectives
- LO 1Name the fiber types that detect painful stimuli (and the chemicals that set them off), and explain why pain arrives in a fast phase and a slow phase.
- LO 2Trace, and be able to sketch, the three-neuron routes that bring pain from the body and from the face up to sensory cortex, including where each one crosses the midline and what that crossing is called.
- LO 3Explain how the brain splits pain into a "where and how strong" stream and a "how much it hurts" stream, and why pain therefore carries emotion.
- LO 4Explain the ways the CNS can turn pain up or down: the spinal gate, descending brainstem control, endogenous opioids, and the placebo response.
- LO 5Map which arteries feed which parts of the spinal cord and brainstem, and predict the ascending sensory and descending motor losses after each one is blocked.
- LO 6Predict how a lesion at any point along the pain pathways changes pain and temperature sensation, and on which side.
★ Step 1 HY
⚠ Step 1 trap
✎ Memory tool
“ Buzzwords
MAPBig picture
- Tissue damage → bradykinin · prostaglandins · K⁺ · substance P → nociceptors
- Aδ → fast, sharp (first pain)
- C → slow, dull (second pain)
- Synapse → dorsal horn (body) · spinal trigeminal nucleus (face)
- 2nd-order neuron crosses immediately → anterior white commissure (body) · caudal medulla (face)
- Lateral stream → VPL / VPM → S1 → where + how strong
- Medial stream → cingulate · insula · amygdala → how bad it feels
- Brake → gate (touch) · PAG → raphe / LC → dorsal horn · endogenous opioids · placebo
- Tract lies in known arterial territories → pinprick exam → localize strokes + cord lesions
LO 1Nociceptors and pain fibersWhich fibers carry pain, and what switches them on
By the end: you can define pain vs nociception, fill in the Aβ / Aδ / C table from memory, explain first vs second pain, and match each inflammatory mediator to its effect.
Q1. What is pain, and why do we have it?
- Pain = an unpleasant sensory and emotional experience associated with actual or potential tissue damage (or described in terms of such damage).
- It is a conscious interpretation of nociceptive input, shaped by memories, emotion, pathology, genetics and cognition → highly subjective (one patient's 3/10 is another's 10/10).
- Nociception = the neural signal; pain = the experience. You can have one without the other.
- Pain is survival. It is always unpleasant (physical + psychological), and it motivates you to:
- escape the damaging stimulus → protect the injured part → avoid the situation in future.
- Acute pain triggers a stress response: ↑ blood pressure, ↑ heart rate, ↑ plasma cortisol, anxiety.
CheckA patient with a crushed leg is unconscious under anesthesia. Is there nociception? Is there pain?
Nociceptors still fire and send signals (nociception yes), but there is no conscious experience, so no pain. Pain needs cortical interpretation.
Q2. What exactly is a nociceptor?
- A relatively unspecialized free nerve ending that initiates the sensation of pain.
- Cell body in the dorsal root ganglion (DRG) for the body, or the trigeminal ganglion for the face; pseudounipolar axon.
- Found everywhere in the body except the brain (brain parenchyma has none; headache comes from meninges and vessels).
- High threshold of activation → fires only for damaging or near-damaging stimuli (that is what separates it from a touch receptor).
CheckWhy can neurosurgeons operate on an awake patient's cortex without causing pain from the cortical cuts?
Brain tissue itself has no nociceptors. Only the scalp, meninges and vessels need anesthesia.
Q3. Which fibers carry pain? (the Aβ / Aδ / C table)
Skin afferents are sorted by diameter and myelin. Thicker + more myelin = faster.
| Feature | Aβ | Aδ | C |
|---|---|---|---|
| Myelin | Thick | Lightly myelinated | Unmyelinated |
| Diameter (µm) | 6–12 | 1–5 | 0.2–1.5 |
| Speed (m/s) | 35–75 | 5–30 | 0.5–2 |
| Carries | Touch, pressure (mechanoreceptors) | Fast, sharp, well-localized pain; cold | Slow, dull, aching/burning pain; warmth; itch |
| Pain role | Not a pain fiber, but closes the gate (LO 4) | First pain | Second pain; persists while tissue repairs |
- Both pain fibers are DRG axons: Aδ = fast pain, lightly myelinated, small; C = slow dull / achy / throbbing pain from repairing tissue, unmyelinated, very small.
CheckWhich fiber would you expect a "burning, poorly localized ache that lingers" to travel on, and why is it slow?
C fibers: unmyelinated and very thin (0.5–2 m/s), so no saltatory conduction.
Step 1 HY — local anesthetics
Local anesthetics block small-diameter and myelinated fibers first: Aδ / C (pain) → then temperature → touch/pressure (Aβ) → motor (Aα) last. Infected (acidic) tissue needs more drug because the base form can't cross membranes.
Memory tool
"C = Crawling, Chronic, Can't localize." "A-delta = Alarm": the quick first warning.
Q4. What chemicals does damaged tissue release to fire nociceptors?
Tissue damagecells rupture, plasma leaks
→
Inflammationmast cells, platelets, PG synthesis
→
"Inflammatory soup"activates / sensitizes nociceptors
→
Pain + hyperalgesialower threshold at the injury
| Mediator | Source | Effect on nociceptor |
|---|---|---|
| Bradykinin | Cleaved from plasma globulins (kininogen) at the injury | Very painful; directly activates |
| Prostaglandins | Arachidonic acid (via COX) in damaged cells | Block K⁺ efflux → extra depolarization → sensitize (more excitable) |
| Histamine | Mast cells | Excites |
| Substance P | Nociceptor (C-fiber) terminals | Excites; enhances pain perception |
| K⁺ | Released from damaged cells | Depolarizes |
| Serotonin (5-HT) | Platelets / mast cells | Excites |
- Substance P is concentrated in the superficial dorsal horn (substantia gelatinosa / nucleus proprius). C-fiber terminals release glutamate (fast) plus substance P (slow, prolonged) onto second-order neurons.
CheckWhy does ibuprofen reduce the tenderness of a sprained ankle without numbing touch?
It inhibits COX → ↓ prostaglandins → nociceptors are no longer sensitized (threshold returns toward normal). Aβ touch fibers are untouched.
Step 1 HY
- Capsaicin activates TRPV1 on C fibers → desensitization and depletion of substance P → topical analgesia.
- NSAIDs = COX inhibitors → ↓ PG-mediated sensitization (peripheral site of action).
- Boards phrase prostaglandin action as "sensitize nociceptors / cause hyperalgesia"; PGs alone cause little pain.
Step 1 trap
The "very painful substance from damaged tissue" is bradykinin, a peptide cut from plasma globulins, not the globulin protein itself. And substance P is a neuropeptide made by the nociceptor, not a tissue or mast-cell product.
Buzzwords
"sharp, pricking, well localized" → Aδ"dull, burning, throbbing" → C fiber"free nerve endings, high threshold" → nociceptor"TRPV1 / chili pepper" → capsaicin, C fibers"inflammatory soup" → bradykinin, PG, K⁺, 5-HT, histamine, SP
ApplyLO 1 application questions
A1A nerve conduction study selectively blocks the fastest-conducting fibers in a cutaneous nerve but leaves the slowest intact. A pinprick then produces what sensation?
A delayed, dull, poorly localized burning ache. With Aβ and Aδ blocked, only C fibers (second pain) remain.
A2A child has a missense mutation that abolishes a sodium channel needed for nociceptor firing. He bites his tongue and breaks bones without complaint but feels touch normally. What part of the system is broken?
Nociceptor transduction/conduction (Aδ and C fibers). Congenital insensitivity to pain (loss-of-function of Nav1.7, SCN9A) shows that pain is a survival system: these children accumulate injuries.
A3After a burn, even light touch on the area hurts and heat is intolerable. Name the two phenomena and one peripheral cause.
Allodynia (normally non-painful touch hurts) and hyperalgesia (painful stimulus hurts more). Cause: inflammatory mediators, especially prostaglandins and bradykinin, sensitizing nociceptors.
LO 2Pain pathways: body and faceThree-neuron relays; crossing at the anterior white commissure (body) and caudal medulla (face)
By the end: you can draw the spinothalamic and trigeminothalamic pathways, name every synapse, name the decussation, and explain why pinprick testing can misjudge the lesion level.
Q1. What pathways carry pain, and which way does each go?
Ascending (to brain)
- Spinothalamic tract = lateral anterolateral system (ALS): pain + temperature (+ crude touch) from the body
- Trigeminothalamic tract: pain + temperature from the face
- Medial anterolateral system: emotional/affective pain (LO 3)
Descending (to cord)
- Cortex + brainstem nuclei project to the dorsal horn to modulate transmission of the ascending signal (LO 4)
Q2. What happens when a pain fiber enters the spinal cord?
- Aδ and C fibers enter via the lateral division of the dorsal root (large Aβ fibers enter medially and go to the dorsal columns).
- They join Lissauer's tract (dorsolateral fasciculus) and run up or down 1–2 segments before synapsing.
- They synapse on ipsilateral dorsal horn neurons in the:
- Substantia gelatinosa (lamina II): the "gate", full of inhibitory interneurons
- Nucleus proprius (laminae III–IV): home of the 2nd-order projection neurons; rich in substance P
CheckClark's column also sits in the dorsal horn. Is it part of the pain pathway?
No. Clark's column (nucleus dorsalis) relays unconscious proprioception to the cerebellum (dorsal spinocerebellar tract).
Q3. Trace the spinothalamic pathway, neuron by neuron.
1st orderDRG cell → Lissauer's tract (±1–2 segments) → synapse in SG + nucleus proprius (ipsilateral)
→
2nd ordernucleus proprius → crosses in the anterior white commissure → contralateral ALS → brainstem → VPL
→
3rd orderVPL → posterior limb of internal capsule → primary somatosensory cortex (S1)
- In the cord: ALS runs in the anterolateral funiculus.
- In the brainstem: it stays lateral (medulla: dorsal to the inferior olive; pons: lateral to the medial lemniscus), keeps its somatotopy, meets the DCML/medial lemniscus in the upper brainstem, and both end in VPL.
- Fibers are added from the lateral side as you ascend: sacral fibers lateral, cervical medial.
- Draw it: DRG → Lissauer's tract → SG / nucleus proprius → cross in the anterior white commissure → ALS → VPL → sensory cortex (3-neuron relay). Know the decussation by name.
- Typical images: a labeled cord section (Lissauer's tract, SG, nucleus proprius, ALS) and a "what does this red line show?" pathway diagram.
CheckName the decussation of the body's pain pathway and the neuron that crosses there.
The anterior (ventral) white commissure, crossed by the 2nd-order neuron (cell body in the nucleus proprius), within 1–2 segments of entry, just ventral to the central canal.
Step 1 HY — which side?
Cord lesion of the ALS → contralateral pain/temperature loss beginning 1–2 levels below the lesion. DCML lesion in the cord → ipsilateral vibration/position loss. Any lesion above the medulla (brainstem, thalamus, cortex) → both modalities contralateral.
Memory tool
"Pain crosses in a hurry; touch takes the elevator to the medulla first." Pain crosses within a segment or two; DCML waits until the medulla.
Q4. Why can a pinprick level misplace the lesion?
- Because 1st-order fibers travel 1–2 segments in Lissauer's tract before synapsing, and 2nd-order axons ascend obliquely while crossing.
- Result: the sensory level found on pinprick usually sits 1–2 segments below the true lesion.
- At the lesion level itself you may see a narrow ipsilateral band of loss (entering fibers and dorsal horn destroyed before they cross).
CheckThe right ALS is cut at T6. Where is pain lost?
Left side of the body from about T7–T8 down. A thin right-sided band at T6 may also be lost.
Step 1 trap
Don't answer "ipsilateral below the lesion" for pain in a cord hemisection; that's the DCML and corticospinal pattern. Pain/temp is the only modality that's contralateral below a cord lesion.
Q5. How does facial pain reach the cortex?
The spinal pain column (Lissauer's tract + SG/nucleus proprius) simply continues up into the brainstem:
| Spinal cord (body) | ↔ | Brainstem (face) |
|---|---|---|
| Lissauer's tract | ↔ | Spinal trigeminal tract |
| Substantia gelatinosa + nucleus proprius | ↔ | Spinal trigeminal nucleus (pars caudalis) |
| Anterior white commissure | ↔ | Crossing in the caudal medulla |
| ALS → VPL | ↔ | Ventral trigeminothalamic tract (VTTT) → VPM |
1st ordertrigeminal ganglion → enters at the pons → descends in the spinal trigeminal tract → synapses in the spinal trigeminal nucleus (caudal medulla)
→
2nd ordercrosses the midline → ascends as the VTTT next to the medial lemniscus → VPM
→
3rd orderVPM → S1 (face area, lateral postcentral gyrus)
CheckWhy do facial pain fibers descend before synapsing?
CN V enters at the mid-pons, but the pain/temperature nucleus (pars caudalis of the spinal trigeminal nucleus) lies in the caudal (closed) medulla down to C2. The fibers get there via the spinal trigeminal tract.
Q6. What do the three parts of the spinal trigeminal nucleus do?
Pars oralis (rostral)
Oral tactile info; works with the main sensory nucleus.
Pars interpolaris
Oral and dental pain.
Pars caudalis (caudal)
Pain + temperature from facial skin (and viscera); the brainstem twin of the nucleus proprius.
- Lesion side: trigeminal nerve, spinal trigeminal tract or nucleus damage → ipsilateral facial pain/temp loss; VTTT damage (after the crossing) → contralateral.
- The DTTT is a backup only for facial touch/pressure (from the main sensory nucleus).
- Pain and temperature have no bilateral redundancy → a VTTT lesion removes facial pain/temp but spares touch.
Memory tool
O-I-C, top to bottom: Oral touch → Inside-the-mouth (teeth) pain → Cutaneous face pain. And VPL = "L for Limbs", VPM = "M for Mouth/face".
Step 1 HY — trigeminal neuralgia
Brief, electric-shock unilateral facial pain in V2/V3, triggered by chewing, talking or light touch; usually vascular compression of the CN V root (MS in a young patient). First line: carbamazepine.
Buzzwords
"dorsolateral fasciculus" → Lissauer's tract"lamina II" → substantia gelatinosa"ventral white commissure" → pain decussation"onion-skin" facial loss → spinal trigeminal nucleus (rostral-caudal map)"VPM" → face; "VPL" → body
ApplyLO 2 application questions
A1A 6-year-old scrapes both hands falling off his bike. Which tract carries the pain into the CNS: spinocerebellar, spinothalamic, corticospinal, DCML or rubrospinal?
Spinothalamic (lateral ALS). DCML carries touch/vibration/proprioception; the others are motor or cerebellar.
A2A lesion in the right dorsolateral caudal medulla hits the spinal trigeminal tract/nucleus and the neighboring ALS. Predict the pain map.
Right face + left body. The trigeminal tract/nucleus is still uncrossed (ipsilateral face); the ALS already crossed in the cord (contralateral body). This "crossed" pattern is the hallmark of a lateral medullary lesion.
A3A small left pontine lesion destroys only the VTTT. What facial sensations are lost?
Pain and temperature on the right (contralateral) face; touch spared, because facial touch also travels in the uncrossed DTTT.
A4After a car accident a patient has lost pain and temperature in the right leg only. Where is the lesion?
Left lateral spinothalamic tract (anterolateral cord) at or above the lumbar segments. The deficit is contralateral and begins 1–2 levels below the lesion.
LO 3Central processing and the emotional side of painLateral (discriminative) vs medial (affective) systems
By the end: you can contrast the lateral and medial pain systems, name the cortical "pain matrix", and explain why anxiety, empathy and stress change pain.
Q1. Why does pain have two dimensions?
The ALS splits into two parallel streams at the thalamus:
| Feature | Lateral system | Medial system |
|---|---|---|
| Older name | Neospinothalamic | Paleospinothalamic |
| Thalamus | VPL (body), VPM (face) | Dorsomedial + intralaminar |
| Targets | Primary somatosensory cortex | Anterior cingulate cortex, insula, amygdala, hypothalamus |
| Function | Sensory-discriminative: location, intensity, quality | Affective-motivational: "suffering", emotion, cognitive modulation |
CheckA patient after a cingulate lesion says, "I can feel exactly where the needle is, and it's sharp, but it doesn't bother me." Which system is damaged?
The medial (affective) system (ACC). The lateral system to S1 is intact, so localization and intensity remain.
Q2. What is the "cortical pain matrix", and what does each part add?
S1 (postcentral gyrus)
Where it hurts, how intense, what quality.
Anterior cingulate cortex
Active during actual pain, thinking about pain, and watching someone else in pain (empathy). Unpleasantness.
Insula
Interoception: links pain to body state; emotional awareness.
Amygdala
Fear, anxiety, emotional memory of pain → learned avoidance.
Hypothalamus
Visceral/autonomic response: HPA stress axis (↑ cortisol, ↑ HR, ↑ BP).
PAG + reticular formation
PAG = opioid-rich modulation hub. Reticular formation = arousal; reticulospinal output shapes posture/body language when hurting.
ALS branches (concept level)
| Branch | Target | Role |
|---|---|---|
| Spinothalamic | VPL; intralaminar thalamus | Awareness, localization |
| Spinomesencephalic | PAG (+ superior colliculus) | Triggers descending modulation |
| Spinoreticular | Reticular formation | Arousal, widespread monoamine activation |
| Spinohypothalamic | Hypothalamus | Autonomic / endocrine responses |
- Lateral ALS (via VPL/VPM → S1) = localization of pain; medial ALS = emotional component + cognitive modulation.
- Hypothalamus = visceral response to pain; ACC fires during pain, thinking about pain, or watching someone else in pain.
- Individual ALS branch names are background; know the concept that pain fans out to emotional and modulatory centers.
CheckWhy do anxious patients rate the same procedure as more painful?
Pain is an interpretation: anxiety and expectation drive the medial system (ACC, amygdala, insula) and reduce descending inhibition, so the same nociceptive input feels worse.
Step 1 HY — central pain syndromes
- Thalamic pain syndrome (Dejerine-Roussy): VPL infarct (lacunar or PCA branch) → contralateral sensory loss, then weeks–months later burning pain, allodynia, dysesthesia in the numb area. Hard to treat (TCAs, gabapentinoids).
- Phantom limb pain: pain in an amputated limb; linked to reorganization of S1 (neighboring map areas invade the limb's territory).
Step 1 trap
Emotional pain ≠ "VPL". If the question stem stresses unpleasantness, suffering, empathy or anticipation, think ACC/insula (medial system), not S1. If it stresses localization or two-point discrimination, think VPL → S1.
Memory tool
Lateral = Location. Medial = Misery (and "Mood").
Buzzwords
"neospinothalamic" → lateral, VPL → S1"paleospinothalamic" → medial, intralaminar → ACC"empathy for pain" → ACC / insula"pain asymbolia / doesn't bother me" → medial system lesion"S1 reorganization" → phantom limb
ApplyLO 3 application questions
A1fMRI of a medical student watching a video of a colleague's finger being pricked shows activation in one region that also lights up during her own pain. Which?
Anterior cingulate cortex (also anterior insula): the empathy/affective component.
A2Acute pain from a kidney stone raises the patient's heart rate, blood pressure and cortisol. Which structure drives this?
The hypothalamus (spinohypothalamic input) → sympathetic output and the HPA axis.
A3Six months after a right thalamic lacunar stroke, a 68-year-old develops severe burning pain over his left arm and leg, which are also numb to pinprick. Diagnosis and nucleus?
Thalamic pain syndrome (Dejerine-Roussy) from a lesion of the right VPL.
LO 4Central modulation of painGate control · descending control · endogenous opioids · placebo
By the end: you can draw the gate (resting, painful, rubbed), trace PAG → raphe/LC → dorsal horn, name the endogenous opioids and their two cellular actions, and explain placebo analgesia.
Q1. What is the gate control theory?
- Proposed by Melzack and Wall (1965).
- In each dorsal horn, a gate-like mechanism (inhibitory interneurons) inhibits or facilitates the flow of afferent impulses before they evoke pain perception.
- The substantia gelatinosa is the essential site of control. The gate is operated by external (touch) and internal (descending) influences.
| Condition | Active fibers | Inhibitory interneuron | Projection neuron | Gate / pain |
|---|---|---|---|---|
| Rest | None | ON (tonically active) | Inhibited | Closed · no pain |
| Painful stimulus | Aδ + C (small) | OFF (inactivated) | Fires to brain | Open · pain |
| Rubbing the injury | Aβ (large) + pain fibers | ON (stimulated by Aβ) | Inhibited | Closed · relief |
CheckWhy does shaking and sucking your thumb after hitting it with a hammer help?
Touch/pressure activates Aβ fibers → they excite SG inhibitory interneurons → the pain projection neuron is inhibited → gate closes → less pain reaches the brain.
Memory tool
Large fibers Lock the gate; Small fibers Swing it open.
Step 1 HY
Gate control is the basis of TENS units, massage, and dorsal column (spinal cord) stimulators for chronic pain: they drive large-fiber input to close the gate.
Q2. How does the brain send pain control down to the cord?
- Cortical nuclei address pain salience: how important is this signal vs the "background noise"? They act via brainstem nuclei and by filtering pain at the thalamus.
- Cortex, limbic system, insula, hypothalamus, amygdala → periaqueductal gray (PAG) → brainstem nuclei:
- Raphe nuclei (nucleus raphe magnus, in the rostral ventromedial medulla) → serotonin
- Locus coeruleus (pons) → norepinephrine
- These project down to the substantia gelatinosa, where they inhibit transmission (partly by exciting enkephalin interneurons).
- Brainstem transmitters: norepinephrine, serotonin and endogenous opioids.
- This is how a soldier or athlete can keep going with a serious wound: stress-induced analgesia overrides pain in life-or-death situations.
- Three modulators of pain relay to cortex: (1) inhibitory interneurons in the substantia gelatinosa (the gate), (2) cortical nuclei input to the PAG (descending control), (3) endogenous opioids, mainly in the medulla and PAG.
CheckWhy do duloxetine and amitriptyline help neuropathic pain?
They block reuptake of NE and 5-HT, boosting the transmitters of the descending raphe/LC inhibitory pathway at the dorsal horn.
Step 1 trap
The PAG itself sends few axons to the cord; it works through the RVM (raphe magnus) and locus coeruleus. And the descending transmitters are 5-HT and NE (plus opioids), not dopamine.
Q3. Where do endogenous opioids act, and how do they stop pain?
Who
- Enkephalins (δ; dorsal horn interneurons)
- β-Endorphin (μ; from POMC)
- Dynorphins (κ)
Where (receptors)
- Dorsal horn
- Brainstem nuclei (medulla)
- Periaqueductal gray
- Medial pain system
- Highest density: PAG + medullary pain nuclei
Opioid receptorGi/o-coupled
→
Presynapticblock voltage-gated Ca²⁺ channels → ↓ glutamate / SP release
+
Postsynaptic↑ K⁺ conductance → hyperpolarization → less excitable
→
Analgesialess signal ascends
CheckState the two cellular actions of opioid receptor activation in five words or fewer each.
Presynaptic: Ca²⁺ in ↓. Postsynaptic: K⁺ out ↑.
Q4. How does a placebo relieve pain?
- Expectation (prefrontal cortex, ACC) activates the PAG → RVM descending system and releases endogenous opioids.
- Proof: placebo analgesia is reversed by naloxone (opioid antagonist).
- So placebo is real, measurable central modulation, not "imagined" relief.
Drug sites along the pathway (overview)
| Drug | Site | Mechanism |
|---|---|---|
| NSAIDs | Peripheral nociceptors | COX inhibition → ↓ prostaglandins / inflammation |
| Lidocaine | Peripheral nerve | Blocks voltage-gated Na⁺ channels |
| Capsaicin | Peripheral nociceptors | TRPV1 → depletes substance P |
| Opioids | Dorsal horn, PAG, medulla | Block presynaptic Ca²⁺; open postsynaptic K⁺ |
| Gabapentin / pregabalin | Dorsal horn | α2δ subunit → ↓ presynaptic Ca²⁺ entry |
| Ketamine, methadone | Dorsal horn | Block NMDA receptors (anti-"wind-up") |
| TCAs / SNRIs | Brainstem → dorsal horn | ↑ 5-HT and NE → ↑ descending inhibition |
Step 1 HY — opioids
- μ receptors mediate analgesia, respiratory depression, miosis, constipation, euphoria; tolerance develops to most effects but not miosis or constipation.
- Overdose triad: coma, pinpoint pupils, respiratory depression → naloxone.
- Methadone = μ agonist + NMDA antagonist; ketamine = NMDA antagonist (blocks central sensitization).
Buzzwords
"rub the bump" → gate control, Aβ"Melzack and Wall" → gate theory, SG"stress-induced analgesia" → PAG / descending"reversed by naloxone" → endogenous opioids (incl. placebo)"raphe magnus" → 5-HT descending"locus coeruleus" → NE descending
ApplyLO 4 application questions
A1Electrical stimulation of a rat's PAG produces profound analgesia. Which drug given beforehand would most reduce the effect?
Naloxone: stimulation-produced analgesia is largely opioid-mediated (PAG → RVM → enkephalin interneurons).
A2A marathoner finishes the race and only then notices a stress fracture. Mechanism?
Descending modulation / pain salience: cortical and limbic drive to the PAG and brainstem nuclei (5-HT, NE, opioids) suppressed dorsal horn transmission during the stressful effort.
A3A TENS unit on the low back reduces pain. Which neurons does it most directly recruit?
Large Aβ afferents → excite substantia gelatinosa inhibitory interneurons → inhibit the projection neuron (gate closed).
A4Morphine reduces substance P release from C-fiber terminals. Which ion channel effect explains this?
Inhibition of presynaptic voltage-gated Ca²⁺ channels → less Ca²⁺-triggered vesicle release.
LO 5Blood supply of the spinal cord and brainstemTerritory → tracts → deficits
By the end: you can shade the ASA and PSA territories on a cord section, sort brainstem structures into medial (paramedian) vs lateral (circumferential) territories, and predict the motor and sensory picture of each occlusion.
Q1. Who feeds the spinal cord?
- One anterior spinal artery (ASA): formed from both vertebral arteries; runs in the ventral median fissure → supplies the ventral 2/3.
- Two posterior spinal arteries (PSAs): from the vertebrals or PICA → supply the dorsal 1/3 (dorsal columns, dorsal horn tips).
- Reinforced along the cord by segmental radicular arteries; the largest is the artery of Adamkiewicz (usually left, T9–L2) that feeds the lower cord.
- Watershed zone: mid-thoracic cord (≈T4–T8) → vulnerable to hypotension.
CheckWhich modality is classically spared in an ASA infarct, and why?
Vibration and position sense: the dorsal columns are in the posterior spinal artery territory.
Step 1 HY — anterior spinal artery syndrome
Classic setting: aortic aneurysm repair / aortic dissection / cross-clamping (loss of the artery of Adamkiewicz), or severe hypotension. Picture: bilateral paralysis below the lesion (flaccid at first, then UMN signs), bilateral loss of pain/temperature, urinary retention, with vibration and proprioception preserved.
Step 1 trap
A teenager who hyperextends her back and then has bilateral leg weakness, Babinski signs and pinprick loss but normal vibration has an ASA problem, not a posterior spinal artery problem. PSA occlusion is rare and gives ipsilateral dorsal column loss with pain spared.
Q2. How is the brainstem supplied? (medial vs lateral)
At every level: paramedian branches feed the midline, circumferential branches feed the side. Medial = mostly motor (corticospinal, motor CN nuclei, medial lemniscus); lateral = pain/temperature, sympathetics, cerebellar connections, CN V/VIII.
| Level | Medial (paramedian) | Lateral |
|---|---|---|
| Medulla | Anterior spinal artery (vertebral) | PICA / vertebral |
| Caudal pons | Basilar paramedian branches | AICA |
| Rostral pons | Basilar paramedian | Superior cerebellar artery |
| Midbrain | PCA / basilar-tip paramedian branches | PCA, SCA (circumferential) |
CheckWhich brainstem strokes spare pain and temperature on the body?
Medial (paramedian) strokes: medial medullary (ASA), medial pontine (basilar paramedian), Weber (midbrain). The ALS runs laterally.
Q3. What does each classic brainstem stroke look like?
Lateral medullary (Wallenberg) PICA / vertebral
Ipsi face + contra body pain/temp (spinal V + ALS); dysphagia, hoarseness, ↓ gag (nucleus ambiguus, specific to PICA); ipsi Horner; vertigo/nystagmus, nausea; ipsi limb ataxia.
Medial medullary (Dejerine) ASA
Contra hemiparesis (pyramid), contra vibration/position loss (ML), tongue deviates toward lesion (CN XII). Pain spared.
Lateral pontine AICA
Same crossed pain pattern + ipsi facial paralysis (CN VII nucleus), ipsi hearing loss (cochlear nuclei / labyrinthine artery), vertigo, ataxia, Horner.
Medial pontine Basilar paramedian
Contra hemiparesis, contra DCML loss, ipsi lateral gaze palsy (CN VI) ± INO. Pain spared.
Locked-in Basilar (ventral pons)
Quadriplegia, can't speak; vertical eye movements and blinking preserved; consciousness intact.
Weber (medial midbrain) PCA paramedian
Ipsi CN III palsy (down and out, ptosis, dilated pupil) + contra hemiparesis (cerebral peduncle).
- For any occlusion, predict both the ascending sensory (pain/temp, DCML) and descending motor (corticospinal) deficits.
- Key contrasts: ASA vs PSA in the cord; lateral (PICA/AICA) vs medial (ASA/basilar) in the brainstem.
Step 1 HY — localize in 2 moves
- Crossed signs (ipsi cranial nerve + contra body) = brainstem.
- Cranial nerve tells the level: III/IV midbrain · V–VIII pons · IX–XII medulla. Pain/temp involved → lateral; hemiparesis + tongue/VI/III → medial.
Memory tool — rule of 4s (medial "M"s)
Medial structures start with M: Motor pathway (corticospinal), Medial lemniscus, MLF, Motor nuclei (III, IV, VI, XII; the CNs that divide evenly into 12). Side structures start with S: Spinothalamic, Sensory nucleus of V, Sympathetics, Spinocerebellar. And for Wallenberg, "don't PICA horse that can't eat" (dysphagia).
Step 1 trap
Wallenberg gives ipsilateral face but contralateral body pain loss. If the face and body are on the same side, the lesion is above the pons crossing of the VTTT (upper pons, midbrain, thalamus, cortex). Also: nucleus ambiguus signs point to PICA (medulla), facial palsy + deafness to AICA (pons).
Buzzwords
"hoarseness + crossed pain loss" → PICA (lateral medulla)"tongue deviates toward lesion" → medial medulla (ASA)"facial palsy + deafness + crossed pain" → AICA"artery of Adamkiewicz" → lower cord ASA supply"down and out eye + contra hemiparesis" → Weber"only vertical gaze + blink" → locked-in (basilar)
ApplyLO 5 application questions
A1After open repair of a thoracoabdominal aortic aneurysm, a man cannot move his legs and cannot feel pinprick below the umbilicus, yet he can tell which way his toe is moved. Which vessel?
Anterior spinal artery territory (via loss of the artery of Adamkiewicz). Dorsal columns (PSA) spared.
A2A 58-year-old has vertigo, a hoarse voice, left ptosis with miosis, loss of pain on the left face and right body, and left arm ataxia. Lesion and vessel?
Left lateral medulla (Wallenberg), left PICA or vertebral artery.
A3A patient has right arm and leg weakness, right-sided loss of vibration and position, and her tongue deviates to the left. Pinprick is normal. Lesion?
Left medial medulla (Dejerine), left anterior spinal artery branch: left pyramid + left ML + left CN XII.
A4Same crossed pain loss as Wallenberg, but with right facial paralysis and right-sided hearing loss. Vessel?
Right AICA (lateral pontine syndrome): facial nucleus + cochlear nuclei/labyrinthine artery.
LO 6Predicting lesions of the pain pathwaysBefore the crossing → ipsilateral; after → contralateral; at it → bilateral
By the end: you can name the side and region of pain/temperature loss for a lesion anywhere from the nerve to the cortex, and recognize syringomyelia, Brown-Séquard and the cord syndromes.
Q1. What is the one rule for predicting pain loss?
Before crossingnerve, DRG, dorsal root, dorsal horn, CN V, spinal V tract/nucleus → ipsilateral
→
At the crossinganterior white commissure → bilateral, only the affected segments
→
After crossingALS, VTTT, VPL/VPM, internal capsule, S1 → contralateral
| Lesion site | Pain / temperature loss | Clue |
|---|---|---|
| Peripheral nerve / dorsal root | Ipsilateral, that nerve's or dermatome's territory | All modalities in that area |
| Trigeminal nerve / ganglion | Ipsilateral face | ± corneal reflex, jaw muscles |
| Spinal trigeminal tract / nucleus | Ipsilateral face | Facial touch may be spared (main sensory n.) |
| VTTT | Contralateral face | Touch spared (DTTT backup) |
| ALS in cord | Contralateral body, starting 1–2 segments below | Narrow ipsi band at level |
| ALS in brainstem | Contralateral body | Usually with cranial nerve signs |
| Anterior white commissure (syrinx) | Bilateral, band ("cape") at affected levels | Touch/vibration spared |
| VPL / VPM / S1 | Contralateral body / face | VPL infarct → later thalamic pain |
Memory tool
"Before = Beside (same side), After = Across, At = All (both sides)."
Q2. The burnt-hands case: what is syringomyelia?
Case: a woman burned her hand and never felt it. Bilaterally she feels a Q-tip but not pinprick or hot/cold. It started in the hands and over months spread to the arms, shoulders and upper torso.
- Syringomyelia = fluid-filled expansion of the central canal (syrinx), usually cervical (C8–T1 classic), often with a Chiari I malformation or after trauma.
- The syrinx compresses the anterior white commissure first → bilateral loss of pain/temperature at those levels only = "cape" or "shawl" distribution.
- Touch, vibration, proprioception preserved (dorsal columns) → "dissociated sensory loss".
- As it expands: ventral horns → LMN signs, wasting of hand intrinsics; lateral corticospinal → UMN signs in legs; hypothalamospinal fibers → Horner.
- Classic stem: bilateral hand numbness to pinprick/temperature (Q-tip still felt) that slowly spreads to arms and shoulders → answer is expansion of the central canal in the cervical cord, not an ASA infarct.
CheckA lesion destroys only the anterior white commissure at T1. What is lost?
Bilateral pain/temperature in the T1 dermatome only. Fibers entering above and below still cross normally; touch and proprioception are spared.
Step 1 HY
Syrinx = cape-like bilateral pain/temp loss + hand LMN weakness/atrophy; associated with Chiari I (cerebellar tonsils below the foramen magnum). Painless scalds or cuts on the hands are the giveaway.
Step 1 trap
ASA infarct also spares vibration and kills pain bilaterally, but it is sudden, involves everything below the lesion, and causes paralysis. A syrinx is slow, segmental (band/cape) and spares legs early.
Q3. Brown-Séquard and the other cord syndromes
| Syndrome | Classic cause | Pain / temp | Vibration / position | Motor |
|---|---|---|---|---|
| Anterior cord | ASA infarct (aortic surgery, hypotension), burst fracture | Lost bilaterally below | Spared | Bilateral weakness below |
| Posterior cord | Tabes dorsalis, B12 deficiency (SCD), Friedreich ataxia | Spared | Lost below | Spared (SCD also hits corticospinal) |
| Central cord | Syringomyelia; neck hyperextension in elderly with spondylosis | Lost bilaterally in a cape | Usually spared | Arms > legs |
| Brown-Séquard (hemisection) | Penetrating injury (stab wound) | Contralateral, starting 1–2 below | Ipsilateral below | Ipsi UMN below; ipsi LMN at level |
- Brown-Séquard extras: at the level, an ipsilateral band of all-modality loss + LMN signs; above T1 → ipsilateral Horner.
- Central cord: arm fibers lie medially in the lateral corticospinal tract (closest to the center) → arms worse than legs.
CheckRight hemisection at T10. Where is pain/temperature lost, and where is vibration lost?
Pain/temp: left body from ≈T11–T12 down (plus a thin right band at T10). Vibration/position: right side below T10. Right leg UMN weakness.
Step 1 HY — Brown-Séquard
"Ipsi motor + ipsi vibration, contra pain." Stab wound to the back is the classic stem. Pain loss starts 1–2 levels below the injury because of Lissauer's tract.
Buzzwords
"cape/shawl distribution" → syringomyelia"painless scalds on hands" → syrinx"stab wound, hemisection" → Brown-Séquard"aortic aneurysm repair, paraplegia" → ASA"burning pain after thalamic stroke" → Dejerine-Roussy"elderly, hyperextension, arms worse" → central cord
Q4. What is referred pain, and why does it happen?
- Convergence: neurons of the nucleus proprius receive both somatic and visceral nociceptive input.
- Higher centers can't tell which source fired, so they attribute it to the body surface where pain usually comes from.
| Organ | Referred to | Segments |
|---|---|---|
| Heart (MI, angina) | Left arm, jaw, chest | T1–T4 |
| Diaphragm, gallbladder irritation | Right shoulder (Kehr sign for spleen = left) | C3–C5 (phrenic) |
| Early appendicitis | Periumbilical | T10 |
| Kidney / ureter | Flank → groin | T10–L1 |
ApplyLO 6 application questions
A1An elderly man with cervical spondylosis falls forward and hyperextends his neck. He has burning pain and weakness in both hands; his legs are much less affected. Syndrome?
Central cord syndrome: central gray + AWC + medially placed arm fibers of the corticospinal tracts.
A2A tumor compresses the left VPM only. Predict the sensory finding.
Right face: loss of pain, temperature and touch (VPM receives both VTTT and the crossed touch input), with the right body spared.
A3A herpes zoster outbreak destroys the left T6 dorsal root ganglion. What is lost?
All modalities in the left T6 dermatome (before any crossing → ipsilateral). Often with burning post-herpetic neuralgia afterward.
A4A 30-year-old with a Chiari I malformation reports painless cuts on both hands and weak, wasted intrinsic hand muscles. What two cord structures are involved?
Anterior white commissure (bilateral pain/temp loss) and ventral horns at C8–T1 (LMN weakness): an expanding syrinx.
IDImage ID drillName it before you open it
1 · What does the red line show?
2nd-order pain axon from the dorsal horn crossing in the anterior white commissure to the contralateral ALS.
2 · Name the crossed tract
Ventral trigeminothalamic tract, from the spinal trigeminal nucleus to VPM. Lesion → contralateral facial pain loss.
3 · Diagnosis?
Syringomyelia: cape-like bilateral pain/temperature loss, touch spared.
4 · Pars caudalis carries?
Pain + temperature from facial skin (homolog of the nucleus proprius).
MCQPractice questionsClick an answer to see the explanation.
Score: 0 / 0
1A 34-year-old woman notices she burned her fingers on a pan without feeling it. Examination shows she feels a cotton swab on both hands but cannot detect pinprick or a cold tuning fork over both hands, forearms and shoulders. Strength and reflexes in the legs are normal. Over months the deficit spreads. Damage to which structure best explains her sensory loss?
C. A cervical syrinx compresses the anterior white commissure, where both sides' 2nd-order pain/temp axons cross → bilateral, segmental ("cape") loss with touch spared. A: dorsal columns carry touch/vibration, which is intact. B and E would cause weakness (UMN or LMN), absent here. D: Lissauer's tract damage would be unilateral and patchy, not bilateral.
2A 64-year-old man has sudden vertigo, nausea, hoarseness and difficulty swallowing. Exam: right ptosis and miosis, loss of pain and temperature on the right face and the left trunk and limbs, and right arm dysmetria. Occlusion of which vessel is most likely?
A. Right lateral medullary (Wallenberg) syndrome: right spinal trigeminal tract/nucleus (ipsilateral face), right ALS (contralateral body), nucleus ambiguus (dysphagia, hoarseness), descending sympathetics (Horner), ICP (ataxia). B: wrong side; ipsilateral signs are on the right. C and D are medial territories that spare pain/temp. E: AICA (pons) would add facial palsy and deafness, not dysphagia.
3A carpenter hits his thumb with a hammer and immediately shakes and rubs it, which eases the pain. Activation of which elements best explains the relief?
D. Gate control: large Aβ touch fibers excite SG inhibitory interneurons, which suppress the pain projection neuron (gate closes). A and B describe pain fibers, which open the gate. C: the locus coeruleus uses norepinephrine, and this is descending, not touch-driven. E: motor pathway, irrelevant to pain transmission.
4A 70-year-old man had a small left-sided stroke 4 months ago that left his right arm and leg numb. He now reports constant, severe burning pain in the same limbs, triggered even by the touch of clothing. Infarction of which structure is most likely responsible?
B. Thalamic pain syndrome (Dejerine-Roussy) follows a VPL infarct: contralateral sensory loss, then allodynia and burning pain. A and C are medial-system structures; lesions reduce the unpleasantness of pain rather than produce limb numbness. D (visual attention) and E (vision) don't relay somatic sensation.
5A 24-year-old man is stabbed in the back just right of the midline at the T8 level. Which set of findings is expected?
E. Brown-Séquard: ALS is already crossed (contralateral pain loss, starting 1–2 segments below because of Lissauer's tract); dorsal columns and lateral corticospinal are uncrossed (ipsilateral). A reverses every side. B = anterior cord (ASA). C = posterior cord. D puts vibration on the wrong side.
6A 71-year-old man wakes from repair of a thoracoabdominal aortic aneurysm unable to move his legs. Pinprick and temperature are absent below T10 bilaterally, but he correctly identifies passive toe movement and feels a vibrating tuning fork at both ankles. Which vessel's territory is infarcted?
D. Loss of the artery of Adamkiewicz during aortic surgery infarcts the ventral 2/3 of the cord (ASA): corticospinal tracts, ALS and AWC, but not the dorsal columns. A would cost vibration/proprioception. B and C are brainstem vessels and would cause cranial nerve signs. E causes contralateral face/arm deficits, not bilateral leg paralysis.
7A volunteer's finger is pricked. She feels an immediate sharp sensation, followed about a second later by a dull, burning, poorly localized ache. The fibers carrying the second sensation are best described as:
E. Second pain is carried by C fibers: unmyelinated, very thin and slow. B describes Aδ fibers (first, sharp pain). A describes Aβ touch fibers. C (Ia) carry muscle spindle input. D: Pacinian corpuscles are Aβ vibration receptors, not nociceptors.
8A 45-year-old woman with multiple sclerosis has a small demyelinating plaque confined to the left dorsal pontine tegmentum. She has lost pain and temperature sensation over the right side of her face, but light touch over the face is normal on both sides. Which statement best explains why touch is spared?
B. The lesion hit the crossed VTTT (contralateral face pain/temp loss). Facial touch from the main sensory nucleus has bilateral redundancy through the uncrossed DTTT, but pain/temp from the spinal trigeminal nucleus does not. A: the AWC is in the cord and carries body pain. C: pars caudalis handles pain/temp, not touch. D and E are false.
9In a clinical trial, patients given a saline injection described as "a powerful painkiller" report substantial relief of postoperative pain. In a second arm, the relief disappears when naloxone is given with the saline. Which structure is most central to this effect?
A. Placebo analgesia is expectation-driven descending modulation: cortex/ACC → PAG (highest opioid receptor density) → RVM → dorsal horn, mediated by endogenous opioids, so naloxone abolishes it. B is dopaminergic motor control. C is visual. D supplies pharynx/larynx. E houses primary afferents, which are not the site of expectation-driven modulation.
10A 62-year-old man with diabetes presents with crushing substernal pressure radiating to the inside of his left arm and jaw. Which mechanism best explains the arm pain?
C. Referred pain: nucleus proprius neurons at T1–T4 receive both cardiac and arm/chest skin input, and the cortex attributes the signal to the more familiar somatic source. A and B: no peripheral nerve injury is involved. D explains suffering, not location. E would increase pain generally, not refer it to a dermatome.
11Morphine given intrathecally reduces glutamate and substance P release from C-fiber terminals in the dorsal horn. This presynaptic effect is due mainly to:
B. Gi/o-coupled opioid receptors inhibit presynaptic Ca²⁺ entry (↓ vesicle release) and open postsynaptic K⁺ channels (hyperpolarization). A = local anesthetics. C = GABA-A/benzodiazepines. D = ketamine/methadone. E = NSAIDs.
12A 66-year-old woman has sudden right arm and leg weakness with a right Babinski sign and loss of vibration and position sense on the right. When she protrudes her tongue it deviates to the left. Pinprick and temperature are normal everywhere. Which vessel is occluded?
D. Left medial medullary syndrome: left pyramid (right hemiparesis), left medial lemniscus (right DCML loss), left CN XII (tongue toward the lesion). Pain is spared because the ALS is lateral. A and C are lateral territories that would affect pain/temp. B is the wrong side. E (midbrain/thalamus/occipital) would not cause XII palsy.
13After a surgical lesion for intractable cancer pain, a patient says, "I can still feel exactly where it is and that it's sharp, but it no longer bothers me." The lesion most likely involved:
E. Cingulotomy disrupts the medial (affective-motivational) system, removing the suffering while sparing the lateral, discriminative system. A, B and C are lateral-system structures; damaging them would remove localization or the sensation itself. D lesions would disturb the gate, generally increasing pain.