What Effector Cells Release in the CNS

1. T Cells (CD4+ and CD8+)

• IL-17 - drives neutrophil recruitment, disrupts blood-brain barrier
• IL-22 - inflammatory, barrier disruption

• Perforin - forms pores in target cell membranes
• Granzymes (A and B) - serine proteases that trigger apoptosis in target cells (neurons, oligodendrocytes)
• IFN-γ - antiviral and pro-inflammatory

Key textbook quote: "Activated T cells and the microglia-macrophages can contribute to tissue injury via non-antigen-restricted mechanisms. Each of these cell types releases an array of soluble factors... Cytokines characteristic of T cells include interleukin 2 (IL-2), interferon gamma (IFN-γ), and tumor necrosis factor β (TNF-β; lymphotoxin)."

• Bradley and Daroff's Neurology in Clinical Practice

2. Microglia / Macrophages (Resident + Recruited)

3. Astrocytes (Reactive Astrogliosis)

• IL-6, IL-1β - amplify inflammatory signals
• Chemokines (CXCL10, CCL2) - recruit T cells and monocytes into CNS
• Glutamate (excess) - excitotoxicity and neuronal death
• VEGF - promotes vascular permeability

4. NK Cells

• Perforin + Granzymes - kill infected or stressed neurons
• IFN-γ - activates macrophages and microglia
• TNF-α - cytotoxic effects

Summary Table

Preganglionic Sympathetic Outflow - Detailed

(Guyton & Hall - Red lines = preganglionic fibers; Black lines = postganglionic fibers)

1. Origin - Cell Bodies

• Located in the intermediolateral cell column (IML) / lateral horn of the spinal cord gray matter
• Spans segments T1 to L2 (some texts say T1-L3)
• This is why the sympathetic system is called the thoracolumbar outflow
• White rami communicantes exist only at T1-L2 levels

2. Fiber Characteristics

3. Path from Spinal Cord to Ganglion

1. Cell body in IML of lateral horn (T1-L2)
2. Axon exits via the ventral (anterior) root
3. Travels briefly in the spinal nerve
4. Diverges into the white ramus communicans (myelinated, so white)
5. Enters the paravertebral sympathetic chain ganglion

4. Three Fates After Entering the Sympathetic Chain

"After entering a paravertebral ganglion, a preganglionic sympathetic axon may (1) synapse within that segmental paravertebral ganglion, (2) travel up or down the sympathetic chain to synapse within a neighboring paravertebral ganglion, or (3) pass through the chain and then through one of the sympathetic nerves radiating outward from the chain, finally synapsing in a peripheral sympathetic (prevertebral) ganglion."

• Medical Physiology (Boron & Boulpaep)

5. Segmental Distribution of Preganglionic Outflow

The distribution is partly determined by the embryological origin of the organ. For example, the heart receives fibers from the neck region of the sympathetic chain because the heart originally developed in the neck of the embryo before descending into the thorax.

• Guyton & Hall Textbook of Medical Physiology

6. Ganglia Where Preganglionic Fibers Synapse

A. Paravertebral (Sympathetic Chain) Ganglia

• 22-23 ganglia arranged bilaterally along the vertebral column from cervical to coccyx
• Key named ganglia:

B. Prevertebral (Collateral) Ganglia

• Lie anterior to the aorta, near the roots of major visceral arteries
• Preganglionic fibers reach them via splanchnic nerves (bypass the chain without synapsing):

7. Special Case: Adrenal Medulla

• Preganglionic fibers from T5-T11 travel via greater splanchnic nerves all the way to the adrenal medulla without synapsing
• The chromaffin cells of the adrenal medulla are modified postganglionic neurons (embryologically derived from neural crest)
• These cells secrete epinephrine (80%) and norepinephrine (20%) directly into the bloodstream in response to ACh from preganglionic fibers
• This is why the adrenal medulla acts like a "sympathetic ganglion released into the blood"

"Preganglionic sympathetic nerve fibers pass without synapsing, all the way from the intermediolateral horn cells, through the sympathetic chains, through the splanchnic nerves, into the adrenal medullae. These secretory cells embryologically are derived from nervous tissue and are actually postganglionic neurons."

• Guyton & Hall

8. White vs. Gray Rami Communicantes

Summary Flowchart

IML lateral horn (T1-L2)
       ↓
Ventral root → Spinal nerve → White ramus communicans
       ↓
Sympathetic chain ganglion
  ├─ Synapse here → postganglionic via gray ramus → body wall, skin, blood vessels, sweat glands
  ├─ Ascend/Descend chain → synapse in cervical/lumbar ganglia → head, neck, legs
  └─ Pass through (no synapse) → splanchnic nerves → prevertebral ganglia → abdominal/pelvic viscera
                                                   ↓ (special)
                                           Adrenal medulla → epinephrine/norepinephrine released

Sympathetic Trunks - Brief

(Gray's Anatomy - Cervical sympathetic trunk with its three ganglia)

Overview

"On each side, a paravertebral sympathetic trunk extends from the base of the skull to the inferior end of the vertebral column where the two trunks converge anteriorly to the coccyx at the ganglion impar."

• Gray's Anatomy for Students

Structure

Regional Parts and Their Ganglia

1. Cervical Sympathetic Trunk

• No white rami here (no direct preganglionic input from the cord at cervical levels)
• Receives ascending preganglionic fibers from upper thoracic cord (T1-T3)
• Has 3 ganglia:

The stellate ganglion (cervicothoracic ganglion) is clinically important - blockade here causes Horner's syndrome (ptosis, miosis, anhidrosis, enophthalmos).

2. Thoracic Sympathetic Trunk

• ~12 ganglia (1st thoracic usually fused into stellate ganglion)
• Has both white and gray rami communicantes at each level
• Position: anterior to necks of ribs superiorly, shifting to costovertebral joints in mid-thorax, then anterolateral to vertebral bodies inferiorly
• Key contribution: gives rise to the splanchnic nerves (preganglionic fibers bypass the chain without synapsing here):

• Also contributes postganglionic fibers to the cardiac plexus, pulmonary plexus, aortic plexus, esophageal plexus

3. Lumbar Sympathetic Trunk

• ~4 ganglia
• Has white rami only from L1-L2 (end of thoracolumbar outflow)
• Gray rami to all lumbar spinal nerves
• Gives lumbar splanchnic nerves → inferior mesenteric ganglion and hypogastric plexus
• Lies on the anterolateral surface of lumbar vertebral bodies, medial to psoas major

4. Sacral Sympathetic Trunk

• ~4-5 ganglia on the anterior surface of the sacrum, medial to the anterior sacral foramina
• No white rami at sacral levels (no preganglionic input directly here)
• Gray rami to all sacral spinal nerves
• Contributes to the hypogastric plexus and innervation of pelvic organs

5. Ganglion Impar (Coccygeal Ganglion)

• Single unpaired ganglion where the two trunks merge in front of the coccyx
• The terminal point of the entire sympathetic chain

Rami Communicantes - Summary

Four Pathways for Preganglionic Fibers Once in the Trunk

1. Synapse in the ganglion at the same level they entered
2. Ascend or descend the trunk and synapse in a ganglion at a different level
3. Pass through the trunk and exit as splanchnic nerves to synapse in prevertebral ganglia
4. Pass through without synapsing to reach the adrenal medulla directly

Clinical Relevance

Increased Sympathetic Activity: Effects on the Body

"Stimulation of the β1-receptor causes positive inotropic and chronotropic effects on the heart, increased renin secretion in the kidney, and lipolysis in adipocytes, as well as bronchodilation and vasodilation in skeletal muscle. The α1 subtype mediates vascular and smooth muscle contraction causing vasoconstriction and increased blood pressure."

• Goldman-Cecil Medicine

1. Piloerection

• Postganglionic sympathetic fibers innervate the arrector pili muscle (smooth muscle attached to hair follicle)
• NE binds α1 receptors → Gq protein → PLC activation → IP3 + DAG → ↑intracellular Ca²⁺ → smooth muscle contraction
• Contraction pulls the hair follicle upright → piloerection
• In animals: traps air for warmth and makes animal appear larger (threat display)
• In humans: vestigial reflex, produces goosebumps (cutis anserina)

2. Respiration - Lungs (Bronchial Effects)

• Epinephrine (from adrenal medulla) and NE bind β2 receptors on bronchial smooth muscle
• β2 → Gs → ↑cAMP → PKA activation → phosphorylates myosin light chain kinase (MLCK) → inactivates it → smooth muscle relaxation → bronchodilation
• Simultaneously, PKA also opens K⁺ channels → hyperpolarization → further relaxation
• Bronchial glands: α1 stimulation → ↓mucus secretion (reduced secretions)
• Pulmonary vasculature: α1 → mild vasoconstriction (diverts blood to better-ventilated areas)
• Net result: ↑airway caliber → ↓airway resistance → ↑airflow to meet increased O2 demand during fight-or-flight

3. Cardiovascular System (General)

4. Renal Blood Flow

• NE → α1 on afferent arterioles → vasoconstriction → ↓glomerular capillary pressure → ↓GFR and ↓renal blood flow
• Simultaneously, NE → β1 on juxtaglomerular (JG) cells → ↑cAMP → ↑renin release → activates RAAS → AngII → further vasoconstriction + aldosterone → Na⁺/water retention → ↑blood pressure
• α1 also acts on efferent arteriole but less potently than afferent
• Net result: ↓renal perfusion (blood diverted to heart, muscles, brain) + ↑renin → longer-term BP support
• Severe sympathetic activation (e.g., shock) can cause acute tubular necrosis from ischemia

5. Skeletal Muscle Blood Flow

• At rest: NE dominates → α1 → mild vasoconstriction (vascular tone maintenance)
• During fight-or-flight: adrenal Epi floods blood → β2 receptors on skeletal muscle arterioles → Gs → ↑cAMP → vasodilation → ↑blood flow to muscles
• Cholinergic sympathetic fibers (unique to skeletal muscle) also release ACh → muscarinic → vasodilation (anticipatory, before exercise begins)
• Local metabolic factors (↑CO2, ↓O2, adenosine) also override sympathetic tone during active exercise
• Net: ↑blood flow to contracting muscle, ↑O2 delivery, ↑glucose delivery

6. Coronary Blood Flow

• Coronary vessels have both α1 and β2 receptors
• Direct sympathetic NE → α1 → mild coronary vasoconstriction
• BUT: ↑heart rate + ↑contractility (β1 effects) → ↑myocardial O2 consumption → local metabolic vasodilators (adenosine, CO2, H⁺, K⁺) released → dominant vasodilation overrides α1 constriction
• Epi via β2 also contributes directly to vasodilation
• DA1 receptors on coronary vasculature: dopamine → vasodilation (exploited in cardiogenic shock treatment)
• Net: coronary blood flow increases during sympathetic activation to meet increased cardiac demand

7. Cerebral Effects

• Cerebral arterioles do have α1 adrenergic receptors but they are far less responsive than peripheral vessels
• Cerebral autoregulation strongly overrides sympathetic tone - maintains constant blood flow across MAP 60-150 mmHg
• Systemic ↑BP (from sympathetic activation) may slightly reduce cerebral perfusion via myogenic response
• CNS arousal effects: sympathetic activation → release of NE from locus coeruleus → ↑alertness, attention, arousal
• ↑Glucose availability to brain (via hepatic glycogenolysis)
• Blood-brain barrier limits access of circulating catecholamines
• In severe hypertension (e.g., pheochromocytoma crisis): autoregulation fails → hypertensive encephalopathy

8. Heart - SA Node (Specifically)

1. NE/Epi binds β1 receptor on SA nodal cells
2. β1 → Gs protein → ↑adenylyl cyclase → ↑cAMP
3. ↑cAMP → directly binds and opens HCN channels (If, "funny current") - these carry inward Na⁺ current during diastolic depolarization
4. Faster If current → more rapid spontaneous diastolic depolarization (phase 4)
5. ↑cAMP also → PKA → phosphorylates L-type Ca²⁺ channels (ICaL) → ↑Ca²⁺ entry → faster upstroke (phase 0) and lower threshold
6. PKA also phosphorylates ryanodine receptors (RyR2) in SR → ↑Ca²⁺ sparks → further acceleration
7. Result: shorter cycle length → ↑heart rate (positive chronotropy)

• AV node: ↑conduction velocity (positive dromotropy)
• Ventricular muscle: ↑contractility (positive inotropy) via ↑Ca²⁺ influx
• ↑Relaxation rate (positive lusitropy) via PKA phosphorylation of phospholamban → ↑SERCA pump activity

9. Gastrointestinal Tract (GIT)

10. Urinary Bladder

• Detrusor muscle (bladder wall): NE/Epi → β2 and β3 → Gs → ↑cAMP → smooth muscle relaxation → bladder fills, does not contract → urine retained
• Internal urethral sphincter (bladder neck): NE → α1 → Gq → ↑Ca²⁺ → smooth muscle contraction → sphincter closes → urine cannot escape
• Trigone and base: α1 → contraction reinforces sphincter closure
• Net: bladder capacity ↑, micturition inhibited - logical during fight-or-flight (you don't urinate when fleeing)
• Clinical relevance: α1 blockers (tamsulosin, prazosin) relax the internal sphincter → used in BPH to aid urination. β3 agonists (mirabegron) relax detrusor → used in overactive bladder.

11. Liver Cells (Hepatocytes)

• NE/Epi → α1 on hepatocytes → Gq → PLC → ↑IP3 → ↑Ca²⁺ from ER + ↑DAG → PKC activation
• ↑Ca²⁺ → activates phosphorylase kinase → activates glycogen phosphorylase → breaks down glycogen → glucose-1-phosphate → glucose released into blood
• Epi → β2 (minor contribution) → Gs → ↑cAMP → PKA → also activates glycogen phosphorylase and inhibits glycogen synthase
• ↑Gluconeogenesis: PKA → ↑expression of PEPCK and other gluconeogenic enzymes
• Net: rapid ↑blood glucose to fuel muscles and brain during stress

12. Insulin (Pancreatic β-Cells)

• NE → α2 receptors on pancreatic β-cells → Gi protein → ↓adenylyl cyclase → ↓cAMP → ↓PKA activity → ↓exocytosis of insulin granules → ↓insulin secretion
• α2 also → opens K⁺ channels → hyperpolarization → prevents Ca²⁺ entry → further ↓insulin release
• Glucagon (α-cells): β2 → Gs → ↑cAMP → ↑glucagon secretion (counteracts hypoglycemia)
• Net metabolic effect: ↓insulin + ↑glucagon → ↑blood glucose (from liver) + ↑lipolysis (from fat)
• This ensures glucose stays available for brain and muscles during emergency

13. Na⁺/K⁺-ATPase (Sodium-Potassium Pump) in Cells

• Epi/NE → β2 receptors on cell membranes → Gs → ↑cAMP → PKA activation
• PKA phosphorylates the Na⁺/K⁺-ATPase α-subunit → ↑pump activity
• Pump moves 3 Na⁺ out and 2 K⁺ in per cycle → net K⁺ uptake into cells
• This occurs in skeletal muscle, liver, heart cells
• Result: serum K⁺ falls (hypokalemia) - transient but significant
• Also occurs via β2 → ↑insulin release (minor) which also stimulates Na⁺/K⁺-ATPase

• Maintains high intracellular K⁺ (needed for resting membrane potential)
• During exercise/stress, K⁺ leaks out of contracting muscles; β2-driven pump activity counteracts excessive hyperkalemia

• Stress-induced hypokalemia (e.g., post-MI surge in catecholamines → ↓K⁺ → arrhythmias)
• β2 agonists (salbutamol) used to treat hyperkalemia by driving K⁺ into cells
• Non-selective β-blockers can blunt this pump stimulation → relative K⁺ retention

Master Summary Table