L06 MSK Physiology 1 Nerves and Neurons

Overview

This is lecture 1 of the Musculoskeletal module’s nerve-and-muscle physiology strand (Dr Mike Gill, Physiology Dept). It builds the structural and electrical foundation for everything that follows: first the cellular and gross anatomy of the nervous system (neurons, glia, peripheral nerve, spinal cord and roots), then the classification of axons by diameter, myelination and conduction velocity, then the physiological basis of the resting membrane potential (concentration gradients plus differential permeability, quantified by the Goldman-Hodgkin-Katz equation), and finally the gated ion channels that allow that potential to be changed. The logic runs structure -> classification -> resting state -> the channels that let the resting state be modulated, which is the entry point to equilibrium potentials and the action potential in lecture 2.

Course map and objectives

The nerve/muscle course is arranged by theme across five lectures:

• Neurons & Nerves — Lecture 1: neurons and nerves; “resting” membrane potential; gated membrane ion channels. Lecture 2: equilibrium potentials; passive (local) potentials; the action potential.
• Synapses — Lecture 3: propagation of action potentials; the chemical synapse.
• Muscle — Lecture 4: skeletal (striated) muscle; excitation/contraction coupling. Lecture 5: physical limits to muscle performance; active control of muscle force.

Related resources: laboratory classes on Nerve and Skeletal Muscle, and the Physiology Case Tutorial “Mrs MG”.

Whole-course objectives (bracketed numbers = the lecture that covers them) — be familiar with the basic anatomy of neurons and nerves and axon classification schemes (1); understand the physiological basis of the RMP (1) and the role and type of ion channels (1); understand passive (local) potentials and action potentials and their generation (2); understand action-potential propagation, determinants of conduction velocity and the role of myelin (2,3); understand synaptic transmission in general and the neuromuscular junction in particular (3, case); understand excitation-contraction coupling in striated muscle (4); understand how muscle force depends on length and velocity of length change (5); understand how the nervous system regulates force generation (5).

Lecture 1 objectives (stated at the start and repeated at the end):

• Be familiar with the basic anatomy of neurons and nerves
• Be familiar with the classification schemes for axons within nerves
• Understand the physiological basis of the resting membrane potential
• Understand the role and types of ion channels

Organisation of the nervous system

• Central Nervous System (CNS) — brain and spinal cord.
• Peripheral Nervous System (PNS), including the enteric nervous system (ENS) — peripheral nerves and ganglia.
• Each division is composed of the same two general cell classes: neurons and glia.

Neurons: structure and morphological types

The structural sequence of a neuron, in order, is: dendrites -> soma (containing the axon hillock) -> axon (myelinated, with nodes of Ranvier separated by internode segments) -> presynaptic terminals, which contact the dendrites of downstream neurons across a synaptic cleft. The four labelled regions are dendrites, soma, axon and synapses.

Four morphological types of neuron:

1. Multipolar — multiple processes emanate from the cell body (dendrites plus an axon).
2. Bipolar — two processes emanate from the cell body.
3. Unipolar — one process emanates from the cell body, then branches into a dendrite (input end) and an axon (output end).
4. Anaxonic (axonless) — no distinct axon; all processes look alike.

Size and shape vary with function. Illustrated with olfactory bulb neurons:

• Projection (output) neurons — tufted cell, mitral cell; their processes extend over long distances, out of the imaged region.
• Local circuit (intrinsic) interneurons — periglomerular cell, granule cell; their processes remain local.

Glia: non-neuronal support cells

Central nervous system

• Oligodendrocytes — form the myelin sheath (one oligodendrocyte wraps several axons).
• Astrocytes — provide nutrients, maintain the extracellular environment, provide structural support.
• Microglia — mount the immune response.
• Ependymal cells — circulate and produce cerebrospinal fluid; they line the fluid space.

Peripheral nervous system

• Schwann cells — form the myelin sheath.
• Satellite cells — provide nutrients and structural support to neurons; they surround the cell body.

Peripheral nerve structure

Connective-tissue layering, outer to inner: epineurium (encloses the whole nerve) -> perineurium (surrounds each fascicle) -> endoneurium (supports individual nerve fibres within a fascicle). A nerve therefore consists of fascicles of nerve fibres, plus blood vessels running within it.

Schwann cell ultrastructure. One Schwann cell wraps a single large axon in myelin; a separate Schwann cell envelops several unmyelinated axons together. Labelled components: Schwann cell and its nucleus, myelin sheath, basal lamina, microtubules, neurofilaments, mitochondrion. Along a myelinated axon, Schwann cell somata sit between nodes of Ranvier. In cross-section a nerve contains myelinated axons of widely varying diameter alongside unmyelinated ones.

Spinal cord, roots and the reflex arc

Spinal cord and nerve roots. Dorsal and ventral root filaments leave the cord and join to form the mixed spinal nerve; the dorsal root ganglion sits on the dorsal root. The cord is wrapped by pia mater, arachnoid and dura mater (with a root sleeve). Other labelled cord features: posterior median septum, posterior intermediate septum, dorsal root entry zone, posterior and anterior gray horns, posterior/lateral/anterior funiculi, anterior median fissure.

Spinal reflex arc — pathway in order: somatic sensory receptor -> sensory axon -> primary sensory neuron (cell body in the dorsal root ganglion) -> dorsal root -> dorsal horn -> interneuron -> motor neuron in the ventral horn -> ventral root -> motor axon -> motor endplate -> skeletal muscle.

Dermatomes. The spinal cord is divided into cervical, thoracic, lumbar and sacral regions, and each spinal segment supplies a defined strip of skin: cervical (C2–C8) over head, neck and upper limb; thoracic (T1–T12) over the trunk; lumbar (L1–L5) over the anterior thigh, leg and foot; sacral (S1–S5) over the posterior leg and perineal region.

Ascending and descending tracts occupy the white matter, colour-coded as ascending, descending, and short ascending/descending pathways:

• Ascending/sensory named tracts: fasciculus gracilis, fasciculus cuneatus, dorsolateral tract (fasciculus) of Lissauer, dorsal (posterior) spinocerebellar tract, lateral spinothalamic and spinoreticular tracts, ventral (anterior) spinocerebellar tract, spinoolivary tract, spinotectal tract, ventral (anterior) spinothalamic tract.
• Descending named tracts: lateral corticospinal (pyramidal) tract (crossed), rubrospinal tract, lateral (medullary) reticulospinal tract, medial longitudinal (sulcomarginal) fasciculus, vestibulospinal tract, ventral (anterior) or medial (pontine) reticulospinal tract, tectospinal tract, ventral (anterior) corticospinal tract (direct).
• Short/propriospinal: fasciculus proprius, septomarginal fasciculus (oval bundle), interfascicular fasciculus (comma tract).

Axon classification and conduction velocity

Two classification schemes are used in parallel: the Erlanger-Gasser (A/B/C) scheme, which applies to both sensory and motor axons, and the numeral (I–IV) scheme, which applies to sensory axons only. Conduction velocity tracks diameter and myelination: large and heavily myelinated = fast.

Sensory and motor (Erlanger-Gasser):

Fibre	Example / function	Diameter & myelination	Conduction velocity
A-alpha	Alpha motoneurons	Large, heavily myelinated	Fast, 80–120 m/s
A-beta	Touch, pressure	Medium, heavily myelinated	Moderate, 33–75 m/s
A-gamma	Intrafusal fibres	Medium, heavily myelinated	Moderate, 33–75 m/s
A-delta	Touch, pressure, temperature, fast pain	Small, heavily myelinated	Moderate, 33–75 m/s
B	Preganglionic autonomic nerves	Small, lightly myelinated	Moderate, 33–75 m/s
C	Slow pain, postganglionic autonomic nerves, olfaction	Small, unmyelinated	Slow, 0.5–2.0 m/s

Sensory only (numeral scheme):

Fibre	Example / function	Diameter & myelination	Conduction velocity
Ia	Muscle spindle afferents	Large, myelinated	Fast, 80–120 m/s
Ib	Golgi tendon organ afferents	Large, myelinated	Fast, 80–120 m/s
II	Secondary afferents of muscle spindles; touch, pressure	Medium, myelinated	Moderate, 33–75 m/s
III	Touch, pressure, fast pain, temperature	Small, myelinated	Moderate, 33–75 m/s
IV	Pain, temperature, olfaction	Small, unmyelinated	Slow, 0.5–2.0 m/s

Cross-mapping of the two schemes, with diameters:

Type	Erlanger-Gasser	Diameter (um)	Myelin	Conduction velocity (m/s)
Ia	A-alpha	13–20	Yes	80–120
Ib	A-alpha	13–20	Yes	80–120
II	A-beta	6–12	Yes	33–75
III	A-delta	1–5	Thin	3–30
IV	C	0.2–1.5	No	0.5–2.0

Resting membrane potential

How it is demonstrated. A voltmeter is connected between an intracellular electrode and an extracellular reference electrode in the bathing solution. While both electrodes are outside the cell the recorded potential is zero; at the moment the electrode enters the cell the potential steps abruptly down to a steady negative value — the RMP — and stays there.

Key facts:

• The RMP is found experimentally.
• The inside of neurons is electrically negative compared with the outside.
• It arises from a combination of: (i) concentration gradients for ions across the membrane, and (ii) differential permeability of the membrane to K+ compared with Na+.

Ions and channels (reminder).

• Ions are charged particles: positive charge = cation (K+, Na+, Ca2+ — think “ca+ion”); negative charge = anion.
• They are influenced by electrostatic forces: like charges repel, opposite charges attract.
• Ions cannot diffuse across cell membranes on their own; diffusion is facilitated by channels and carriers, specialised protein structures.
• There are many different types; they exist in open and closed states; open/closed can be regulated — therefore ion movement can be regulated.

Electrochemical gradient

The gradient has two components plus a permeability requirement:

1. Chemical potential — concentration dependent; ions move from high to low concentration. The gradients are maintained by the Na+/K+-ATPase, an energy-dependent primary active transporter that moves 3 Na+ out for every 2 K+ in, using ATP.
2. Electrical potential — charge (valence) dependent; driven by the chemical potential, so if you change the chemical gradient the electrical potential will shift.
3. Permeability — all of this only works if specific ions can cross the membrane via channels and carriers. When channels open, ions flow.

Typical concentrations given:

Ion	Outside	Inside
Na+	145 mM	10 mM
K+	4 mM	150 mM

Na+ moves down its gradient into the cell and K+ down its gradient out of the cell, with the pump restoring both; the inside of the cell sits at -70 mV.

Calculating the RMP: the Goldman-Hodgkin-Katz equation

$\Delta \psi =\frac{RT}{F}\ln \frac{P_K[K{]}_o+P_{Na}[Na{]}_o+P_{Cl}[Cl{]}_i}{P_K[K{]}_i+P_{Na}[Na{]}_i+P_{Cl}[Cl{]}_o}$

Where $R$ = universal gas constant, $T$ = temperature (K), $F$ = Faraday’s constant, $\ln$ = natural log, $P_X$ = relative permeability of ion X, $[X{]}_o$ = concentration outside, $[X{]}_i$ = concentration inside.

• The equation calculates the RMP, taking into account the concentration difference of the main ions involved and their experimentally determined permeability.
• $P$ is a ratio — in effect, how many ion channels there are and whether they are open.
• Concentration gradients matter: if the ratio [out]/[in] changes, the RMP changes too.
• The formula therefore allows the RMP to be calculated if the ionic composition of the ECF or ICF changes.

Changes in extracellular K+ can change the RMP -> change excitability -> paralysis, cardiac arrhythmia, death.

The RMP is highly sensitive to [K+]out. GHK-calculated values:

Manipulation	Values	Effect on RMP
Double/halve extracellular K+ (0–10 mmol/L)	-68.2 mV at [K]o 9; -79.8 mV at [K]o 4.5; -88.2 mV at [K]o 2.25	Steeply rising curve; shifts RMP by roughly 8–12 mV
+4.5 / -2.25 mmol/L extracellular Na+ (135–145 mmol/L)	-79.5 mV at [Na]o 144.5; -79.8 mV at [Na]o 140; -79.9 mV at [Na]o 137.25	Essentially flat — equivalent absolute changes in Na+ barely move the RMP
Double/halve extracellular Na+ (0–300 mmol/L)	-85.1 mV at [Na]o 70; -79.8 mV at [Na]o 140; -71.5 mV at [Na]o 280	Shallower rise — even doubling/halving Na+ produces a smaller shift than the equivalent change in K+

The same slide shows human electrocorticography (ECoG): an electrode strip laid on the exposed cortical surface intraoperatively, with the recording site marked relative to the central sulcus (CS).

Clinical application: spreading depolarisation after brain injury

“Spreading depolarization”, involving extracellular K+ ([K+]o), worsens brain injury.

• In the healthy brain, astrocytes and neurons around a blood vessel have normal slender processes. In tissue at risk undergoing spreading depolarisation, neurons are swollen with beaded, blebbed processes.
• After stroke, a brain section shows a central core of dead tissue surrounded by a rim of penumbra.
• Recordings from an electrode array spanning core -> penumbra -> healthy tissue show the boundary shifting over time, with traces taken at 1 day and 5 days post stroke (power scales 0.7 mV${}^2$, and 0.2 mV${}^2$ for the lowest trace at 5 days; 30 min and 60 min time bases).

This slide carries only the title as text; the interpretation of the trace panels beyond their labels is not stated on the slide.

Gated ion channels

The functional chain is: “gated” ion channels -> controlled changes in selective permeability to ions -> changes in membrane potential -> signalling in the nervous system. In a lipid bilayer, an open channel permits ion flux through its pore while a closed channel permits none. Three gating mechanisms are covered.

(1) Voltage-gated ion channels — e.g. the voltage-gated Na+ channel. Other voltage-gated channels exist for K+ and Ca+. Some voltage-gated K+ channels are also sensitive to intracellular ions, e.g. Ca+, Na+.

• Sodium channel — three states: Closed -> Open (Na+ flows in) -> Inactivated (the inactivation gate plugs the pore). It opens and inactivates very rapidly.
• Potassium channel — two states: Closed <-> Open (K+ flows). It opens and closes slowly.

(2) Mechanically gated ion channels — e.g. touch receptors, auditory receptors. Sequence: a physical stimulus presses on the membrane while the pore is shut -> membrane deformation (the bilayer bends/stretches) -> the channel subunits are pulled apart -> the pore opens.

(3) Chemically (ligand) gated channels — e.g. synapses, olfaction, taste, pain. Two sub-types:

• (a) Direct gated — e.g. the nicotinic AChR. The receptor site is part of the channel itself; the ligand binds to the receptor site on the channel’s subunits while the channel is closed, and binding opens the pore directly so ions flow through.
• (b) Indirect gated — e.g. the muscarinic AChR. The receptor is a separate protein from the channel; the ligand binds the receptor, which activates an associated G-protein, which acts via a 2nd messenger system that then opens the channel — so the pore opens through an intermediate signalling step rather than by direct ligand binding.

Self-test

1. Name the two divisions of the nervous system, state what each consists of, and name the two general cell classes found in both.
2. List, in order, the structural regions of a typical neuron from input to output.
3. List the four morphological types of neuron and give one distinguishing feature of each.
4. Distinguish projection (output) neurons from local circuit interneurons, and give one example of each from the olfactory bulb.
5. List the four CNS glial cell types and state the function of each.
6. List the two PNS glial cell types named in the lecture and state the function of each.
7. Name the three connective-tissue layers of a peripheral nerve, from outermost to innermost, and state what each surrounds.
8. Explain how a single Schwann cell relates differently to a large myelinated axon compared with unmyelinated axons.
9. Describe, in order, the components of a spinal reflex arc from sensory receptor to skeletal muscle.
10. Explain what a dermatome is and state which spinal levels supply the trunk and the anterior thigh, leg and foot.
11. Name three ascending and three descending tracts of the spinal cord.
12. State the two axon classification schemes used, and explain which fibre types each one applies to.
13. Give the diameter, myelination and conduction velocity of Ia/Ib, II, III and IV fibres.
14. Explain why alpha motoneuron axons conduct at 80–120 m/s whereas C fibres conduct at 0.5–2.0 m/s.
15. State the Erlanger-Gasser fibre types that carry: preganglionic autonomic traffic, slow pain, fast pain, and intrafusal (muscle spindle) motor supply.
16. Describe the experiment used to demonstrate the resting membrane potential and what the voltage trace shows.
17. Explain the two factors that together produce the resting membrane potential.
18. Explain why ions require channels and carriers to cross the membrane, and how ion movement can be regulated.
19. State the intracellular and extracellular concentrations of Na+ and K+ given in the lecture, and the resulting membrane potential.
20. Describe the stoichiometry and energy source of the Na+/K+-ATPase and explain its role in the electrochemical gradient.
21. Write out the Goldman-Hodgkin-Katz equation and define each of its terms.
22. Explain what $P$ represents physically in the GHK equation.
23. Predict, using the lecture’s calculated values, what happens to the RMP when extracellular K+ falls from 4.5 to 2.25 mmol/L, and when it rises to 9 mmol/L.
24. Explain why doubling extracellular Na+ shifts the RMP less than doubling extracellular K+.
25. State the clinical consequences of a change in extracellular K+ acting through the RMP.
26. Describe what happens to neurons in tissue undergoing spreading depolarisation, and how the core and penumbra are distinguished after stroke.
27. Describe the functional chain by which gated ion channels produce signalling in the nervous system.
28. Distinguish the gating states and kinetics of the voltage-gated Na+ channel from those of the voltage-gated K+ channel.
29. Describe the sequence by which a mechanically gated ion channel opens.
30. Distinguish direct from indirect ligand gating, naming the example receptor for each.
31. A patient develops a rise in serum K+. Using the GHK equation, explain the mechanism by which this could cause cardiac arrhythmia.
32. A stimulus produces a sensation of sharp, well-localised pain followed seconds later by a dull ache. Using the fibre classification, explain the two-stage timing.
33. Integrative: explain how the Na+/K+-ATPase, membrane permeability, and gated ion channels together account for both the stability of the resting membrane potential and the ability of a neuron to signal.

Answers

Reveal answers

1. CNS = brain and spinal cord; PNS (including the ENS) = peripheral nerves and ganglia. Both are composed of neurons and glia.
2. Dendrites -> soma (containing the axon hillock) -> axon (myelinated, with nodes of Ranvier separated by internodes) -> presynaptic terminals/synapses onto downstream dendrites.
3. Multipolar — multiple processes from the cell body (dendrites plus axon). Bipolar — two processes. Unipolar — one process that then branches into a dendrite (input) and axon (output). Anaxonic — no distinct axon; all processes look alike.
4. Projection (output) neurons have processes extending over long distances beyond the local region — tufted and mitral cells. Local circuit (intrinsic) interneurons keep their processes local — periglomerular and granule cells.
5. Oligodendrocytes form the myelin sheath; astrocytes provide nutrients, maintain the extracellular environment and give structural support; microglia mount the immune response; ependymal cells circulate and produce cerebrospinal fluid.
6. Schwann cells form the myelin sheath; satellite cells provide nutrients and structural support to neurons, surrounding the cell body.
7. Epineurium encloses the whole nerve; perineurium surrounds each fascicle; endoneurium supports individual nerve fibres within a fascicle.
8. One Schwann cell wraps a single large axon in myelin, whereas a separate Schwann cell envelops several unmyelinated axons together.
9. Somatic sensory receptor -> sensory axon -> primary sensory neuron (cell body in the dorsal root ganglion) -> dorsal root -> dorsal horn -> interneuron -> motor neuron in the ventral horn -> ventral root -> motor axon -> motor endplate -> skeletal muscle.
10. Each spinal segment supplies a defined strip of skin. Thoracic T1–T12 supplies the trunk; lumbar L1–L5 supplies the anterior thigh, leg and foot. (Cervical C2–C8: head, neck, upper limb; sacral S1–S5: posterior leg and perineal region.)
11. Ascending — fasciculus gracilis, fasciculus cuneatus, lateral spinothalamic tract (also dorsal/ventral spinocerebellar, spinoreticular, spinoolivary, spinotectal, ventral spinothalamic, dorsolateral tract of Lissauer). Descending — lateral corticospinal (pyramidal) tract, rubrospinal tract, vestibulospinal tract (also reticulospinal, tectospinal, medial longitudinal fasciculus, ventral corticospinal tract).
12. The Erlanger-Gasser scheme (A-alpha, A-beta, A-gamma, A-delta, B, C) applies to both sensory and motor axons. The numeral scheme (I a/b, II, III, IV) applies to sensory axons only.
13. Ia and Ib: 13–20 um, myelinated, 80–120 m/s. II: 6–12 um, myelinated, 33–75 m/s. III: 1–5 um, thinly myelinated, 3–30 m/s. IV: 0.2–1.5 um, unmyelinated, 0.5–2.0 m/s.
14. Alpha motoneuron axons are large and heavily myelinated, which gives fast conduction; C fibres are small and unmyelinated, which gives slow conduction. Conduction velocity tracks diameter and myelination.
15. Preganglionic autonomic — B (small, lightly myelinated). Slow pain — C. Fast pain — A-delta. Intrafusal fibres — A-gamma.
16. A voltmeter is connected between an intracellular electrode and an extracellular reference electrode in the bathing solution. With both electrodes outside the cell the potential reads zero; at the moment the electrode enters the cell the potential steps abruptly down to a steady negative value, the RMP, and remains there.
17. Concentration gradients for ions across the membrane, plus differential permeability of the membrane to K+ compared with Na+. The result is that the inside of the neuron is electrically negative relative to the outside.
18. Ions are charged particles and cannot diffuse across the lipid membrane themselves; diffusion is facilitated by channels and carriers (specialised proteins). These exist in open and closed states and the open/closed state can be regulated, so ion movement can be regulated.
19. Na+ 145 mM outside, 10 mM inside; K+ 4 mM outside, 150 mM inside; the inside of the cell is at -70 mV.
20. It moves 3 Na+ out of the cell for every 2 K+ in, using ATP — energy-dependent primary active transport. It maintains the concentration (chemical) gradients that the electrical potential is driven by.
21. $\Delta \psi =\frac{RT}{F}\ln \frac{P_K[K{]}_o+P_{Na}[Na{]}_o+P_{Cl}[Cl{]}_i}{P_K[K{]}_i+P_{Na}[Na{]}_i+P_{Cl}[Cl{]}_o}$, where R = universal gas constant, T = temperature in kelvin, F = Faraday’s constant, ln = natural log, P_X = relative permeability of ion X, [X]o = extracellular concentration, [X]i = intracellular concentration.
22. $P$ is a relative permeability ratio — in practical terms, how many ion channels there are for that ion and whether they are open.
23. Falling from 4.5 to 2.25 mmol/L takes the RMP from -79.8 mV to -88.2 mV (hyperpolarisation); rising to 9 mmol/L takes it from -79.8 mV to -68.2 mV (depolarisation). Doubling or halving [K+]o shifts the RMP by roughly 8–12 mV.
24. Because the membrane’s permeability to K+ is much greater, K+ terms dominate the GHK equation. Doubling/halving extracellular Na+ moves the RMP only from -79.8 mV to -71.5 mV or -85.1 mV, a smaller shift than the equivalent change in K+; equivalent absolute changes in Na+ (a few mmol/L) barely move it at all.
25. A change in extracellular K+ changes the RMP, which changes excitability, which can produce paralysis, cardiac arrhythmia and death.
26. In spreading depolarisation the neurons become swollen with beaded, blebbed processes, in contrast to the slender processes of healthy tissue. After stroke, a central core of dead tissue is surrounded by a rim of penumbra; electrode recordings across core -> penumbra -> healthy tissue show the boundary shifting over time (1 day vs 5 days post stroke). [The slide does not state an interpretation of the trace panels beyond their labels.]
27. “Gated” ion channels -> controlled changes in selective permeability to ions -> changes in membrane potential -> signalling in the nervous system.
28. The Na+ channel has three states — Closed -> Open (Na+ enters) -> Inactivated (inactivation gate plugs the pore) — and opens and inactivates very rapidly. The K+ channel has two states, Closed <-> Open, and opens and closes slowly.
29. A physical stimulus presses on the membrane while the pore is shut; this causes membrane deformation (the bilayer bends or stretches), which pulls the channel subunits apart so the pore opens. Examples: touch receptors, auditory receptors.
30. Direct gating (nicotinic AChR): the receptor site is part of the channel itself, so ligand binding to the subunits opens the pore directly. Indirect gating (muscarinic AChR): the receptor is a separate protein; ligand binding activates an associated G-protein, which acts via a 2nd messenger system to open the channel.
31. Raising [K+]o increases the $P_K[K{]}_o$ term in the numerator of the GHK equation, which makes the calculated RMP less negative (depolarised). A changed RMP changes membrane excitability, and in cardiac tissue this can produce arrhythmia (and, at the extreme, death).
32. Fast, sharp pain is carried by A-delta (type III) fibres, which are small but heavily/thinly myelinated and conduct at moderate speed (33–75 m/s, or 3–30 m/s for type III). Slow pain is carried by C (type IV) fibres, which are small and unmyelinated and conduct at 0.5–2.0 m/s, so their signal arrives much later.
33. The Na+/K+-ATPase uses ATP to pump 3 Na+ out and 2 K+ in, maintaining the concentration gradients (Na+ 145 out/10 in; K+ 4 out/150 in). Those gradients only generate a voltage because the membrane is differentially permeable — much more permeable to K+ than Na+ — giving a stable RMP of about -70 mV, quantifiable by the GHK equation. Gated ion channels (voltage-, mechanically- and ligand-gated) then produce controlled changes in selective permeability; changing the $P$ terms changes the membrane potential, and those changes in membrane potential are the signals of the nervous system.