12

PHYSIOLOGY OF PAIN

13

‘For every complex issue, there is an answer that issimple, neat...and wrong!’ There are no ‘pain fibers’in nerves and no ‘pain pathways’ in the brain. Pain isnot a stimulus. The experience of pain is the finalproduct of a complex information-processingnetwork.

AFFERENT RECEPTORSPeripheral sensory receptors are specialized termi -nations of afferent nerve fibers exposed to the tissueenvironment, even when the fiber is myelinated morecentrally. Such receptors are plentiful in the epider -mis/dermis and display differentiated functions (2):• Low-threshold mechanoreceptors: Aα, Aβ in

humans; Aα, Aβ, Aδ, and C in animals.• Displacement: Ruffini endings–stretch; hair

follicle with palisade endings of 10–15 differentnerve fibers each.

• Velocity: Meissner corpuscle.• Vibration: Pacinian corpuscle, fluid environment

with onion-like lamellae acting as high-pass filter.

• Thermal receptors.◦ Cold: discriminates 0.5ºC, 100 µm diameter

field, Aδ.◦ Warm: mostly C fibers.

• Nociceptors:◦ Myelinated: Aδ, most conduct in 5–25 m/s

range, 50–180 µm field, 10–250 receptors/mm2.◦ C polymodal nociceptors; pain.

As terminations of afferent nerve fibers, peripheralsensory receptors allow the receptor to transduce ortranslate specific kinds of energy into actionpotentials. Most peripheral receptors act either bydirect coupling of physical energy to cause changes inion channel permeability or by activation of secondmessenger cascades. Chemoreceptors detect productsof tissue damage or inflammation that initiatereceptor excitation. Free nerve endings are also inclose proximity to mast cells and small blood vessels.Contents of ruptured cells or plasma contents,together with neurotransmitters released fromactivated nerve terminals, create a milieu of proteins,allowing the free nerve endings, capillaries, and mastcells to act together as an evil triumvirate to increasepain (3).

Although there are no pain fibers or painpathways, there are anatomically and physiologicallyspecialized peripheral sensory neurons–nociceptors–which respond to noxious stimuli, but not to weakstimuli (Table 1). These are mostly thinly myelinatedAδ and unmyelinated C afferents, and they end asfree, unencapsulated peripheral nerve endings in mosttissues of the body including skin, deep somatictissues like muscles and joints, and viscera. (The brainitself is not served by these sensory fibers, which iswhy cutting brain tissue does not hurt.) Thicklymyelinated Aβ afferents typically respond to lighttactile stimuli. They also respond to noxious stimuli,but they do not increase their response when thestimulus changes from moderate to strong, i.e. theydo not encode stimuli in the noxious range. AlthoughAβ afferents do respond to painful stimuli, electricalstimulation, even at high frequency, normallyproduces a sensation not of pain, but of nonpainfulpressure. Convergence of large- and small-diameterafferents of various sorts at the level of the dorsalhorn, with further processing in the brain, gives riseto a variety of everyday sensations.

2 Afferent receptors are widely dispersed and serve differentfunctions, allowing the animal to sense its environment.(Adapted from: Tranquilli WJ, et al. Pain Management for theSmall Animal Practitioner. Teton NewMedia 2004, 2nd edition(with permission)).

2

Carpalpad

Dorsal branchof ulnar nerve

Palmar branchof ulnar nerve

Mediannerve

Merkels discs

Free nerve endings

Tactile hair

Muscle spindle

Krause's corpuscle

Pacinian corpuscle

Golgi tendonapparatus

Ruffiniendings

Meissnercorpuscle

3

3 A milieu of inflammatory mediators results in receptor excitation that transduce or translate specific forms of energy into actionpotentials. Such action potentials become the nociceptive messengers for pain.

Dorsal horn

Laminae ofspinal cord

Ventral horn

Low-thresholdmechanoreceptors

Temperature and painreceptors

Afferent(sensory)

Efferent(motor)

Proprioceptors

Dermis

Subcutis

Epidermis

Paciniancorpuscle

Meissnercorpuscle

Merkel cells

Ruffiniendings

Hair rootplexus

Hairfollicle

Freenerve

endings

Third-orderneuron

Second-orderneuron

First-orderneuron

Table 1 Nociceptors and fiber types.

Nociceptors Fiber type and response

Aδ Small myelinated fibers; slowest conducting are nociceptors

AMH type I Respond to mechanical stimuli;(A mechano-heat) have heat threshold of 53ºC, but sensitize rapidly to heat; most common

AMH type II Respond to mechanical stimuli; threshold 47ºC, also respond to noxious cold

AM Respond only to noxious mechanical stimulation

CMH Most common C (polymodal nociceptor); responds to mechanical stimuli; thermal threshold45–49ºC; noxious cold ≤4ºC

CH Responds to heat only; thermal threshold 45–49ºC

CMC Like CMH, responds to noxious cold instead of heat

CC Responds to noxious cold only

Silent nociceptors Do not fire in absence of tissue injury

In addition, there is a synergism between an acid pHand the capsaicin (VR1) receptor, such thattransmembrane current is significantly increased fromthe inflammatory environment.4 To date, strongevidence exists showing that nociceptor firing andhuman perception of pain are correlated (the animalcorollary is not yet validated).

Cell bodies manufacture neurotransmitters andmodulators of all kinds, as well as receptors and ion

channels. These are transported from the DRG bothcentrally and peripherally (5). Glutamate is the majorexcitatory neurotransmitter of nociceptors.sP and CGRP are peptide transmitters of nociceptors.Ion channels exist along the length of the primaryafferent fibers and functional receptors, whilemechanisms to release at least some neuro -transmitters also prevail along the length of theaxon. Several neurotransmitters can exist in a singleneuron.

Depolarization induces the release of neurotrans -mitters (6), and excesses of released neurotransmit ters(e.g. glutamate) are recycled by the presynapticterminal. Further, it has been shown that calciumflow through transient receptor potential (TRV)receptors along the course of the axon is sufficient tocause release of neurotransmitters, independent ofaxon depolarization.5 This implies that inflammatorymediators, heat, or changes in pH can cause release ofpotentially pain-producing substances along theentire length of a nerve. However, the patient willsense the pain emanating from the peripheralterminations. It is also noted that the release of someneurotransmitters cannot be evoked by individualinflammatory mediators, such as prostaglandin (PG)E2; however, together with bradykinin, PGE2 canenhance neurotransmitter release.

PHYSIOLOGY OF PAIN

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A change in temperature or an agonist binding to amembrane may cause a conformational change in theshape of a receptor protein allowing influx of ions ortriggering second messenger pathways (4). Whentransient receptor potential (TRP) (vanilloid orcapsaicin) receptors are activated, they directly allowcalcium ion cell influx, which can be sufficient toinitiate neurotransmitter release.

Primary afferents will fire action potentials atdifferent adaptive rates. For example, touch receptorsor vibration detectors and hair follicle afferents fire atthe beginning and sometimes at the end of amaintained stimulus–they respond to the change(delta) of a stimulus. In contrast, nociceptors neverfully adapt and stop firing in the presence of astimulus. They are difficult to turn off once they areactivated.

The term vanilloid refers to a group of substancesrelated structurally and pharmacologically tocapsaicin, the pungent ingredient of chili peppers. Theprincipal action of capsaicin and other vanilloids onthe sensory neuron membrane is to produce anonselective increase in cation (+) permeability,associated with the opening of a distinct type ofcation channel. The inward current responsible fordepolarization and excitation of the neurons iscarried mainly by sodium ions, but the channel is alsopermeable to divalent cations, including calcium. Thevanilloid receptor VR1 (also called TRPV1) shows aremarkable characteristic of heat sensitivity (and alsoacidic pH), with robust channel opening in responseto increases in ambient temperature. The physio -logical effects of capsaicin are numerous:• Immediate pain.• Various autonomic effects caused by peripheral

release of substance P (sP) and calcitonin gene-related peptide (CGRP), inducing profoundvasodilatation, while release of sP promotesvascular leakage and protein extravasation;components of the neurogenic inflammatoryresponse: rubor (redness), calor (heat), and tumor(swelling).

• An antinociceptive effect of varying duration,associated with desensitizative effect of capsaicinon the peripheral terminals of C fibers. Thecellular mechanisms underlying theneurodegenerative consequences of capsaicinlikely involve both necrotic and apoptotic celldeath.

• A fall in body temperature: a reflex responsegenerated by thermosensitive neurons in thehypothalamus following capsaicin activation ofprimary afferent fibers.

Capsaicin acts on nonmyelinated peripheral afferentfibers to deplete sP and other transmitter peptides; thenet effect is first to stimulate and then to destroy Cfibers.1

A number of receptor systems reportedly play arole in the peripheral modulation of nociceptorresponsiveness. The vanilloid receptor, TRPV1, ispresent on a subpopulation of primary afferent fibersand is activated by capsaicin, heat and protons.Following inflammation, axonal transport of TRPV1mRNA is induced, with the proportion of TRPV1-labeled unmyelinated axons in the periphery beingincreased by almost 100%.2 The inflammatorymediator bradykinin lowers the threshold of TRPV1-mediated heat-induced currents in dorsal rootganglion (DRG) neurons, and increases theproportion of DRG cells that respond to capsaicin.3

14

4

4 Receptor activation may allow ion influx or trigger a secondmessenger pathway that initiates an action potential.

Cold

TRPM8? TRPV3?

Ca++

Generator potential

Actionpotential

TRPV1 ASIC

P2X/P2YTRPA1, TRP?

ATP

Heat H+ Mechanical

5 Neurotransmitters and modulators are transported from theDRG both centrally and peripherally.

5Spinal cord

Synapticrelease

Centralterminal

Dorsal rootganglion

Periphery

Dorsal horn

Neurogenicrelease

Distal terminal

Exocytosis

6 At the synapse, there is a chemical transmission of the nerve impulse.

6

Actionpotential

Ca++

Presynapticterminal

Synapticcleft Postsynaptic

membrane

Postsynaptic channelreceptors

Neurotransmitter-filled vesicles fused with membrane

1. Action potential reaches presynapticterminal.

2. Depolarization of presynaptic terminalopens ion channels allowing calcium(Ca++) into cell.

3. Ca++ triggers release of neurotransmitterfrom vesicles.

4. Neurotransmitter binds to receptor siteson postsynaptic membrane.

5. Opening and closing of ion channelscause change in postsynaptic membranepotential.

6. Action potential propagates through nextcell.

7. Neurotransmitter is inactivated ortransported back into presynapticterminal.

Actionpotential

16

PHYSIOLOGY OF PAIN

17

MEDIATORS OF PAINPGs are not the only chemical mediators ofinflammation and hypersensitivity. The acidity andheat of injured, inflamed tissue enhances pain andhypersensitivity through response of thecapsaicin/vanilloid receptor (TRPV1). sP and CGRPcan be released from the peripheral terminals ofactivated C fibers and contribute to neurogenicinflammation by causing vasodilatation. Affectedtissues are subsequently in a state of peripheralsensitization. sP is an 11-amino-acid peptideneurotransmitter, often co-occurring with CGRP,which, when released in the spinal dorsal horn,activates second-order transmission neurons thatsend a nociceptive (‘pain’) signal to the brain.

PLASTICITY ENCODINGRené Descartes (1596–1650) proposed that ‘pain’was transmitted from the periphery to a higher centerthrough tubes of transfer (8). From the concept ofDescartes came the Cartesian model: a fixedrelationship between the magnitude of stimulus andsubsequent sensation (9).

The Cartesian model has evolved over the centuriesthrough the contributions of many, includingC.S. Sherrington (1852–1952), who coined the

term ‘nociception’, stating that a nociceptive stimuluswill evoke a constellation of responses whichdefine the pain state. Nociception, per se, separatesthe detection of the event (noxious stimulus) from theproduction of a psychological or other type ofresponse (pain). In a simple example, injury in thelegs of a paraplegic produces nociception fromimpulses in nociceptors, exactly as in a normalsubject, but there is no pain perceived. A commonclinical example is routine surgery, whereneurobiolgical data confirms nociception (response tothe noxious stimulus), but pain is not experiencedwhile the patient is at an appropriate stage ofanesthesia, i.e. there is no cognitive processing of thenociception.

The classic Cartesian view of pain stemmed fromRené Descartes’ ‘bell ringer’ model of pain in whichpain, as a purely quantitative phenomenon, isdesigned to alert us to physical injury. Studying WorldWar II injuries, Henry Beecher observed that somesoldiers with horrendous injuries often felt no pain,while soldiers with minor injuries sometimes hadsevere pain. Beecher concluded that Descarte s’ theorywas all wrong: there is no linear relationship betweeninjury and the perception of pain.

Neurotransmitters are noted as such only if theyhave a receptor for binding. Other criteria include: (1) synthesis in the neuron DRG, (2) seen inpresynaptic terminal (central or peripheral) andreleased in sufficient quantities to exert a definedaction on the postsynaptic neuron or tissue, (3)exogenous admin istration mimics endogenouslyreleased neurotrans mitter, (4) a mechanism exists forits removal, and (5) it is released by neuronal

7

7 Many different types of receptors may reside on primary afferent terminals. (Adapted from Woolf CJ, Costigan M.Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci 1999; 96: 7723–7730).

NGF

TNFαIL-6LIF

CRHIL-1β

PKC

PKA

Platelets

Platelets

Macrophage

GIRK

Adenosine

Immune cell

Tissue damage

Mast cell

SSTR2a

Keratinocytes

Endorphins

Inhibitory

Gene regulation

Heat

Bradykinin

Histamine

Vasodilatation

ASIC

GABAA

mGluR1.5µ

iGluR

H

M2

P2X3 TrKA IL-1-R B2/B1 EPH1 5-HTA2

PGE2

IL-Tβ

sP

TRPV1

TTXr

8 In the seventeenth century, René Descartes proposed thatpain was transmitted through tubes of transfer.

8

depolarization in a Ca++-dependent fashion. Manydifferent neuro transmitters exist, most notably gluta -mate, sP, and CGRP. Glutamate is the most prevalentneurotransmitter in the CNS, and is synthesized notonly in the cell body, but also in the terminals.

Several receptors reside on primary afferentterminals, which regulate terminal excitability:serotonin, somatostatin, interleukin, tyrosine kinase,ionotropic glutamate, etc. (7).

9 Cartesian model: psychophysical experience (pain report) = f(stimulus intensity).

9

Pain

sco

re

Bloo

d pr

essu

re c

hang

e

Stimulus Stimulus

Verbal report Physiologicalresponse

ATP

Glutamate

H

PAF

10 first theory to propose that the CNS controlsnociception. The basic premises of the gate controltheory of pain are that activity in large (non-nociceptive) fibers can inhibit the perception ofactivity in small (nociceptive) fibers and thatdescending activity from the brain also can inhibitthat perception, i.e. interneurons of the substantiagelatinosa regulate the input of large and small fibersto lamina V cells, serving as a gating mechanism.Most simplistically: fast moving action potentials inmyelinated fibers activate inhibitor neurons that shutdown second-order neurons before slower arrivingsignals reach the inhibitor neurons via nonmyelinatedfibers (11). These signals from unmyelinated fiberswould normally shut down inhibitor neurons, therebyallowing further transmission through second-orderneurons. With the gate theory, Melzack and Wallformalized observations that encoding of high-intensity afferent input was subject to modulation.Although their concept was accurate, details of theirexplanation have since been more accuratelymodified.

As an example, transcutaneous electrical nervestimulation (TENS) therapy is a clinical implementa -tion of the gate theory. TENS is thought to act bypreferential stimulation of peripheral somatosensoryfibers, which conduct more rapidly than nociceptivefibers. This results in a stimulation of inhibitoryinterneurons in the second lamina of the posterior

horn (substantia gelatinosa) that effectively blocksnociception at the spinal cord level. Further, the gatetheory may explain why some people feel a decreasein pain intensity when skin near the pain region isrubbed with a hand (‘rubbing it better’), and how alocal area is ‘desensitized’ by rubbing prior toinsertion of a needle. An additional example wouldbe the shaking of a burned hand, an action thatpredominantly activates large nerve fibers.

ACTIVITY OF NOCICEPTORSInjured nerve fibers develop ectopic sensitivity.A substantial proportion of C fiber afferents arenociceptors, and abnormal spontaneous activity hasbeen observed in A fibers and C fibers originatingfrom neuronal-resultant nerve transections. Inpatients with hyperalgesic neuromas, locallyanesthetizing the neuroma often eliminates the pain.9

Nociceptor activity induces increased sympatheticdischarge. In certain painful patients, nocipeptorsacquire sensitivity to norepinephrine (NE;noradrenalin) released by sympathetic efferents. Paincaused by activity in the sympathetic nervous systemis referred to as sympathetically maintained pain. Inhuman studies of stump neuromas and skin,10 it isconcluded that apparently sympatheticallymaintained pain does not arise from too muchepinephrine (adrenalin), but rather from the presenceof adrenergic receptors that are coupled tonociceptors. In sympathetically maintained pain,nociceptors develop α-adrenergic sensitivity such thatthe release of NE by the sympathetic nervous systemproduces spontaneous activity in the nociceptors.This spontaneous activity maintains the CNS in asensitized state. Therefore, in sympathet icallymaintained pain, NE that normally is released fromthe sympathetic terminals acquires the capacity toevoke pain. In the presence of a sensitized centralpain-signaling neuron (second order), pain inresponse to light touch is induced by activity in low-threshold mechanoreceptors–allodynia. In thiscircumstance, α1-adrenergic antagonists lessennociceptor activity and the resultant hyperalgesia orallodynia.

VOLTAGE-GATED ION CHANNELSFollowing thermal, mechanical or chemical stimula tionof primary afferents, the excitatory event must initiate aregenerative action potential involving voltage-gatedsodium, calcium or potassium channels culminating inneurotransmitter release, if sensory information is to beconveyed from the periphery to the second-orderafferent neuron located in the spinal cord dorsal horn.

PHYSIOLOGY OF PAIN

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Pain

sco

rePa

in s

core

Bloo

d pr

essu

re c

hang

eBl

ood

pres

sure

cha

nge: Normal

: +Injury

Injury

Hyperalgesia

Allodynia

Normal pain response

Pain

inte

nsity

Stimulus

: +Morphine

: Normal

: +Morphine

: Normal

: +Injury

Analgesic provideshypoalgesia

Nociceptive agonistsresult in hyperalgesia

: +Injury

: Normal

While

: Normal

Physiologicalresponse

Physiologicalresponse

Verbal report

Stimulus Stimulus

Stimulus Stimulus

10 Pain encoding is dynamic. An analgesic can provide hypoalgesia, while complementary nociceptive agonists can result inhyperalgesia. A left shift in the stimulus–response curve can result in allodynia, i.e. a normally non-noxious stimulus becomesnoxious.

Verbalreport

It is now appreciated that there exists a plasticity ofpain encoding. A diminished response (as with theanalgesic morphine) to a given noxious stimulus cangive rise to hypoalgesia/analgesia. On the other hand,local injury can shift the stimulus–response curve tothe left, giving rise to the same pain report with alower stimulus: hyperalgesia. If the curve is shiftedsuch that a non-noxious stimulus becomes noxious,the state is referred to as allodynia (10).

Hyperalgesia to both heat and mechanical stimulusthat occurs at the site of an injury is due tosensitization of primary afferent nociceptors.6,7

Mechanisms of the phenomenon have been studied invarious tissues, including the joint, cornea, testicle,gastrointestinal tract, and bladder. Hyperalgesiaat the site of injury is termed primary hyperalgesia,while hyperalgesia in the uninjured tissuesurrounding the injury is termed secondaryhyperalgesia.

GATE THEORYThe existence of a specific pain modulatory systemwas first clearly articulated in 1965 by Melzack andWall8 in the gate control theory of pain. This was the

11Nodes of Ranvier Fast

transmittingmyelinatedfiber

Inhibitorneuron

Slow transmittingnonmyelinated fiber

Transmitter neuron

+

+

––

+

11 Melzack and Wall’s gate control theory of pain; the firsttheory proposing that nociception was under modulation bythe CNS.

–

+ + + K+ + + +

voltage-dependent conformational change in thechannel from a resting, closed conformation to anactive conformation, the result of which increases themembrane permeability to sodium ions (12). Basedon the sensitivity to a toxin derived from puffer fish,tetrodotoxin (TTX), sodium currents can be subdi -vided as being either TTX-sensitive (TTXs: Nav1.7channel, plentiful in the DRG) or TTX-resistant(TTXr: Nav1.8 and Nav1.9, which are exclu sivelyexpressed in cells of the DRG, and predom inantly innociceptors). Loss of function mutation of the genethat encodes Nav1.7 is associated with the conditionof insensitivity or indifference to pain, e.g. hot-emberbarefoot walkers. In contrast, a gain of functionmutation is the major cause of erythromelalgia–acondition of heat allodynia in the extremities ofhumans.

Accumulating evidence shows that upregulation ofsubtyes of sodium channels takes place in bothneuropathic and inflammatory models of pain.13

Many drugs used clinically to treat human peripheralneuropathies, including some local anesthetics(e.g. lidocaine), antiarrhythmics (e.g. mexiletine), andanticonvulsants (e.g. phenytoin and carbamazepine)are VGSC blockers.

In contrast to VGSCs, voltage-gated potassiumchannels act as brakes in the system, repolarizing

active neurons to restore baseline membranepotentials. The hyperpolarization-activated cyclicnucleotide-gated (HCN) channel is structurallyhomologous to the potassium channel, prevails incardiac tissue and DRG neurons, and modulatesrhythm and waveform of action potentials–therebyalso contributing to resting membrane potentials.14

Calcium ions play an important role in neurotrans -mission, being essential for transmitter release fromterminals (13). They also play a key role in neurons,linking receptors and enzymes, acting as intracellularsignals, forming a channel-gating mechanism, andcontributing to the degree of depolarization of thecell. The means by which calcium enters the neuronand terminal is via calcium channels, making calciumchannels targets for a variety of neurotransmitters,neuromodulators, and drugs. Two families of voltage-dependent calcium channels (VDCC) exist:• Low threshold, rapidly activating, slowly

deactivating channels (low-voltage activated(LVA) also referred to as T-type).

• High-threshold, slowly activating, fast-deactivating channels (high-voltage activated(HVA)). Zicnotide (a synthetic version of a ω-conotoxin found in the venoms of predatorymarine snails) blocks depolarization-inducedcalcium influx through VDCC binding.

PHYSIOLOGY OF PAIN

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Within the dorsal horn, the CNS ‘decides’ if themessage lives or dies. The hyper sensitization ofwindup is testimonial that the CNS dorsal horn isdynamic, and the important role of these voltage-gated ion channels makes them attractive targets fornovel and selective analgesics. Voltage-gated calciumchannels open when the membrane potentialdepolarizes and they cause intracellular calciumconcentration to rise. The calcium then causescontraction of muscle and secretion ofneurotransmitters and hormones from nerves. Thereare at least nine different types of voltage-gatedsodium channel (VGSC) genes expressed inmammals11 and three calcium channel genefamilies.12 In the field of pain, calcium channeldiversity is meaningful because N-type channels(from subtypes L, N, P, R and T) are critical forneurotransmission in sensory neurons, but relativelyless important for excitatory transmission in the CNS.Therefore, it is important that the most effectiveanalgesics, opiates, act upon sensory neurons byinhibiting their N-type calcium channels. Voltage-

gated potassium channels are not essential for theaction potential, but influence the shape of actionpotentials and tune their firing time. When open, theysteer the membrane potential toward the potassiumequilibrium potential, thereby decreasing theexcitability of a cell. This makes them primemolecular targets for suppressing hyperactive neuronsand suppressing hyperalgesia.

Excitability of a neuron can be changed bychannels as well as receptors:• Na+: increased excitability with increased

permeability.• K+: increased excitability with decreased

permeability, and vice versa.• Ca++: increased neurotransmitter release;

increased second messenger action.• Cl–: variable, depending on chloride equilibrium

potential.VGSC are complex, transmembrane proteins thathave a role in governing electrical activity in excitabletissue. The sodium channel is activated in response todepolarization of the cell membrane that causes a

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12 Sequential events during the actionpotential showing the normal restingpotential, development of a reversalpotential during depolarization, and re-establishment of the normal restingpotential during repolarization.

13 Neurohumoral transmission. The axonal action potential expresses a depolarization–repolarization of the axon, characterizedby an influx of sodium and efflux of potassium. Arriving at the nerve terminal, the action potential facilitates an inwardmovement of calcium, which triggers the discharge of neurotransmitters from storage vesicles into the junctional cleft. Theneurotransmitters react with specialized receptors on the postjunctional membranes and initiate physiological responses in theeffector cell.

13Ca++

Na+

Axon

Receptors

Effector cell

0

mV

-85

Action potential

Depolarization

Repolarization

Storage vesicles

K+

Resting State

+ + +Na+ + + +

– – –K+ – –

+ + + + + +

MuscleFiber

Cell bodyNode of Ranvier Schwann cell

– – –Na+ – – –

– – – – – –

+ + K+ + + + +

Axon

+ + + + + +

– – Na+ – – – –

Depolarization

Repolarization

12