pain pathways in humans

7/28/2019 Pain Pathways IN HUMANS

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PRESENTED BY:ASHISH VYASPGT,ORAL ANDMAXILLOFACIAL SURGERYRDC,GUWAHATI

GUIDED BY:DR A.K.ADHYAPOK

PRINCIPAL AND H.O.DDEPARTMENT OF ORAL AND

MAXILLOFACIAL SURGERY

RDC,GUWAHATI


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INTRODUCTIONMany, if not most, ailments of the body cause pain.

Pain includes not only the perception of an

uncomfortable stimulus but also the response to that

perception.

Pain, is currently considered as the f i f th vi tal signthat should be included in the routine patient

assessment (Arnstein, 2005).

We must recognize that pain is also an important

component of the persons protective system.Without the sense of pain, we would not be

immediately aware of injuries to tissues.


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DEFINITION In 1900, Sherr ing ton, was among the f i rst modern

neural sc ient ists todefine pain as the psychicaladjunct to an imperative protective reflex.

This is a concise definition, and it underlines the urgent

primitive dimension of pain-the motor response that is

teleologically oriented to remove tissue from potentiallydamaging insults.

The Internat ional Associat ion for the Study o f

Pain(2004)has proposed the following definition:

pain is an unpleasant sensory and emot ional

experience associated w ith actual or po tent ia l t issue

damage, or descr ibed in terms of such damage.


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Thus, even though traditionally viewed as an entirely

sensory phenomenon, pain differs fundamentally from

other conventional sensory modalities in that numerous

and diverse types of stimuli are capable of initiating acomplex multifaceted pain response.

In many ways, pain transcends attempts to define it

and is best regarded as an experience involving both a

physiologic sensation and an emotional or, as is the

case for nonverbal animals, behavioral reaction to that

sensation.

Pain includes not only the perception of an

uncomfortable stimulus but also the response to that

perception.


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Pain Is a Protective Mechanism

Pain is a protective mechanism which alerts us to a

problem and prompts us to take action. Even such simple activities as sitting for a long time on

the ischemia can cause tissue destruction because of

lack of blood flow to the skin where it is compressed by

the weight of the body.

When the skin becomes painful as a result of the

ischemia, the person normally shifts weight

subconsciously.

But a person who has lost the pain sense, as after spinal

cord injury, fails to feel the pain and, therefore, fails to

shift.

This soon results in total breakdown and desquamationof the skin at the areas of ressure.


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1.SPECIFICITY THEORY

2. PATTERN THEORY

3. GATE CONTROL THEORY

4. BEYOND THE GATE

(CONCEPT OF

NEUROMATRIX)


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SPECIFICITY THEORY The Specificity theory was originated in Greece .This

theory was highlighted by Descartes in 1664 anddescribed by VON FREY in 1894.

Descartes explained that when someone pulls the rope

to ring the bell, the bell rings in the tower. Hence, specificity theory suggests that pain is caused

by injury or damage to body tissue.

The damaged nerve fibres in our bodies sends direct

messages through the specific pain receptors and fibresto the pain center, the brain which causes the individualto feel pain.

This theory suggest that there is a strong link betweenpain and injury and that the severity of injury determinesthe amount of pain experienced by the person.


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Thus this theory does not allow for any possible

changes of psychological origin, such as might result

from attention or from past experiences that give aparticular meaning to a particular situation.
http://thebrain.mcgill.ca/flash/a/a_12/a_12_p/a_12_p_con/a_12_p_con.htmlhttp://thebrain.mcgill.ca/flash/a/a_12/a_12_p/a_12_p_con/a_12_p_con.html


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PATTERN THEORY

It was put forward by GOLDSCHEIDER. The Pattern theory was incorporated into the specificity

theory which added more concepts to explain and

extended its hypothesis of pain

The pattern theory states that nerve fibres that carry painsignals can also transmit messages of cold, warmth and

pressure can also transfer pain if an injury or damage to

body tissue occurs.

These theories added to the linear ascending pathwayvarious relays that begin the process of integrating the

activity of nerve fibres that have different receptive

properties.

The Specificity theory and Pattern theory are not


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GATE CONTROL THEORY

In 1965, Melzack and Wall proposed the gate controltheory of pain.

It is the first theory of pain that incorporated the central

control processes of the brain.

The gate control theory of pain proposed that the

transmission of nerve impulses from afferent fibers to

spinal cord transmission (T) cells is modulated by a

gating mechanism in the spinal dorsal horn.

This gating mechanism is influenced by the relative

amount of activity in large small diameter fibers, so that

large fibers tend to inhibit transmission (close the gate)

whereas small fibers tend to facilitate transmissiono en the ate .


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In addition, the spinal gating mechanism is influenced bynerve impulses that descend from the brain.

When the output of the spinal T cells exceeds a critical level,

it activates the action system:-those neural areas thatunderlie the complex, sequential patterns of behavior andexperience characteristics of pain.

The theory's emphasis on the modulation of inputs in thespinal dorsal horns and the dynamic role of the brain in pain

processes had a clinical as well as a scientific impact. Psychological factors, which were previously dismissed as

"reactions to pain" were now seen to be an integral part ofpain processing, and new avenues for pain control bypsychological therapies were opened.

Similarly. cutting nerves and pathways was graduallyreplaced by a host of methods to modulate the input.

Physical therapists and other health-care professionals whouse a multitude of modulation techniques were brought into

the picture. and transcutaneous electrical nerve stimulationTENS became an im ortant modalit for the treatment of


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The large (L) and small (S) fibers project to the substantia

gelatinosa (SG) and first central transmission (T) cells. The

central control trigger is represented by a line running from thelarge fiber system to central control mechanisms, which in turn

project back to the gate control system. The T cells project to

the entry cells of the action system. +. excitation: -, inhibition.


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This concept can be explained by that the soldiers

during World War II reported slight pain even though

they had sever damage to tissue due to the battle.

These soldiers had positive thinking and were distractedbecause injury meant that the soldiers would be allowed

to go home or sustain no further injury.

The gate control theory states that non painful stimulus

such as distraction competes with the painful impulse to

reach the brain.

This rivalary limits the number of impulses that can be

transmitted in the brain by creating the hypotheticalgate.

The specificity theory and the pattern theory suggests

that pain occurs only due to damage to body tissue

while the gate control theory claims that pain may beex erienced without an h sical in ur and individuals


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BEYOND THE GATE (CONCEPT OF

NEUROMATRIX)

It is evident that the gate control theory has taken us along way.

Yet as historians of science have pointed out, good

theories are instrumental in producing facts that

eventually require a new theory to incorporate them.

And this is what has happened.

Melzack's analysis of phantom limb phenomena,

particularly the astonishing reports of a phantom bodyand severe phantom limb pain in people with a total

thoracic spinal cord section, has led to four conclusions

that point to a new conceptual model of the nervous

system.


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First, because the phantom limb (or other body part)feels so real, it is reasonable to conclude that the bodywe normally feel is subserved by the same neural

processes in the brain as the phantom; these brainprocesses are normally activated and modulated byinputs from the body but they can act in the absence ofany inputs.

Second, all the qualities we normally feel from the body,including pain, are also felt in the absence of inputsfrom the body; from this we may conclude that theorigins of the patterns that underlie the qualities ofexperience lie in neural networks in the brain; stimuli

may trigger the patterns but do not produce them. Third, the body is perceived as a unity and is identified

as the "self," distinct from other people and thesurrounding world.

The experience of a unity of such diverse feelings,


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Fourth, the brain processes that underlie the body-self are"built in" by genetic specification, although this built-insubstrate must, of course, be modified by experience.

These conclusions provide the basis of the new conceptualmodel.

OUTLINE OF THE THEORY The anatomic substrate of the body-self, Melzack proposed,

is a large, widespread network of neurons that consists ofloops between the thalamus and cortex as well as betweenthe cortex and limbic system.

He has labeled the entire network, whose spatial distributionand synaptic links are initially determined genetically and are

later sculpted by sensory inputs, as a NEUROMATRIX. The loops diverge to permit parallel processing in different

components of the neuromatrix and converge repeatedly topermit interactions between the output products ofprocessing.

The repeated cyclical processing and synthesis of nerve


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The neurosignature of the neuromatrix is imparted on allnerve impulse patterns that flow through it; theneurosignature is produced by the patterns of synaptic

connections in the entire neuromatrix.All inputs from the body undergo cyclical processing

and synthesis so that characteristic patterns areimpressed on them in the neuromatrix.

Portions of the neuromatrix are specialized to processinformation related to major sensory events (such asinjury, temperature change, and stimulation oferogenous tissue) and may be labeled asneuromodules that impress subsignatures on the larger

neurosignature. The neurosignature, which is a continuous output from

the body-self neuromatrix, is projected to areas in thebrain ,the sentient neural hub-in which the stream of

nerve impulses (the neurosignature modulated byon oin in uts is converted into a continuall chan in


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The neurosignature patterns may also activate aneuromatrix to produce movement.

That is, the signature patterns bifurcate so that a

pattern proceeds to the sentient neural hub

(where the pattern is transformed into the

experience of movement) and a similar patternproceeds through a neuromatrix that eventually

activates spinal cord neurons to produce muscle

patterns for complex actions.


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BODY SELF NEUROMATRIX The body is felt as a unity with different qualities at different

times.

Melzack proposed that the brain mechanism that underlies

the experience also comprises a unified system that acts as

a whole and produces a neurosignature pattern of a whole

body.

The conceptualization of this unified brain mechanism lies at

the heart of the new theory, and the word "neuromatrix" best

characterizes it.

The neuromatrix (not the stimulus, peripheral nerves or

"brain center") is the origin of the neurosignature; theneurosignature originates and takes form in the neuromatrix.

Although the neurosignature may be triggered or modulated

by input, the input is only a "trigger and does not produce

the neurosignature itself.


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The array of neurons in a neuromatrix is genetically

programmed to perform the specific function of

producing the signature pattern.

The final, integrated neurosignature pattern for the body-

self ultimately produces awareness and action.

The neuromatrix, distributed throughout many areas of

the brain, comprises a widespread network of neurons

that generates patterns, processes information that

flows through it, and ultimately produces the pattern thatis felt as a whole body.

The stream of neurosignature output with constantly

varying patterns riding on the main signature pattern


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CONCEPTUAL REASONS FOR

NEUROMATRIX

It is difficult to comprehend how individual bits ofinformation from skin, joints, or muscles can all come

together to produce the experience of a coherent,

articulated body.

At any instant in time, millions of nerve impulses arriveat the brain from all the body's sensory systems,

including the proprioceptive and vestibular systems.

How can all this be integrated in a constantly changing

unity of experience? Where does it all come together?

Melzack conceptualized a genetically built in

neuromatrix for the whole body, producing a

characteristic neurosignature for the body that carrieswith it atterns for the m riad ualities we feel.


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The neuromatrix, as Melzack conceived of it, produces

a continuous message that represents the whole body

in which details are differentiated within the whole as

inputs come into it. We start from the top, with the experience of a unity of

the body, and look for differentiation of detail within the

whole.

The neuromatrix, then, is a template of the whole, which

provides the characteristic neural pattern for the whole

body (the body's neurosignature) as well as subsets of

signature patterns (from neuromodules) that relate to

events at (or in) different parts of the body.

There are no external equivalents to stinging, smarting,

tickling, itch; the qualities are produced by built in

neuromodules whose neurosignatures innately produce

the qualities.


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The inadequacy of the traditional peripheralist view

becomes especially evident when we consider

paraplegics with high-level complete spinal breaks.

In spite of the absence of inputs from the body, virtuallyevery quality of sensation and affect is experienced.

The neuromatrix is a psychologically meaningful unit,

developed by both heredity and learning, that

represents an entire unified entity.

The phenomenon of phantom limbs has allowed us to

examine some fundamental assumptions in psychology.

One assumption is that sensations are produced only

by stimuli and that perceptions in the absence of stimuli

are psychologically abnormal. Yet phantom limbs, as

well as phantom seeing, indicate this notion is wrong.


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The brain does more than detect andanalyze inputs; it generates perceptualexperience even when no external inputsoccur.

In short, phantom limbs are a mysteryonly if we assume the body sends

sensory messages to a passivelyreceiving brain.

Phantoms become comprehensible once

we recognize that the brain generatesthe experience of the body.

Sensory inputs merely modulate that

experience; they do not directly cause it.


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TYPES OF PAIN

PAIN

PHYSIOLOGICAL

PATHOLOGICAL

INFLAMMATORY

NEUROPATHIC


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PHYSIOLOGIC PAIN An important conceptual breakthrough in understanding pain

physiology is the recognition that the pain that occurs aftermost types of noxious stimulation is usually protective and

quite distinct from the pain resulting from overt damage to

tissues or nerves.

This first type of pain is termed phys io log ic pain.

It plays an integral adaptive role as part of the body's normal

defense mechanisms, warning of contact with potentially

damaging environmental insults and initiating behavioral and

reflex avoidance strategies.

It is also often referred to as nocicept ive painbecause it is

only elicited when intense noxious stimuli threaten to injure

tissue.

Although the extrapolation of this physiologic model of pain to

the clinical setting has several inherent limitations, an


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PATHOLOGIC PAIN The traditional stimulus-response model of physiologic

pain is conceptually appealing and has laid thefoundation for a more comprehensive understanding ofnociceptive pathways.

Nevertheless, it must be recognized that physiologicpain alone is a rare entity in the clinical setting.

In most situations, the noxious stimulus is not transientand may be associated with significant tissueinflammation and nerve injury.

Under such circumstances, the classic "hard-wired

system becomes less relevant, and dynamic changes inthe processing of noxious input are evident in bothperipheral and central nervous systems.

This type of pain is called patholo gic pain (because it

impl ies that the t issu e damage has alreadyoccurred)


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NOCICEPTIVE PROCESSING

The physiologic component ofpain is termed nociception,

which consists ofthe

processes oft ransduct ion,

t ransm ission , andmodulat ionof neural signals

generated in response to an

external noxious stimulus.

It is a physiologic process that

results in the conscious

perception of pain when

carried to completion.

In its simplest form, the

pathway can be considered as


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PHERIPHERAL NOCICEPTORS

The first process of nociception involves the encoding of

mechanical, chemical, or thermal energy into electricimpulses by specialized nerve endings termed

nociceptors.

Unlike other specialized somatic sensory receptors,

nociceptors exist as free nerve endings of primary afferent

neurons and function to preserve tissue homeostasis by

signaling actual or potential tissue injury.

As such, they have considerably higher stimulusthresholds for activation than thermoreceptors or low-

threshold mechanoreceptors, which are capable of

generating spontaneous action potentials under ambient

conditions.


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Nociceptors are unique among sensory receptor classes

in that under certain circumstances, repeated activation

actually lowers their threshold and results in an

enhanced response to subsequent stimuli. This phenomenon, is called sensi t izat ion.

Interestingly, nociceptors are also capable of exhibiting

fatigue or habituation, a characteristic of all other

sensory systems whereby repeated or sustained

presentation of a noxious stimulus actually leads to a

diminished response.

Thus, the composite afferent message induced by a

given stimulus is complex, resulting from the activation

of various types of nociceptors with differing thresholds

and response characteristics.


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(A)ASCENDINGPATHWAYS

(B)DESCENDINGPATHWAYS


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AFFERENT NERVE FIBRES

Conventional nomenclature based onneurophysiologic studies has classified nociceptors

into two categories:

A-f iber (A delta) mechanoheat nociceptors and C-

f iber m echanoheat no ciceptorsaccording to theirassociated afferent nerve fibers and stimulus

sensitivities.

A delta fibers are large d iameter th inly myel inated

axons and consequently conduct impulses rapidly.

In contrast, transmission in the smallerunmyel inated

C fibersis much slower and acts to reinforce the

immediate response of the A fibers, becoming

increasin l im ortant as the duration of the stimulus


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A DELTA FIBRES


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A-DELTA FIBRES These fibers are small, thinly myelinated neurons, 1 to

5 m in diameter, with conduction velocities in the

range of 5 to 30 m/s. A-delta fibers have small receptive fields and are

relatively modality specific.

This latter quality is a function ofspecific, high-

threshold ion channels on the free endings of A-deltaafferents that are differentially activated by distinct highintensity thermal or mechanical input (Julius &Basbaum, 2001).

A-delta thermoresponsive fibers respond toextremes of temperature.

One population is activated by noxious heat, with aninitial response threshold in the range of 40 to 45 C.

Response function increases directly, although notnecessarily linearly, as a consequence of temperature

A d l ti hi h th h ld ld ff t


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A second population, high threshold cold afferents,

responds to cold temperatures at or below a threshold of

approximately 8C, with increasing cold sensitivity to

temperatures less than 25C (Price & Dubner, 1977). A-delta mechanoreceptive afferents are activated by

high-intensity mechanical stimulation (deep pressure,

stab, pinch, stretch), although these fibers may be

sensitized by, and become secondarily responsive to,noxious heat.

Unlike A-delta thermal afferents, sensitized A-delta

mechanoreceptive afferents respond to suprathreshold

heat (usually in excess of 50 to 55C) and/or repetitivepresentation of noxious heat, rather to a singular

exposure to a heat stimulus at or above the nociceptive

threshold (Kumazawa & Perl, 1976).


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C FIBRES C-fibers are small, unmyelinated afferents with broader

receptiv fields than A-delta fibers. C-fiberdiametersrange from 0.25 to 1.5 m, and the absence of myelin

leads to slower conductance velocities that vary from 0.5

to 2 m/s.

This slower conductance together with the broadreceptorfields subserve clinical second pain, a diffuse,

poorly localized burning, throbbing, or gnawing sensation

that follows and that is temporally and qualitatively

distinct from the initial sensation of firstpain(Toreb jo rk , 1974).

Numerically, C-fibers constitute the majority of primary

nociceptive afferent innervation of cutaneous tissue.

C fib


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C-fibers are po lymodal, and can be act ivated by

thermal, mechanical, and chemical st imul i .

In addition to responding to noxious (thermal,

mechanical, and chemical) stimuli, C-fiberpolymodalafferents may be sensitized by substrates of the

inflammatory cascade (e.g., prostaglandin-E2, bradykinin)

that are released following thermal or mechanical insult

(Go ld et al., 1998; Levine & Reich ling , 1999). Once sensitized, these C-fibers can be activated by

certain types of nonnoxious, low-intensity stimulation.

This may account for the persistent second pain and

hyperalgesia that occurs following burn injury or other

inflammatory states (Rowbo tham & Fields , 1996).

In this light, C-fibers may contribute to multiple sensations

from a painful region.

C fib l i t l ti l li d t th


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C-fibers also innervate muscle tissue, localized to the

intrafibril matrix, tendons, and areas surrounding the

vascular walls (Iggo, 1974).

C-fibermuscle afferents are polymodal and areresponsible for the nociceptive response to intense

mechanical stimulation (Jo nes, Newham, Ob letter, &

Giamberard ino , 1987)that produces numerous

substances as a consequence of both aerobic andanaerobic metabolism.

C-fibers innervating muscular tissues are activated by H

ions as a constituent of the acidic postmetabolic

environment (Mil ls, Newham , & Edwards , 1982)aswell as end products ofinflammation due to exercise-

induced micro- or macrotraumatic insult ( including

bradyk inin , his tamine, and 5-HT; Vecchiet,

Giamberard ino , & Marini, 1987), mechanical distention


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Primaty afferent pain transmission. First pain

and second pain sensations aftera noxious stimulus (A ). The f irst pain sensat ion

is abol ished when the A f ibers are blocked

(B), whi le the second pain sensat ion is

abo l ished when the C fibers are bloc ked (C)

NEUROCHEMISTRY OF PRIMARY


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NEUROCHEMISTRY OF PRIMARY

AFFERENT PAIN

The principal neurochemical mediator at the synapticcleft between primary afferent nociceptors and dorsal

horn cells is glutamate.

Postsynaptically, glutamate is capable of binding to two

types of dis crete recepto rs (Woo lf, 2004).

The first, the AMPA (alpha-amino-3-hydroxy-5-

methylisoxazole-4 propionic acid) receptor, appears

to be the initial orfirst molecular target for glutamate

binding.

Glutamate-induced AMPA receptor activation evokes a

ligand-gated sodium current in postsynaptic second-

order neurons of the dorsal horn that produces a rapid

de olarization.

AMPA receptor mediated depolarization modulates


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AMPA receptor-mediated depolarization modulates

glutamate-induced activation of the second class of

receptor, the N-methyl-D-aspartate(NMDA) receptor,

by allosteric modulation of magnesium binding to ashared or cooperative domain of the NMDA receptors.

With persistent AMPA receptor activation, the rise in

intracellular sodium displaces a magnesium gate fromthe NMDA receptor, thereby increasing its sensitivity or

releasing it from an inaccessible configuration to actively

bind glutamate (Woolf & Salter,2000).


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AMPA RECEPTOR

Each AMPA receptor contains 4 subunits with integralglutamate binding sites that surround a central cationchannel designated as GluR1 , GluR2 , GluR3 ,and GluR4.

Agonist binding at two or more sites activates thereceptor, opening the channel and allowing passage ofNa ions into the cell.

This brief increase in Na ions flux depolarizes second-order spinal neurons, allowing noxious signals to berapidly transmitted to supraspinal sites of perception.

The AMPAR's permeability to calcium and othercations,such as sodium and potassium, is governed by theGluR2 subunit. If an AMPAR lacks a GluR2 subunit, then

it will be permeable to sodium, potassium, and calcium.
http://en.wikipedia.org/wiki/GRIA1http://en.wikipedia.org/wiki/GRIA2http://en.wikipedia.org/wiki/GRIA3http://en.wikipedia.org/wiki/GRIA4http://en.wikipedia.org/wiki/Calciumhttp://en.wikipedia.org/wiki/Cationhttp://en.wikipedia.org/wiki/Sodiumhttp://en.wikipedia.org/wiki/Potassiumhttp://en.wikipedia.org/wiki/Potassiumhttp://en.wikipedia.org/wiki/Sodiumhttp://en.wikipedia.org/wiki/Cationhttp://en.wikipedia.org/wiki/Calciumhttp://en.wikipedia.org/wiki/GRIA4http://en.wikipedia.org/wiki/GRIA3http://en.wikipedia.org/wiki/GRIA2http://en.wikipedia.org/wiki/GRIA1


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NMDA RECEPTORS

NMDARs display a number of unique properties thatdistinguish them from other ligand-gated ion channels.

First, the receptor controls a cation channel that is highly

permeable to monovalent ions and calcium.

Second, simultaneous binding of glutamate and glycine,

the coagonist, is required for efficient activation of

NMDAR.

Third, at resting membrane potential the NMDAR

channels are blocked by extracellular magnesium and

open only on simultaneous depolarization and agonist

binding.

Native NMDARs are composed of NR1 NR2 (A B C


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Native NMDARs are composed of NR1, NR2 (A, B, C,

and D) and NR3 (A and B) subunits.

Co-expression studies have demonstrated that

formation of functional NMDAR channels requires acombination of NR1, an essential channel-forming

subunit, and at least one of the NR2 subunits.

Most obvious subunit-dependent properties of NMDARs

are their single-channel conductance and sensitivity tomagnesium block.

For example, the NR2A or NR2B subunits-containing

NMDARs generate high conductance channel openings

with a high sensitivity for blocking by magnesium,

whereas NR2C- or NR2D-containing receptors give rise

to low conductance openings with a lower sensitivity to

magnesium.


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Peripheral nociceptive fibers express NR2B and NR2D


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Peripheral nociceptive fibers express NR2B and NR2D

subunits, whereas NR2A subunits appear to be absent

from the peripheral terminals of primary afferents.

Because NR2B-selective antagonists (e.g.

IFENPRODIL) potentiate NMDAR inhibition by

endogenous protons , this mode of action may be

beneficial under conditions of tissue injury, ischemia, orinflammation (presumably accompanied by acidosis)

when a greater degree of inhibition of NMDARs can be

expected in the affected tissues than normal .

This could also explain the improved efficacy of NR2B-

selective antagonists under these conditions.


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While brief, suprathreshold primary nociceptor activity

causes the release of glutamate, prolonged and/or

intense C-fiberactivation induces the release of the

substance-P (Cao et al., 1998).

Initially, substance-P binds postsynaptically to

neurokinin-2 (NK-2) receptors on second-order dorsal

horn neurons.

However, with more prolonged excitation, substance-P

also binds to NK-1 receptors to activate G protein

mediated, metabotropic, slow onset, durable shifts in

membrane potential (Woolf, 2004).


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Dorsal Horn Neurons

Cell bodies of both types of afferent nociceptive nerve

fibers are contained in the dorsal root ganglia and extend

axons to synapse with dorsal horn neurons within the gray

matter of the spinal cord.

It is in the dorsal horn that initial integration and

modulation of nociceptive input occur.

Before going into details of dorsal horn neurons, first we

will understand its organisation.

ORGANISATION OF DORSAL


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ORGANISATION OF DORSAL

HORN

The posterior horn (posterior cornu, dorsalhorn, spinal dorsal horn) of the spinal cord is the dorsal

(more towards the back) grey matterof the spinal cord.

The dorsal horn is a major receptive zone (zone of

termination) of primary afferent fibres, which enter thespinal cord through the dorsal roots of spinal nerves.

Organisation of the dorsal horn is in the form of different

laminae called as REXEDS LAMINAE.

REXEDS LAMINAE
http://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Spinal_cord


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REXED S LAMINAE


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The Rexed laminae comprise a system of ten layers

ofgrey matter(I-X), identified in the early 1950s by Bror

Rexed to label portions of the spinal cord.

The laminae are numbered sequentially in a dorsoventral

sequence .

Lam inae I-IVcorrespond to the head o f the dorsal horn,

and are the main receiving areas for cutaneous primary

afferent terminals and collateral branches.

Many complex polysynaptic reflex paths (ipsilateral,

contralateral, intrasegmental and intersegmental) start

from this region and many long ascending tract fibres

which ass to hi her levels arise from it.

LAMINA I(LAMINA
http://en.wikipedia.org/wiki/Grey_matterhttp://en.wikipedia.org/wiki/Bror_Rexedhttp://en.wikipedia.org/wiki/Bror_Rexedhttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Bror_Rexedhttp://en.wikipedia.org/wiki/Bror_Rexedhttp://en.wikipedia.org/wiki/Bror_Rexedhttp://en.wikipedia.org/wiki/Grey_matter


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LAMINA I(LAMINA

MARGINALIS)

It is a very thin layer with an ill-defined boundary at thedorsolateral tip of the dorsal horn.

It has a reticular appearance, reflecting its content of

intermingling bundles of coarse and fine nerve fibres.

It contains small, intermediate and large neuronalsomata, many of which are fusiform in shape.


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LAMINA II

It occupies most of the head of the dorsal horn andconsists of densely packed small neurones responsible

for its dark appearance in Nissl-stained sections.

With myelin stains, Lamina II is characteristically

distinguished from adjacent laminae by the almost totallack of myelinated fibres.

Lamina II corresponds to the subs tant ia gelat inosa.


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LAMINA III

It consists of somata which are mostly larger, morevariable and less closely packed than those in lamina II.

It also contains many myelinated fibres.

Some workers consider that the substantia gelatinosa

contains part or all of lamina III as well as lamina II.

The ill-defined nucleus propr iusof the dorsal horn

corresponds to some of the cell constituents of laminae

III and IV.


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LAMINA IV

It is a thick, loosely packed, heterogeneous zonepermeated by fibres.

Its neuronal somata vary considerably in size and

shape, from small and round, through intermediate and

triangular, to very large and stellate.


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LAMINA V

Lamina V is a thick layer which includes the neck of thedorsal horn.

It is divisible into a lateral third and medial two-thirds.

Both have a mixed cell population but the former

contains many prominent well-staining somatainterlaced by numerous bundles of transverse,

dorsoventral and longitudinal fibres.


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LAMINA VI

Lamina VI is most prominent in the limb enlargements. It has a densely staining medial third of small, densely

packed neurones and a lateral two-thirds containing

larger, more loosely packed, triangular or stellate

somata. Lamina VI corresponds approximately to the base of the

dorsal horn.Laminae V and VI receive most of the terminals of

proprioceptive primary afferents and profuse corticospinal

projections from the motor and sensory cortex and

subcortical levels, which suggests their intimate involvement

in the regulation of movement.


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LAMINA VII

Lamina VII includes much of the intermediate (lateral)horn.

It contains prominent neurones of Clarke 's co lumn

(nucleus do rsalis, nucleus thoracis, thoracic

nucleus) and intermediomedial and intermediolateralcell groupings.

The lateral part of lamina VII has extensive ascending

and descending connections with the midbrain and

cerebellum (via the spinocerebellar, spinotectal,spinoreticular, tectospinal, reticulospinal and

rubrospinal tracts) and is thus involved in the regulation

of posture and movement.

Its medial art has numerous ro rios inal reflex

LAMINA VIII


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LAMINA VIII Lamina VIII spans the base of the thoracic ventral horn

but is restricted to its medial aspect in limbenlargements.

Its neurones display a heterogeneous mixture of sizes

and shapes from small to moderately large.

Lamina VIII is a mass ofprop r iospinal interneurones. It receives terminals from the adjacent laminae, many

commissural terminals from the contralateral lamina VIII,

and descending connections from the interstitiospinal,

reticulospinal and vestibulospinal tracts and the mediallongitudinal fasciculus.

The axons from these interneurones influence motor

neurones bi laterally, perhaps d irect ly bu t more

robab l b excitat ion of small neu ronessu l in

LAMINA IX


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LAMINA IX Lamina IX is a complex array of cells consisting of and

motorneurones and many interneurones.

The large motorneurones supply motor end-plates of

extrafusal muscle fibres in striated muscle.

The smaller motorneurones give rise to small-diameterefferent axons (fusimotor fibres), which innervate the

intrafusal muscle fibres in muscle spindles.

There are several functionally distinct types of motor

neurone. The 'static' and 'dynamic' responses of musclespindles have separate controls mediated by static and

dynamic fusimotor fibres, which are distributed variously

to nuclear chain and nuclear bag fibres.


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LAMINA X

Lamina X surrounds the central canal andconsists of the dorsal and ventral grey

commissures.


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The majority ofA delta fibers terminate in the most

superficial layer, lamina I (also called the marginal

zone), w ith somefibers projecting more deeply to

lamina V.

Most C fibers are also destined for the superficial dorsalhorn, with the focus in lamina II (the substantia

gelatinosa).


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NEURONS


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Primary afferent axons may form direct or indirectconnections with one of three functional populations of

dorsal horn neurons:(1) Inteneurons: frequently divided into exc i tatory andinh ib itory subtyp es, which serve as relays andparticipate in local processing;

(2) Propriospinal Neurons, which extend over multiplespinal segments and are involved in segmental reflexactivity and interactions among stimuli acting atseparate loci; and

(3) Projection Neurons, which participate in rostraltransmission by extending axons beyond the spinalcord to terminate in supraspinal centers such as themidbrain and the cortex.

All three components are interactive and are essential

for the processing of nociceptive information, which

TYPES OF PROJECTION


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NEURONS

Projection neurons have been subclassified into threegroups:-

1. NOCICEPTIVE SPECIFIC (NS) NEURONS:concentratedin laminaI and lamina II, are excited solely by noxiousmechanical or thermal input from both A Delta and C

fibers. They arearranged somatotopically and respond toafferent impulses originating from discrete topographicareas.

2. WIDE DYNAMIC RANGE (WDR) NEURONS:

predom inate in lam ina V and receive innocuous inp ut

from low-thresho ld mechano receptors as wel l as

nocicept ive informat ion. They respond in a gradedmanner over a larger receptive field than do NS neuronsand often receive convergent deep and visceral input.

Although WDR neurons are considered to be ambiguouswith re ard to modalit the enerate their stron est


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The spinothalam ic tract is somatotop ically organized.

Axons from neurons in rostral segments of the spina l cord

ascend medially relat ive to axon s o rginat ing from caudal

segments. The somatotop y is m aintained w ith in the majortarget nucleus o f the thalamus , the ventrop os ter ior lateral

nucleus. Pr imary senso ry co rtex is somatotop ically

org anized w ith lumbar segments (e.g. leg) represented

medial ly wi th in the postcentral gyru s and cervical

WIDE DYNAMIC RANGE


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NEURONS

These neurons have three interesting functionalcharacteristics:

(1) Given their connectivity, the neurons display excitationdriven by low and high threshold afferent input. Thisgives the WDR neurons the property of respondingwith increased frequency as the stimulus intensity iselevated; they have a wide dynamic response range.Light innocuous touch evokes activity that increases asthe intensity of pressure or pinch is increased.

(2) Organ convergence: Depending on the spinal level,WDR neurons may be activated by both somatic stimuliand by activation of visceral afferent. This convergenceresults in a comingling of excitation for a visceral organ

and a specific area of the body surface and leads to

These viscerosomatic andl ti


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musculosomaticconvergences onto dorsalhorn neurons underlie thephenomenon of referredvisceral or deep muscle orbone pain to particularbody surfaces.

(3) Low-frequency (above0.33 Hz) repetitivestimulation of C fibers, butnot A fibers, produces a

gradual increase in thefrequency discharge untilthe neuron is in a state ofvirtually continuousdischarge ("wind-up").

Example of organ convergence:

T1and T5 root stimulation activates

WDR neurons that are also

excited by coronary arteryocclusion.These results indicate

that the phenomenon of referred

visceral pain has its substrate in

the viscerosomatic and

musculosomatic convergenceonto dorsal horn neurons.

WIND UP


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WIND UP Wind-up is a progressive, frequency-dependent

facilitation of the responses of a neurone observed on

the application of repetitive (usually electrical) stimuli of

constant intensity.

The phenomenon of wind-up was first described by

Lorne Mendell as a frequency-dependent facilitation ofspinal cord neuronal responses mediated by afferent

C-f ibres.

Mendell suggested that this phenomenon may be due to

a reverberatory activity evoked by afferent C-fibres ininterneurones of the spinal cord lasting for 2-3 s.

If in this period of time another stimulus arrives to the

cord, it sums with the ongoing activity to produce a more

intense discharge in the interneurones than the one

The observation that there were prolonged increases in


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the excitability of dorsal horn neurones subsequent to

the application of a wind-up evoking stimulus (Cervero

et al., 1984; Cook et al., 1987).

This led to the proposal (Coo k et al., 1987; Dickenson ,

1990)that there was a causal relationsh ip between

w ind-up and the hyperexc i tabi l i ty o f sp inal co rdnocicept ive neurones ob served after peripheral

damage known as central sens i t isat ion.

The blockade of the N-methyl-D-aspartate (NMDA)

subtype of glutamate receptors inhibited the generation

of windup.


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3. COMPLEX NEURONS:less well-studiedgroup of dorsal horn neurons and are typically

located in lam ina VII.

It is believed that thesecells function in the

integration of somatic and visceral afferentactivity.


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ASCENDING

SPINALTRACTS

Dorsal horn nociceptive input is conveyed to supraspinal


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centers by projection neurons extending through

following ascending pathways:

(A ) NEOSPINOTHALAMIC PATHWAYS

SPINOTHALAMIC PATHWAY

(B ) PALEOSPINOTHALAMIC PATHWAY

SPINORETICULAR PATHWAY

SPINOCERVICOTHALAMIC PATHWAY

SPINOTECTAL PATHWAYSPINOHYPOTHALAMIC PATHWAY

Anatomically, axons from second-order neurons in the


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superficial dorsal horn (laminae I and II) are segregated

from those of deeper laminae (lamina V).

This provides anatomical separation between the

neospinothalamic (NSTT) and paleo-spinothalalmic

(PSTT) tracts.

While both the NSTT and PSTT may be considered

labeledlines for the transmission of pain signals, the

differential localization of NS neurons to laminae I and II,

in contrast to a greater abundance of WDR neurons in

lamina V, subserves functional distinctions in the type of

nociceptive information that is transmitted in these

pathways.

The NSTT projects directly to the ventroposterior lateral


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p j y p

(VPL) nuclei of the thalamus and is composed

predominately of NS neurons from lamina I and II

(Kenshalo et al., 1980).

WDR neurons are in smaller numbers within these

laminae, and they comprise only a minority of NSTT

fibers.

NS neurons receive almost completely homogeneous

input from A-delta and high-threshold polymodal C-fiberafferents, and encode stimulus localization and modality.

Therefore, the main role of the NSTT appears to involve

transmission of these signal qualities to the thalamus

The PSTT is composed of axons from second-order


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neurons arising in lamina II and V of the spinal cord.

WDR neurons constitute the majority of cells from this

lamina, with only a smaller number of NS neuronscontributing to the axonal pool of the PSTT.

Given the role of lamina V WDR neurons to encode

noxious stimulus intensities, the co-localized

transmission of both nociceptive and non-nociceptiveafferent information within the PSTT appears to serve a

st imulus d iscr im inatory funct ion.

Unlike the NSTT, the PSTT is not a direct thalamic

pathway.

PSTT fibers project to several supraspinal sites that are

involved in (nociceptive) sensory processing and that

exert pain modulatory control.


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Tract of Lissauer


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Tract of Lissauer It is a small strand situated in relation to the tip of

the posterior column close to the entrance ofthe posterior nerve roots.

It contains centrally projecting axons carrying

discriminative pain and temperature information

(location, intensity and quality), which enter the spinalcolumn ascend or descend one or two spinal segments

in this tract before penetrating the grey matter of the

dorsal horn where they synapse on second-order

neurons. The axons of these second-order neurons cross the

midline and ascend in the anterolateral quadrant of the

contralateral half of the spinal cord, where they join

the s inothalamic tract.
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It consists of fine fibers which do not receive their myelin
http://en.wikipedia.org/wiki/Fetal


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sheaths until toward the close offetal life.

In addition it contains great numbers of fine non-

myelinated fibers derived mostly from the dorsalroots but partly endogenous in origin.

These fibers are intimately related to the substantia

gelatinosa.
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The spinothalamic tracts consist of second-orderneurones which convey pain temperature coarse (non-


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neurones which convey pain, temperature, coarse (non-discriminative) touch and pressure information to thesomatosensory region of the thalamus.

Axons arise from neurones in diverse laminae in allsegments of the cord.

Tract fibres decussate in the ventral white commissure.

Pain and temperature fibres do so promptly, withinabout one segment of their origin, whilst fibres carryingother modalities may ascend for several segmentsbefore crossing.

Spinothalamic fibres mostly ascend in the white matter

ventrolateral to the ventral horn, partly intermingled withascending spinoreticular fibres and descendingreticulospinal fibres.

Some authorities describe two spinothalamic tracts

(lateral and ventral) with more-or-less distinct

The lateral sp ino thalam ic tractis sited in the lateralfuniculus lying medial to the ventral spinocerebellar tract


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funiculus, lying medial to the ventral spinocerebellar tract.

Clinical evidence indicates that i t subserves pain andtemperature sensations .

The ventral sp inothalam ic tractlies in the anteriorfuniculus medial to the point of exit of the ventral nerve rootsand dorsal to the vestibulospinal tract, which it overlaps.

On the basis of clinical evidence, it sub serves coarse

tact i le and pressure modali t ies. A dorsolateral spino thalamic tracthas been described in

animals, arising mainly from lamina I neurones whose axonscross to ascend in the contralateral dorsolateral funiculus.

These neurones respond maximally to noxious, mechanicaland thermal cutaneous stimuli.

That such a projection exists in man is suggested byexamples of clinical pain relief following dorsolateralcordotomy.


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On reaching the lower brain stem, spinothalamic tract axons

separate.


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separate.

Axons in the ventral tract join the medial lemniscus. Axons

in the lateral tract continue as the spinal lemniscus.

There is clear somatotopic organization of the fibres in the

spinothalamic tracts throughout their extent.

Fibres crossing at any cord level join the deep aspect of

those that have already crossed, which means that both

tracts are segmentally laminated .

Somatotopy is maintained throughout the medulla oblongata

and pons.

In the midbrain, fibres in the spinal lemniscus conveying pain

and temperature sensation from the lower limb extend

dorsally, while those from the trunk and upper limb are more

ventrally placed.

Both lemnisci ascend to end in the thalamus.


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On the basis of laminar site, functional properties, and

specific thalamic termination of their axons,

spinothalamic tract neurones may be divided into three

separate groups.

These are the:-

apical cel ls o f the dors al grey column (lam ina I),

deep do rsal co lumn cel ls (laminae IV-VI), and

cells in the ventral grey co lumn (lam inae VII, VIII).


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Lam ina I cel ls wh ich p roject to the thalamusshow

the following characteristics:-

In essence they respond maximally to noxious orthermal cutaneous stimulation, and consist mainly of

high-threshold, but also some wide-dynamic-range,

units.

Their receptive fields are usually small, representing a

part of a digit or a small area of skin involving several

digits.

Lam ina I sp ino thalam ic tract neurones receive inpu t

fromAand C fibres.

Lamina I spinothalamic tract neurones project

preferentially to the ventrop os terolateral nucleus of

the thalamus, with limited projections to the


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The population ofdeep dorsal co lumn (laminae IV-VI)

sp inothalam ic neuronescontains wide-dynamic-range(60%), high-threshold (30%), and low-threshold (10%)

type units.

They can code accurately both innocuous and noxious

cutaneous stimuli.

Laminae IV-VI spinothalamic tract units project either to

the ventroposterolateral (VPL) nucleus or to the

centrolateral nucleus of the thalamus, and sometimes to

both.

Units projecting to the ventroposterolateral nucleus

receive input from all classes (A,A and C) of

cutaneous fibres.

Ventral g rey column (lamin ae VII and VIII)spinothalamictract cells respond mainly to deep somatic (muscle and


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p y p (jo in t) s t imu li , bu t also to innocuous and /o r nox ious

cutaneous st imul i .

Cells of this group, which project exclusively to the medialthalamus , receive inpu t fromA,Aand C classes o fafferent fib res, and many respond to convergent input fromreceptors of deep structures.

This population of neurones contains wide-dynamic-range(25%), high-threshold (63%), and low-threshold or deep(12%) units.

Most of the spinothalamic tract cells in the ventral greycolumn project to the intralam inar nuc lei of the thalamus .

Wide-dynamic-range type neurones are particularly effectivefor discriminating between different intensities of painfulstimulation.

It has been suggested that the spinothalamic projectionto the ventroposterolateral nucleus is concerned withthe discriminative as ects of ain erce tion whereas


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SPINORETICULAR PATHWAYS


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SPINORETICULAR PATHWAYS

Spinoreticular fibres are intermingled with those of thespinothalamic tracts, and ascend in the ventrolateralquadrant of the spinal cord.

Evidence from animal studies suggests that cells of originoccur at all levels of the spinal cord, particularly in the upper

cervical segments. Mos t neurones are in lam ina VII, some are in lam ina VIII,

and o thers are in the dors al horn , especially lam ina V.

Most axons in the lumbar and cervical enlargements crossthe midline, but there is a large uncrossed component incervical regions.

Spinoreticular neurones respond to inputs from the skin ordeep tissues. Innocuous cutaneous stimuli may inhibit orexcite a particular cell, whereas noxious stimuli are often

excitatory.


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It terminates in the brainstem at the medul lary-

pont ine ret icu lar format ion.

Information is sent from there to the intradmedian

nucleus of the thalam ic intralam inar nuc lei .

The thalamic intralaminar nuclei project diffusely to

entire cerebral cortex where pain reaches conscious

level and promotes behavioral arousal .


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S i i th l i th


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Spinocervicothalamic pathway

Lesser contributions to nociceptive transmission aremade from neurons located in lam inae III and IVof the

dorsal horn, which project axons through the

spinocervical tract and the postsynaptic dorsal

column pathway, which both relay impulses indirect lyto the thalamus through the lateral cervical nuc leus

and the dorsal column nu clei , respect ively.

SPINOTECTAL PATHWAY


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SPINOTECTAL PATHWAY

Spinotectal projections terminate within the tectum andperiaqueductal gray (PAG) region of the midbrain.

Sinotectal tract neurons are of low-threshold, wide-

dynamic-range, or high-threshold classes.

Their receptive fields may be small, or very complex andencompass large surface areas of the body.

They are likely to be involved in the motivational-

affective component of pain. Electrical stimulation of

their site of termination in the periaqueductal grey matterresults in severe pain in man.

SPINOHYPOTHALAMIC PATHWAY


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More recently, a direct projection transmitting primarily

nociceptive information from the dorsal horn to the

hypothalamus has been discovered.

This is the spinohypothalamic tract, which provides an

additional alternative route of activating the motivational

component of pain and initiating neuroendocrine and

autonomic responses. In fact, most SHT neurons (60%) project to the contralateral

medial or lateral hypothalamus and, therefore, are

presumed to have a considerable role in autonomic and

neuroendocrine responses to painful stimuli. Therefore, the SHT appears to form the anatomic substrate

that coordinates reflex autonomic reactions to painful

stimuli. Some of the connections of SHT, for example, to the

suprachiasmatic nucleus that partly controls the sleep/wake


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INTRODUCTION


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The trigeminal system receives afferent input from the

three divisions of the trigeminal nerve (i.e., ophthalmic,

maxillary, and mandibular) that serve the entire face as

well as the dura and the vessels from a large portion of

the anterior two thirds of the brain.

The trigeminal system has three sensory nuclei, all ofwhich receive projections from cells that have cell

bodies located within the trigeminal ganglion, a

structure similar to DRG.

Major transmitters of painful stimuli within the mouthand orofacial complex are the free nerve endings from

the trigeminal nerve.

Peripheral afferents from the trigeminal are thought to

react to specific noxious stimuli and respond to

TRIGEMINAL GANGLION


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The trigeminal ganglion (orGasserian ganglion,

orsemilunar ganglion, orGasser's ganglion) is a

sensory ganglion of the trigeminal nerve (CN V) that

occupies a cavity (Meckel's cave) in the dura mater,

covering the trigeminal impression near the apex of

the petrous part of thetemporal bone.

The trigeminal ganglion is a main generator of

information from the orofacial complex in the human as

well as in different types of mammals.

Just like cells within the dorsal root ganglia of the spinalcord, cells in the trigeminal ganglion possess peripheral

and central processes.

The peripheral processes of trigeminal ganglionneurons distribute to pain and temperature receptors on
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neurons distribute to pain and temperature receptors onthe face, forehead, mucous membranes of the nose,anterior two-thirds of the tongue, hard and soft palates,nasal cavities, oral cavity, teeth, and portions of cranialdura.

The central processes enter the brain at the level of thepons (this is where all trigeminal sensory fibers enter

the brain stem and where trigeminal motor fibers leavethe brain stem).

These central processes of trigeminal ganglion neuronsconveying pain and temperature descend in the brain

stem and comprise the SPINAL TRACT V. Fibers of spinal tract V terminate upon an adjacent cell

group called the SPINAL NUCLEUS V, which forms along cell column medial to spinal tract V (spinal tractand nucleus V form a slight elevation on the lateral

On entering the pons, the fibres of the sensory root of thetrigeminal nerve run dorsomedially towards the principal

l hi h i it t d t thi l l


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sensory nucleus, which is situated at this level.

Before reaching the nucleus ,50% of the fibres divide into

ascending and descending branches - the others ascend ordescend without division.

The descending f ibres, of wh ich 90% are less than 4min diameter, form the sp inal tract o f the tr igeminal nerve,

which reaches the upper cervical spinal cord.

The tract embraces the spinal trigeminal nucleus.

There is a precise somatotopic organization in the tract.

Fibres from th e ophthalm ic roo t l ie ventro lateral ly,

those from the mandibular root l ie do rsom edial ly, and

the maxi l lary f ib res l ie between them .

The tract is completed on its dorsa l rim by f ibres from thesensory roots of the facia l, glossopharyngeal and

vagus nerves.

Al l of these f ibres synapse in the nucleus caudal is.


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We are particularly concerned with the caudal most

portion of spinal nucleus V, because ALL of the


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p p ,

PAIN and TEMPERATURE fibers from the face

terminate in this caudal region of the nucleus (knownas SUBNUCLEUS CAUDALIS).

The other 2 parts of spinal nucleus V are the

subnucleus oral is(which is most rostral and adjoins

the principal sensory nucleus); the subnu cleusinterpolar is.

The structure of the subnucleus caudalis is different

from that of the other trigeminal sensory nuclei.

It has a structure analogous to that of the dorsal hornof the spinal cord, with a similar arrangement of cell

laminae.

Cutaneous nociceptive afferents and small-diameter

muscle afferents terminate in la ers I II V and VI of


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Many of the neurones in the subnucleus caudalis thatrespond to cutaneous or tooth-pulp stimulation are also

i d b i l i l h i l h i l


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excited by noxious electrical, mechanical or chemicalstimuli derived from the jaw or tongue muscles.

This indicates that convergence of superficial and deepafferent inputs via WDR or NS neurones occurs in thenucleus.

Similar convergence of superficial and deep inputs

occurs in the rostral nuclei and may account for thepoor localization of trigeminal pain, and for the spreadof pain, which often makes diagnosis difficult.

Cells within spinal nucleus V possess axons that curve

medially to CROSS the midline and course rostrallyclose to (but not as a part of) the medial lemniscus.

These crossed fibers retain their close association withthe medial lemniscus as they ascend in the brain stemand are called the trigeminothalamic tract (TTT).


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Spinal tract and spinal nucleus V are not exclusivelyassociated with C.N. V., It is also assoc iated w ith


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C.N.s VII (facial), IX (glosso pharyngeal) and X

(vagus).

The pain and temperature fibers associated with C.N.VII innervate the skin of the external ear, the wall of theexternal auditory meatus and the outer surface of thetympanic membrane.

These fibers are the peripheral processes of cells thatlie in the GENICULATE ganglion (located in the facialcanal).

The central processes of these neurons enter the brain

with C.N. VII (at pontine levels, caudal to thetrigeminal), travel in spinal tract V and end in spinalnucleus V. The pain and temperature information is thenconveyed rostrally in the TTT (trigeminothalamic tract)to reach the VPM, from which it is relayed to

somatosensor cortex areas 3 1 and 2

Like C.N. VII, C.N. IX is involved in the pain and

temperature innervation of the EAR.


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In addition, C.N. IX conveys pain and temperaturefrom the pos ter ior one-th i rd o f the tongue, the

aud i tory tube and the upper part of the pharynx .

The cell bodies of these pain and temperature axonsassociated with C.N. IX lie in the relatively small

SUPERIOR GANGLION IX (located just outside of the

jugular foramen).

The central processes of cells in the superior ganglion

enter the brain with C.N. IX (at the lateral medulla), then

enter our friend spinal tract V and synapse in the caudal C.N. X innervates the

EAR (along with C.N.s VIIand IX).


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)

In addition, pain and

temperature from the lowerpharynx, the larynx and theupper esophagus areconveyed by C.N. X.

The cell bodies of thesepain and temperatureaxons lie in the SUPERIORGANGLION X (located justoutside the jugular

foramen). The central processes of

cells in the superiorganglion X pass into the

brain at the lateral medulla

REMEMBER


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REMEMBER Lesion of spinal tract V along its entire course (the pain

information never gets to the caudal spinal nucleus) resultsin IPSILATERAL deficits in pain and temperature from theface etc.

Interruption of the trigeminothalamic tract, which is

comprised of axons that have crossed the midline, results indeficits in pain and temperature on the contralateral side ofthe face etc.

Spinal tract and nucleus V are present in the pons andmedulla

The cells of origin of spinal tract V lie in the trigeminalganglion

Axons in spinal tract V terminate in the spinal nucleus V

Axons of cells within spinal nucleus V project to the

contralateral VPM

AN INTERESTING CLINICAL

OBSERVATION


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OBSERVATION

Reports in the clinical literature note that vascular lesionsthat interrupt the blood supply to the spinal nucleus and

tract V in the medulla (for example a thrombosis of the

posterior inferior cerebellar artery) sometimes are

immediately followed by sharp stabbing pain in andaround the eye and on the ipsilateral face (hyperalgesia).

A possible explanation for this paradox is that the pain

fibers are highly irritated before they die (spontaneous

pain also sometimes occurs on the contralateral side ofthe body immediately following a lesion of the

anterolateral system).

Please remember that lesions of spinal tract and nucleus

V can result in PAIN in the face (in addition to loss of


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Integration of pain in higher centers is complex and

poorly understood.


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At a basic level, the integration and processing of

painful stimuli may fall into the following broadcategories:

Discriminative component: This component is

somatotopically specific and involves the primary (SI)

and secondary (SII) sensory cortex. This level of integration allows the brain to define the

location of the painful stimulus.

Integration of somatic pain, as opposed to visceral pain,

takes place at this level.

The primary and secondary cortices receive input

predominantly from the ventrobasal complex of the

thalamus, which is also somatotopicallyorganized.

AFFECTIVE COMPONENT

The integration of the affective component of pain is


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g p p

very complex and involves various limbic structures.

In particular, the cingulate cortex is involved in theaffective components of pain (i.e., it receives input from

the parafascicular thalamic nuclei and projects to

various limbic regions).

The amygdala is also involved in the integration ofnoxious stimuli.

MEMORY COMPONENTS

Recent evidence has demonstrated that painful stimuli

activate the CNS regions such as the anterior insula.

MOTOR CONTROL AND PAIN

The supplemental motor area is thought to be involved

in the integration of the motor response to pain

THALAMUS


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THALAMUS

THALAMIC NUCLEI ASSOCIATED

WITH PAIN


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WITH PAIN

A. VENTRAL POSTERIOR NUCLEUS (VP)B. INTRALAMINAR THALAMIC NUCLEI

C. MEDIALIS DORSALIS

VENTRAL POSTERIORNUCLEUS


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NUCLEUS The ventral posterior (VP) nucleus is the principal

thalamic relay for the somatosensory pathways.

It is thought to consist of two major divisions, theventral postero lateral (VPl) and vent ral

posteromedial (VPm) nuclei.

The VPl nucleus receives the medial lemniscal andspino thalam ic pathways , and the VPm nucleus

receives the tr igem ino thalam ic pathway.

There is a well-ordered topographic representation of

the body in the ventral posterior nucleus. The VPl is organized so that sacral segments are

represented laterally and cervical segments medially.

The latter abut the face area of representation

tri eminal territor in VPm

There is evidence that spinothalamic tract neurones

carrying nociceptive and thermal information terminate


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in a distinct nuclear area, identified as the posterior part

of the ventral medial nucleus (VMpo).

The VP nucleus projects to the pr imary somat ic

sensory co rtex (SI) of the postcentral gyru s and to

the second somatic sensory area (SII) in the parietal

opercu lum. VMpo projects to the insu lar co rtex.

INTRALAMINAR TALAMICNUCLEUS


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NUCLEUS

The term intralaminar nuclei refers to collections ofneurones within the internal medullary lamina of the

thalamus.

Two groups of nuclei are recognized.

The anterior (rostral) group are subdivided intocentral medial, paracentral and central lateral nuclei.

The posterior (caudal) intralaminar group consists

of the centromedian and parafascicular nuclei.

The central lateral nucleus receives afferents from thespinothalamic tract.

central lateral nucleus projects mainly to parietal and

temporal association areas.

MEDIALIS DORSALIS NUCLEI


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MEDIALIS DORSALIS NUCLEI

The medial dorsal nucleus is the only nucleus in themedial group, and it receives two kinds of inputs.

Part of this nucleus receives pain afferents from the

LSTT and the TTT, projects to the frontal lobe, and is

involved in the response to pain. The other part of MD receives olfactory inputs from

primary olfactory cortex.

This nucleus is unique because it receives these

olfactory inputs after they have been to cortex, and thenrelays them to insular and orbitofrontal cortex for

associative olfactory functions.

The thalamus is a complex structure that acts as therelaying center for incoming nociceptive stimuli.

The NSTT and PSTT project to different regions ithin


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The NSTT and PSTT project to different regions withinthe thalamus.

NSTT neurons project to a caudal area of theventroposterior lateral nucleus (VPLc).

Nociceptive inputs from the NSTT are arranged incolumnar zones that are somatotopically organized.

Thalamic neurons within these zones retain manyresponse characteristics of WDR and NS units.

Thalamic wide-range neurons have centersurroundreceptive fields with distinct, small areas sensitive to low

threshold excitation and a broad area that is excited byhigh-threshold nociceptive input.

Thalamic NS neurons, like their spinothalamiccounterparts, have smaller receptive fields that are

excited by high intensity mechanical or thermal input


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Both WDR and NS neurons of the VPLc summateresponses as a function of stimulus frequency andintensity


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intensity.

The PSTT pro jects to the intralam inar thalam ic

nuclei , the do rsal nu cleus central is lateralis, andmedial is do rsal is.

Most of the neurons within these thalamic areas are ofthe wide range type, sensitive to both nociceptive and

non-nociceptive activation and with extensiveoverlapping input from cutaneous and visceralinnervation.

These units do not have the adaptive properties of

neurons of the VPLc; intralaminar neurons summateresponses, but response patterns do not reflect directspatial or temporal transformation of increments instimulus frequency or intensity.

Unlike neurons of the VPLc, intralaminar neurons

CORTICAL PROJECTIONS

Neurons from the NSTT project to the VPLc of the


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Neurons from the NSTT project to the VPLc of the

thalamus; thalamo-cortical fibers from this region

terminate in S-I (and to a lesser extent S-II areas) of thesomatosensory cortex.

Thalamo-cortical fibers from the intralaminar, lateral,

and medial dorsal nuclei, driven by the PSTT, project

more diffusely, with a smaller number terminating in S-I,

while the majority project bilaterally to S-II.

The somatotopic organization of the thalamus is

preserved in S-I and to some extent SII; nociceptive

input contributes to distinct regions of somatosensory

activation within the cortex.

There are projections from S-II to the anterior cingulate

via the insula and to the posterior cingulate through a

The role of the anterior cingulum in pain sensation andpain related behavioral responses is such that the

superior anterior cingulate is commonly referred to as


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superior, anterior cingulate is commonly referred to as

the nociceptive cingulate area (NCA).

Anterior cingulate hypothalamic projections mediate

components of neuroendocrine and autonomic

responses to pain sensation.


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GENERAL CHARACTERISTICS


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It is well established that the brainstem has a significant

role in regulating pain-related signals at the spinal cord

level.

It has been commonly considered that brainstem -spinal

pathways predominantly inhibit pain. However, there is accumulating evidence indicating that

descending pathways also have pain facilitatory effects.

Properties

of Descending Inhibitory Controls


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g y

Descending pain inhibitory controls are immature at birth

and do not become functionally effective until postnatal

day 10, although all descending projections are already

present at birth.

With advanced age the function of descending paininhibition is impaired and this is associated with a loss of

noradrenergic and serotoninergic fibers in the spinal

dorsal horn.

Conditioning noxious stimulation, which presumablyactivates descending pain modulatory pathways, has

induced a weaker pain suppressive effect in females

than in males (Staud et al., 2003)suggesting that

descending inhibitory controls may have gender-specific


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Although the somatotopic organization of descending

inhibitory influence is quite diffuse, a preferentialipsilateral antinociception induced by electrical

stimulation of the midbrain periaqueductal gray (PAG)

indicates that the descending inhibitory effect may not

be equally distributed throughout the body.

(B )SPINAL MECHANISM MEDIATING THE

DESCENDING PAIN INHIBITORY ACTION

A number of mechanisms are involved in mediating the

descending inhibitory effect at the spinal dorsal horn

level.


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Direct (postsynaptic) inhibition ofspinal

pain-relay neurons.

Descending axon terminals have direct contacts with

presumed pain-relay neurons of the spinal dorsal horn,

l t i l ti l ti f th b i t i d d i hibit


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electrical stimulation of the brainstem induced inhibitory

postsynaptic potentials in nociceptive neurons of thespinal dorsal horn and and spinal appl icat ion of

no radrenal ine, a transm itter released from

descending axons , hyperpolarized a population of

nociceptive spinal neurons(North and Yoshimura,

1984).

These findings indicate that neurotransmitters releasedfrom descending axons may block the ascending pain

signal by producing a hyperpolarization of spinal relay

neurons (direct postsynapt ic inh ibi t ion).


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Indirect inhibition of spinal pain relayneurons through activation

of inhibitory interneurons.


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Superficial laminas of the spinal dorsal horn have apopulation of interneurons containing inhibitory

neurotransmitters such as -aminobutyric acid (GABA),

glycine and enkephalin (Ruda et al., 1986).

Descending pathways excite some of these putativeinhibitory interneurons of the spinal dorsal horn (Millar

and Williams, 1989) and this provides one more

mechanism for descending inhibition of spinal pain-

relay neurons (indirect inhibition via excitation ofinhibitory interneurons)


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A hypothetical scheme for volume transmission

of an inhibitory neurotransmitter from thedescending axons to central terminals of

nociceptive primary afferent nerve fibers

(presynaptic inhibition of nociceptive afferent

barra e to the s inal cord

Descending pathways may also suppress nociceptive

signals due to action on central terminals of primary afferent

fibers (presynaptic inhibition).


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(p y p )

Accordingly, central terminals of nociceptive primary

afferents have receptors for neurotransmitters released inthe spinal cord only by descending axons, such as

noradrenalin.

In line with this, postsynaptic responses evoked by dorsal

root stimulation in a population of lamina II neurons of thespinal dorsal horn were reduced by noradrenaline, without

influence on direct activation of the same neurons by

excitatory amino acids (Kawasak i et al., 2003).

Due to rareness of axo-axonic synapses betweennociceptive primary afferent nerve fibers and central

neurons, it has been proposed that volume transmission

may play a major role in presynaptic inhibition of nociception

in the spinal dorsal horn (Rudom in and Schm idt, 1999); i.e.

(C) Physiological Significance of Descending

Pain Inhibition


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Descending pain inhibitory pathways have an important

role in the ascendingdescending circuitry, providing

negative feedback control of nociceptive signals at the

spinal cord level (Fields and Basbaum , 1999); i.e. a

painfu l s t imulus act ivates brains tem nuclei invo lved

in descending ant inoc icept ion and p revents

excess ive pain by at tenuat ing the su ccess ive

painfu l signals.

This implies that a full activation of descending inhibitionis observed only under painful conditions.

The activation of descending inhibitory controls by a

painful stimulus may not only serve reduction of

excessive pain by negative feedback but it may also

Importantly, analgesia induced by some centrally actingdrugs involves activation of descending pain inhibitorypathways (e.g. morphine).


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p y ( g p )

(D)DESCENDING PAIN INHIBITION UNDER

PATHOPHYSIOLOGIC CONDITIONS

Pathophysiological conditions may cause complexchanges in descending pain regulatory circuitry.

Descending inhibition was stronger followinginflammation as indicated by enhanced spinalantinociceptive effect by midbrain stimulation ininflamed animals (Morgan et al., 1991).

Inflammation has been associated with increasedtu rnov er of no radrenaline (Weil-Fugazza et al., 1986)

and increased number of alpha 2adrenoceptors inthe sp inal cord (Brandt and Liv ingston, 1990).

These changes are likely to contribute to an increase indescending pain inhibition, and they probably explain

the enhanced antinociceptive potency of spinally


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p p y p y

administered alpha 2-adrenoceptor agonists in inflamed

conditions.

Additionally, nerve in jury or inf lammat ion may

act ivate descend ing faci l i tat ion.

Increased inhibitory controls potentially help to maintain

the capacity to use an inflamed body part for flight or

fight in case of emergency, whereas decreased

inhibition or increased facilitation of pain might in some

cases help the healing process by promoting

immobilization and protection of the injured region.

However, a prolonged decrease of pain inhibition or

increase of pain facilitation may not serve any useful

purpose but they just cause unnecessary suffering and

Motor control and pain regulatory systems share manycommon neurotransmitters.

Disorders of neurotransmitter systems in the motor


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so de s o eu ot a s tte syste s t e otocontrol circuitries of the basal forebrain are quite

common and they are known to be associated withmotor dysfunction such as in Parkinsons disease.

In analogy, it may be proposed that similar disorders ofneurotransmitter systems potentially occur also in pain

regulatory circuitries and can underlie some chronicpain conditions by causing hypofunction of descendinginhibitory controls.

This possibility is supported by a recent series of

studies indicating that striatal dopamine D2 receptorbinding potential is associated with the occurrence ofchronic orofacial pain as well as baseline painsensitivity (Hagelberg et al., 2004); i.e. hypo func tionof the nigrostr iatal dopam ine system may cause no t

on l moto r d iso rders bu t also chr

pain pathways in humans

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