pain pathways in humans
TRANSCRIPT
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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
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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
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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
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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