Pain PhysioIogy

1his web-page assumes a basic knowledge o medicine. \e

assume that the reader is amiliar with such basic concepts
as interneurones, synapses, oncogenes, G proteins and
prostaglandins, and has had preious sketchy exposure to
neuroanatomy. \e will try to briely describe the
neuroanatomy o pain. Once we hae described the main
structures transmitting pain, we will explore
the connections between
them, neurotransmitters mediating pain, and what
happens within nere cells carrying painul stimuli. \e
conclude with a short note on pain pharmacology.
What is pain?
\e attach dierent attributes to pain. I a child injures
hersel, she will cry, and say "It's sore". ler mother might
enquire "\here does it hurt, darling" 1hink o these as
two dierent approaches to pain - the "motiational-
aectie" component which is phylogenetically primitie,
and concerned with pain as something nasty to be aoided,
and the eolutionarily more recently
acquired "sensory,discriminatie" ability to perceie
exactly rbere the pain is, and respond appropriately. As we
explore the complex structures that mediate our
appreciation o and response to pain, we will ind that we
can coneniently categorize them into two groups, those
that deal with the response to pain as an unpleasant
sensation, and those that are more concerned
with sensory,discriminatie aspects o pain. \e will
consistently colour code the pathways concerned with these
two 'types' o pain.
Pain in the Cortex
It used to be said that cortical structures are only
tangentially inoled in the perception o pain, i at all. 1his
is clearly extremely silly, as a host o connections link higher
cortical structures with pain-centred nuclei in the thalamus
and brainstem. Major cortical players are:
O 1he primary sensory cortex, S I
O 1he secondary sensory cortex, S II
O 1he anterior part o the insula
O 1he cingulate gyrus.
1he next three pictures clearly show their location - S I is
concerned with localisation o pain, while the other three
structures are thought to be concerned with the
motiational-aectie aspects which rom now on or the
sake o breity we will call "aectie" pain, although "sore"
pain might be a better term!

1he human brain seen from the side, showing the SI
and SII sensory cortex. SI is a thin strip made up of
Brodman areas 3,J and 2 posterior to the central
sulcus, while SII lurks just above the lateral sulcus.

1he temporal lobe has been retracted to reveal the
insula in all its splendour
- the anterior portion is probably concerned with pain
perception.

Next we look at the medial aspect of a hemisphere,
showing the cingulate gyrus.
1he anterior part o the cingulate gyrus is important in the
perception o 'aectie' pain.

%he %haIamus
1he thalamus is the 'central switching station' o the brain.
Seeral o its multiple nuclei are concerned with pain. 1he
lateral nuclei deal mainly with sensory,discriminatie
aspects, the medial ones with 'aectie' pain. Because the
thalamus is such a complex three-dimensional structure it's
extremely diicult to isualise it. \e thereore adopt the
approach o "building it" rom medial to lateral
,successiely adding nuclei, in the ollowing diagram
,ollow the arrows,:
Medially we add the poorly-
deIined midline nuclei. Lateral to
these we plonk on the
dorsomedial nucleus (dm) and,
more anteriorly the anterior
nuclei (ant).
The internal medullary
lamina bounds the
dorsomedial nucleus
laterally, and separates
it Irom the anterior
nuclei. Within the
internal medullary
lamina are the
intralaminar nuclei,
including the
centromedian (cm)
and centrolateral nuclei.
Lateral to the internal
medullary lamina (iml)
lies the ventral
posteromedial nucleus
(vpm) and anterior to
this is the ventral
anterior nucleus (va).
Even Iurther laterally
we have the lateral
dorsal(ld), lateral
posterior(lp), ventral
lateral(vl) and ventral
posterolateral nuclei.

The pulvinar (grey) is
situated posteriorly.

A Diagram of the Thalamic nuclei. The lateral thalamus is thought to be mainly concerned
with 'discriminative' pain, the medial with "affect/motivation".

1ake note o the inconspicuous midline nuclei - the
irst group that we put in place as we 'built' the
thalamus. 1hey include the:
O nucleus reuniens
O rhomboidal nucleus
O submedius nucleus
Although diicult to identiy, and glossed oer in most
neuroanatomy texts, these nuclei, particularly the
submedius, may turn out to be ery important in pain
perception!
idbrain
1here is a host o pain-related structures in the midbrain.
Most o this circuitry is inoled in 'aectie' pain, with
extensie connections to the reticular system o the
brainstem. Important components are:
O 1he peri-aqueductal grey matter ,PAG,
O eep layers o the superior colliculus
O 1he red nucleus
O 1he pre-tectal nuclei ,anterior and posterior,
O 1he nucleus o arkschewitsch
O the interstitial nucleus o Cajal
O 1he intercolliculus nucleus, nucleus cuneiormis and
een the Ldinger-\estphal nucleus.

Many o these are shown in the ollowing diagrams:

#ostral midbrain, with the anterior pretectal nucleus,
interstitial nucleus of Cajal, and nucleus of
Darkschewitsch in red.



A more caudal section through the midbrain, showing
the superior colliculus (SC), periaqueductal grey
matter (PAG), and red nucleus (#N).

%he Pons
1he most important pain-related nucleus in the pons is
probably the tocv. coervtev.. 1his is jam-packed with
noradrenaline-containing neurones, and projects to a ariety
o brainstem structures that modulate pain through
pathways that descend to the spinal cord. Another notable
group is the parabrachial nuclei, which receie a ast
number o ascending spinoreticular ibres. Both are shown
in the ollowing cross-section through the pons.

A cross-section through the pons, showing the locus
coeruleus (LC) and the lateral parabrachial nucleus
(PB)

%he eduIIa
1his too is inoled in the motiational,aectie aspects o
pain. Important cell groups are the nucleus gigantocellularis
and related nuclei, the lateral reticular nucleus, and a ariety
o other nuclei. Some o these are shown in the ollowing
diagram.

1he rostral medulla, with the nucleus gigantocellularis
and lateral reticular nucleus clearly shown.
1ake note o the raphe nuclei near the midline, which are
important in the descending pathways that suppress pain.

ow do these nucIei tie together?
Connections between the aboe structures are complex and
conusing, but can be diided into seeral groups. \e gie
you our:
1. 'iscriminatie' ibres ascending rom the spinal cord
to the lateral thalamus and thence to S I 1hese hae
been called the 3eo.i3otbatavic ibres, because they
appeared on the scene long ater the:
2. 'Aectie' ibres that ollow a similar course rom the
spinal cord, but end up in the reticular ormation o
the hindbrain. 1hese .i3oreticvtoaie3cebatic ibres
hae extensie connections throughout the
brainstem, and rom there project to the medial
thalamus and the cortex ,S II,.
3. Descending fibres that pass down rom brainstem
to spinal cord, inhibiting incoming sensations o
pain. A lot o these descending ibres originate in the
locus coeruleus, others in the raphe nuclei.
4. A ariety o interesting and sometimes clinically
important connections, some o them only recently
elucidated!
Beore we look at the connections in more detail, let's look
at pain connections in the spinal cord:
%he SpinaI Cord
1raditionally it was thought that most pain ibres entered
the dorsal root o the spinal cord ,the "sensory" root, and
then synapsed in the dorsal part o the spinal grey matter,
beore passing the message up through the spinothalamic
tract. It is now known that this is a gross oersimpliication.
In act, anything up to 40 o sensory ibres enter in the
entral root!
listologically the grey matter o the spinal cord is diided
into ten 'laminae'. 1he dorsal part is diided into ie
laminae ,I to V,, components o which deal with most
incoming pain ibres. VII is in between these laminae and
the more entral laminae VIII and IX, and X reers to the
grey matter around the central canal o the spinal cord. And
what about lamina VI 1his is only discernible in the bulges
in the cord related to where the inneration o the limbs
originates.

A transverse section through the thoracic spinal cord,
showing the grey matter and various laminae.
Much enthusiasm was generated when the "gate control"
theory o pain was irst described. Although this
mechanism has now been well documented, and has some
clinical utility, it is known to be a gross oer-simpliication.
1he basic idea is that incoming pain stimuli can be "gated"
,shut o, by other stimuli, because many nere cells talk to
one another in the dorsal horn. Important ibres coming
rom the periphery into the dorsal horn include:
O 1iny unmyelinated 'C' ibres that are important
carriers o the long-lasting burning pain that makes a
surgical wound ,or example, such an unpleasant
experience. 1here is controersy about where these
ibres terminate - according to \illis and \estlund,
in primates many terminate in the deep dorsal horn
and een the entral horn, although conentionally
lamina II has been said to be their destination.
O 1hin myelinated 'A delta' ibres, concerned with
more accurate localisation o pain, and terminating
mostly laterally in laminae I and V.
O #ather chunky 'A beta' ibres that carry inormation
about ibration and position sense rom the
periphery to the cord.
&npleasant stimuli entering ia the C ibres can be
suppressed by concurrent stimulation o A delta ibres
,high amplitude low requency stimulation, or example by
acupuncture, or by impulses passing through A beta ibres.
Lxamples o the latter include 1LNS ,transcutaneous
electrical nere stimulation, and the simple expedient o
rubbing the skin, which is well known by mothers to
decrease perception o pain!
scending Pain Connections
\e now hae suicient resources to examine the arious
ascending pain pathways. lirst, the primitie spino-reticulo-
diencephalic connections:

!athways from the spinal cord to the brainstem, and from there to the thalamus
(diencephalon).
Some Iibres pass directly to the medial thalamus, while others end in (or send collaterals to) a
variety oI nuclei in the brainstem. Connections between the reticular system and thalamus are not
shown Ior reasons oI clarity.

Next, we examine the phylogenetically more modern
pathways rom cord to lateral thalamus and thence to the
S I cortex. 1hese pathways are discriminatie pain
pathways, and hae little to do with perception o pain as a
'sore' stimulus! 1hese pathways hae ew or no opioid
receptors - morphine ,or example, will hae no eect on
such pathways!


The neospinothalamic tract.


escending Pain Connections
As important as the ascending pathways are ibres that
descend rom brainstem to spinal cord to modulate the
incoming signals. Notable neurotransmitters mediating this
anti-nociceptie eect include noradrenaline
,norepinephrine,, especially in the locus coeruleus, and
serotonin in the raphe nuclei. Opioid receptors are
prealent here. Some descending connections are:

Descending
connections that
modulate incoming
pain impulses.

Incoming painIul
stimuli are transmitted
(A) to the dorsal horn,
and Irom there (B) to
the periaqueductal grey
(PAG). Descending
impulses pass (C) to
the raphe nuclei,
especially the nucleus
raphe magnus, in the
upper medulla, and
thence back to the
dorsal horn via
reticulospinal Iibres
(D).
The above
shows only the
serotonergic
descending
Iibres. Other
pain-
suppressing
impulses pass
Irom the PAG
to the locus
coeruleus, and
Irom there to
the dorsal
horn.

Pain in the periphery - the nociceptor
1he aboe connections are awully complex. One might
think that once we moed out to the periphery, things
might become more simple. Not so! Most tissues are well
proided with specific pain receptors called nociceptors.
lormerly it was thought that painul stimuli were detected
through 'oerstimulation' o receptors or other modalities.
1his is incorrect. 1he quality o the pain perceied on
stimulation o nociceptors seems to depend on the site o
stimulation, and the nature o the ibres transmitting the
sensation. Len in the periphery, there is a distinction
between the sharp immediate pain ,"irst pain", transmitted
by A delta ibres, and the prolonged unpleasant burning
pain mediated through the smaller unmyelinated C ibres.
Nociceptors hae numerous dierent receptors on their
suraces that modulate their sensitiity to stimulation. 1hese
include GABA, opiate, bradykinin, histamine, serotonin and
capsaicin receptors, but the arious roles o these receptors
are poorly characterised.
1he most ascinating aspect o pain perception in the
periphery is that normally most nociceptors lie dormant.
Inlammation sensitizes this ast population o nociceptors,
making them ar more sensitie to stimulation
,hyperalgesia,. lyperalgesia may be primary ,elt at the site
o stimulation, related to sensitization o the neurones
innerating that area, or secondary ,elt at a site remote
rom the original injury, and probably related to NMA-
mediated "wind-up",.

Neurotransmitters
A plethora o neurotransmitters mediates transmission o
the sensations o pain in both brain and spinal cord. 1he
list is intimidating, and grows daily. \e can try and 'lump'
these neurotransmitters into arious groups:
O citator, 3evrotra3.vitter.:
Important are glutamate and the tachykinins,
agents that act at the arious neurokinin receptors
including as substance P ,'P is or pain',, neurokinin
A and neurokinin B. Other substances that transmit
pain impulses rom incoming neres in the dorsal
horn including calcitonin gene-related peptide,
asoactie intestinal polypeptide, somatostatin and
bombesin.
O 3bibitor, 3evrotra3.vitter.:
1here are seeral inhibitory neurotransmitters, but in
the central nerous system, gamma amino butyric
acid ,GABA, appears to reign supreme. Oer orty
percent o inhibition in the mammalian central
nerous system is GABAergic.
O Neurotransmitters inoled in e.ce3ai3 Pai3
Revtatio3:
lere, the alpha-2 stimulatory eects
o noradrenaline ,norepinephrine, and the eects
o serotonin are prominent. Opiates reliee pain by
stimulating mu and delta receptors at a host o sites.
Specific neurotransmitters
Glutamate
A brie Medline search or articles using the abbreiation
"NMA" in the past ten years will garner about twele
thousand reerences. 1his attests the anatical interest
researchers hae in this, the hottest o the glutamate
receptors, but one mustn't orget that there are at least two
others, the "AMPA" receptor and the obscure and deious
metabotropic receptor. 1he NMA receptor mediates a
host o spinal responses to seere painul stimulation, but
there are seeral catches to understanding how it works.
Normally, the receptor is inactie as it is physiologically
choked by a magnesium ion sitting in its ion channel. In
order or this ion to be remoed, adjacent peptide receptors
hae to be stimulated - the Mg
--
then pops o, and an
emphatic painul response occurs. Neurophysiologists hae
known about this phenomenon or ages, gracing it with the
label "wind-up" - as the requency o C-ibre stimulation
increases there is a dramatic and long-lasting central
response, with some populations o spinal neurones
becoming more and more sensitie to stimulation.
Consequences o glutamate receptor actiation include
production o c-os ,discussed below, and spinal
production o prostanoids and the ubiquitous r NO,
nitric oxide. &nortunately all this knowledge beneits
clinicians surprisingly little, as drugs that antagonise the
eect o glutamate at the NMA receptor tend to induce
psychosis in humans, but the combination o low dose
NMA antagonists with opioids may be supra-additie
with ewer side eects.
GABA
GABA is widespread in the brain and spinal cord. 1ogether
with its partner glycine, it has major inhibitory eects,
dramatically eident in poisoning with strychnine, which
antagonises glycine. Interneurones in laminae I, II and III
are GABA-rich, and mediate gate control in the dorsal horn
by synapsing on neurones that contain substance P.
1here are seeral distinct GABA receptors that work quite
dierently - the GABAA receptor is a "ligand-gated ion
channel" that allows chloride ions to leak into the cell, while
the GABAB receptor is a "seen-spanning" transmembrane
structure that actiates G proteins.
Again, the clinical utility o this knowledge is small, as
GABAB receptor agonists such as bacloen, which are
analgesic at the spinal leel in rats, hae little eect in man,
although they may potentiate the analgesia o morphine.
Benzodiazepines modulate the GABAA receptor
allosterically - but GABAA seems more important at
supraspinal than spinal sites.
1achykinins
It will probably be seeral years beore newer agents such
as neurokinin antagonists hae been tested suiciently or
widespread clinical use, although ,or example, NK-1
antagonists such as CP-96 345 hae been shown to
moderately decrease isolurane MAC in tail-clamped rats
,shudder!, when gien intrathecally. Neurokinin receptors
probably do mediate pain in the spinal cord - substance P
binds to the NK-1 receptor while neurokinins A and B bind
respectiely to the NK-2 and NK-3 receptors. Collectiely
these substances are known as 'tachykinins'. 1he tachykinin
receptors are G-protein coupled, and increase intracellular
calcium leels, triggering gene transcription.

at the CeIIuIar LeveI
Probably the most signiicant discoery erer in the ield o
pain has been the gene c-os. 1he cellular analogue o a
iral oncogene, this rather special gene and its cellular
product, the protein called o. seem crucial to the proound
central nerous system changes that occur when an animal
,or man, eels pain. Central nerous system c-os
expression correlates extremely well with painul
stimulation. Generically, los is one o the inducible
transcription factors ,I1ls, that controls mammalian gene
expression.
We now have a molecular marker for pain! Len more
important, we know that because c-os is a proto-oncogene
- that is, it can promote ast intracellular changes including
cellular restructuring and prolieration - it is almost certainly
inoled in the long-term neurological consequences o
noxious stimulation.
Noxious peripheral stimulation not only causes los to
appear in the spinal cord, but also the I1ls called Jun and
Krox. Certain "constitutie transcription actors" also
change their actiity ,or example, C#LB becomes
phosphorylated,. Brie stimulation ,10 min, causes I1ls to
appear within 30 min, peak at one to two hours, and
disappear within about eight hours. Prolonged stimulation
causes a many-old increase in I1l expression, and
substantially prolongs expression. Nociceptie C-ibre
stimulation seems to be the main stimulus or I1l
production in the spinal cord, as is the case with painul
isceral stimulation ,or example, introduction o
cyclophosphamide into the bladder,. In the latter c-os
appears within an hour in laminae I and II, the
parasympathetic column, the dorsal grey commissure, as
well as in the hindbrain ,periaqueductal grey matter, locus
coeruleus, the parabrachial area, and seeral other areas
including the dorsal agal complex and entrocaudal bulbar
reticular area,.
Centrally, the reuniens, rhomboid and submedius nuclei all
express c-os, as do a number o areas in the cortex,
thalamus, hypothalamus and amygdala. More caudally, the
parabrachial nucleus also lights up!
A remarkable inding is that with prolonged stimulation, c-
os disappears rom spinal neurones ater two to seen
days! 1his disappearance is despite increased neuronal
excitability and a marked increase in expression o
neurokinin and glutamate receptors, and may be simply
because the neuronal changes are ixed, so the I1l is no
longer needed! Conersely, chronic lesions o sensory
neres ,or example, the neurophysiologist's aourite,
partial sciatic nere ligation, can induce chronic c-os
expression een in neres which don't normally express the
I1l!
Consequences o I1l production include neuropeptide
production and synthesis o a ariety o receptors. los is
inoled in cell replication and dierentiation, but we are
still horribly conused about its precise eects on
neurones.
los may be important in expression o genes or dynorphin,
enkephalin and tyrosine hydroxylase, or example, as these all hae
binding sites or AP1, the transcription complex that actually binds
to NA and does the job! ,AP1 is the term used to describe the
combination o los and the I1l Jun, or the dimer Jun:Jun. AP1
seems to bind the NA consensus sequence 1GAC1CA,.
It is now well known that "anaesthesia" ,or example the
combination o halothane and N2O, does 3ot suppress
production o c-os within the spinal cord, despite an
apparent "adequate" leel o anaesthesia. lentanyl reduces
c-os production by about 50, and appropriate neuraxial
block with local anaesthetic agents can almost totally ablate
the c-os response.

piates
Opioids act by stimulating mu, delta and kappa receptors.
Other receptors ,such as sigma and epsilon, hae been
postulated, but probably don't exist. 1he status o opioid
receptor subtypes ,mu1, mu2, delta 1, delta 2 and so on, is
also controersial. I one looks at the genes or these
receptors, there do not appear to be subtypes, but this
doesn't mean that post-translational modiication may not
hae created distinct subclasses o, say, the mu receptor. O
more interest is the identiication o a so-called "orphan"
receptor called O#-1 ,or "opiate-like receptor 1",, with
about 60 sequence homology with the other opiate
receptors. An endogenous ligand that acts at O#-1 has
recently been identiied and called nociceptin, otherwise
known as orphanin l2.
Len more recently its precursor, prenociceptin, has been ound
to gie rise to other opioid-like substances called Noc II, Noc III
and nocistatin, but the unction ,i any, o all these ancy new
substances is unclear, to say the least!
A ariety o G proteins are associated with opioid
receptors, including Gi and Go. Generally, mu and delta
agonists seem to decrease cyclic AMP production, and
hyperpolarise membranes by stimulating an inward
rectiying potassium channel. 1his hyperpolarisation
decreases the release o neurotransmitters rom the nere
cell, as such release depends on opening o oltage-sensitie
calcium channels.
Many researchers hae tried to ind out where opiates work
in the central nerous system. 1he best-characterised site is
undoubtedly the periaqueductal grey, where morphine
micro-injection is prooundly analgesic. Other probable
sites o action include the mesencephalic reticular
ormation, the substantia nigra, and the nucleus
gigantocellularis & areas near the nucleus raphe in the
medulla. Mu receptors also seem to be present in the
amygdala, and the entral orebrain.
Descending control mechanisms: Adrenergic and
serotonergic pathways rom the brainstem to the spinal
cord inhibit incoming painul stimuli. Opiates release these
pathways rom GABAergic inhibition, increasing actiity in
the descending pathways and thus suppressing pain. Stimuli
or opiate release in or example the periaqueductal grey
include pain stimuli ascending rom the spinal cord, and
stimuli passing along the multiple connections that the
brainstem pain structures hae with other local nuclei, the
midbrain, and higher centres.
Spinal opioid receptors: 1hese are prealent and are ery
eectie in modulating pain - in lamina I the predominant
receptors seem to be mu and delta, and in laminae II to V,
kappa.
Peripheral opioid receptors: Although some studies hae
shown an inhibitory eect o opiates on peripheral
nociceptors, the mechanisms and releance o such
obserations remain uncertain. I these peripheral opioid
receptors ,predominantly mu and kappa, hae a unction, it
is probably mainly in the terminals o C ibres already
sensitized by inlammation. Practically, intra-articular
morphine has a powerul analgesic-sparing eect ater knee
surgery! Another unusual reelation is that ivvv3e cells
appear to be prooundly inluenced by opiates, ollowing
stimulation o their delta and kappa receptors.
on-steroidal anti-inflammatories (SADs)
Classically the eectieness o NSAIs against
inlammation has been attributed to their eects in
inhibiting prostaglanding biosynthesis. 1hey do this by
seeral dierent eects on cyclo-oxygenase ,COX,, the
crucial enzyme in the initial synthesis o prostaglandins:
1. irreersible inactiation o COX, or
2. reersible competitie inhibition, or
3. reersible non-competitie inhibition ,"ree-radical
trapping",
Aspirin, the prototype NSAI, acts through the irst
mechanism, irreersibly acetylating COX. Many drugs such
as ibuproen, meenamic acid and sulindac are reersible
competitie inhibitors, and ,surprisingly, paracetamol may
scaenge hydroperoxides generated during arachidonic
metabolism, and thus quench prostaglandin ormation ,1he
hydroperoxides normally stimulate COX, causing positie
eedback,!
Much in the news has been the identiication o two
subtypes o COX. COX-1 is the constitutie ariant that
makes prostaglandins ital or protecting the stomach
through mucus production, and maintenance o renal blood
low. COX-2 is the inducible orm that mediates the pain o
inlammation by sensitising peripheral nociceptors. Most
conentional NSAIs inhibit COX-1 more than COX-2,
consequently pharmaceutical companies hae inested
ortunes in making selectie COX-2 inhibitors.
NSAIs hae many other eects ar remoed rom their
COX inhibition. 1hese include cell membrane eects
,inhibition o neutrophil aggregation, inhibition o
l2O2 generation ,piroxicam,, and een phosphodiesterase
inhibition ,indomethacin, dicloenac,. Some o these eects
may be mediated through intererence with G protein
unction. In addition, NSAIs may hae central
antinociceptie eects! 1his has been seen both
experimentally ,NSAIs preent the usual rise in
cerebrospinal luid prostaglandins ater NMA receptor
actiation, and clinically. escending serotonergic pathways
seem to be actiated by NSAIS, and part o the central
action o NSAIs in animal models appears to be
preented by naloxone! In addition, NSAIs may interere
with spinal production o nitric oxide in response to
NMA receptor stimulation. 1hey may een reduce c-os
expression!
Summary
In conronting the bewildering complexity o pain
pathways, we tend to orget that undamentally, aboe all
else, pain is .ore! 1here is another aspect o pain, that is, the
localisation o a painul stimulus, but long beore our
primitie ancestors acquired the high-tech pathways
necessary to perceie the sensory-discriminatieaspects o
pain, they were still sore. 1hroughout the nerous system,
we can identiy these two orms o pain transmission. In
the periphery we hae ast pricking pain transmitted by
myelinated A-delta ibres, and 'slow' burning pain mediated
by the primitie C ibres. In the spinal cord, the aectie
component o pain is transerred by spinoreticular ibres,
and ibres to the medial thalamus, and thence to those parts
o the cortex where 'sore' pain is perceied. 1he
phylogenetically newer 'neospinothalamic tract' transmits
discriminatie components o pain to the SI cortex ia the
lateral thalamus.
As important as the ascending pathways, are descending
pathways that modulate the incoming signal. 1hese are
predominantly noradrenergic and serotonergic, and can be
modulated by stimulation o opiate receptors. Opiates, still
the mainstay o therapy or moderate to seere pain, hae a
ariety o receptors that are widespread in the central
nerous system. Only now are we beginning to understand
the subcellular mechanisms o pain, particularly how c-os
works. \e hope that such understanding will eentually
help us to manage more eectiely man's second greatest
scourge - pain.

#eferences
lrom the ast pain literature, we'e pulled out a ew good
articles and books or your delectation. \e used these
extensiely in constructing the aboe reiew.
rilliant Reviews
1. Cashan JN. rugs 1996 52 S5 13-23. 1he
Mechanisms o Action o NSAIs in Analgesia. 3
i3creaibt, rettrritte3 articte.
2. Cross SA. Mayo Clin Prog 1994 69 35-83.
Pathophysiology o Pain. $titt o3e of tbe be.t rerier. re
cove acro...
orthwhile Reading
1. \illis \ & \estlund KN. J Clin Neurophys 199
14 2-31. Neuroanatomy o the Pain System and o
the Pathways that Modulate Pain. covrebe3.ire a3a
rece3t rerier, 3ot for tbe fai3tbeartea
2. lerdegen 1 & eah J. Brain #esearch #eiews
1998 28 30-490. Inducible and constitutie
transcription actors in the mammalian nerous
system: control o gene expression by Jun, los and
Krox, and C#LB,A1l proteins. vavvotb rerier of
cfo. a3a otber tra3.critio3 factor.
3. Malcangio M & Bowery NG. 1iPS 1996 1 45-62.
GABA and its receptors in the spinal cord. co3ci.e,
rortbrbite rerier of avva avi3o bvt,ric acia.
4. aksh 1. Acta Anaes Scand 199 41 94-111.
Pharmacology and mechanisms o opioid analgesic
actiity. ooa rerier of oiate..
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NMA receptor antagonists: interactions with
opioids. rief.
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A few eb References on rain Anatomy!
O Great neuroanatomy slides
O M#I images at the \hole Brain Atlas
O Bookstein & larrison's neuroanatomy slides
0ate of F|rst Pub||cat|on