PAIN from sign to disease

Esta é uma pré-visualização de arquivo. Entre para ver o arquivo original

P
Be PT*,†
sional
after
periph
the p
s can
mage
l, and
urther
ed as
sform
l nox
ologic
ess of
contr
to giv
l proc
ls and
nisms
provides the veterinarian with a better direction of how to approach pain therapeutically.
Clin Tech Equine Pract 6:120-125 © 2007 Elsevier Inc. All rights reserved.
T
tio
da
Alt
exp
vet
an
gen
com
cor
ph
du
ua
da
thu
*D
†D
Add
120
KEYWORDS pain, nociception, nociceptive signaling, anatomy and physiology of pain path-
ways, peripheral and central sensitization, primary hyperalgesia, secondary hyperalgesia,
physiological pain, maladaptive pain, pain classification
he International Association for the Study of Pain (IASP)
has defined pain as “an unpleasant sensory and emo-
nal experience associated with actual or potential tissue
mage, or described in terms of such damage or both.”1
hough originally phrased in the context of the human
erience, this definition may very well be applied in the
erinary field as well. It implies that pain is a very subjective
d complex multidimensional sensory experience that is
erated within the brain (especially cerebral cortex) after
plex neuronal processing of signals arriving via the spinal
d from peripheral nociceptors.2,3 At the same time, it is a
ysiological phenomenon or symptom that eventually pro-
ces responses that serve to warn and protect the individ-
l, whether human or animal, from impending tissue
mage, thereby helping to maintain bodily integrity and
s secure survival. Insofar pain resulting from activation
of nociceptors may be referred to as adaptive or physio-
logical pain, because it minimizes tissue damage by acti-
vating reflex withdrawal mechanisms and increasing be-
havioral, autonomical, and neurohumeral responses that
are aimed at maintaining body integrity, preventing fur-
ther tissue damage, and promoting healing.4 If persistent,
physiological pain may progress to a pathological condi-
tion in and of itself, often referred to as maladaptive pain,
in which case pain is dissociated from the original noxious
stimulation or the healing process and thus does not rep-
resent anymore a symptom of disease but rather abnormal
sensory processing due to damage to tissues (inflamma-
tory pain) or the nervous system (neuropathic pain), or to
abnormal function of the nervous system itself (functional
pain).5 It is this transformation of pain from a protective
phenomenon to a disease entity that causes persistent dis-
comfort and stress, sometimes even in patients with ade-
quate wound healing or trauma repair. In view of eutha-
nasia of horses with uncontrollable or chronic pain being
still very common in equine veterinary practice,4 the de-
structive potential of pain as a persistent sensory experi-
ence requires a sophisticated approach to pain manage-
epartment of Clinical Studies-New Bolton Center, School of Veterinary
Medicine, University of Pennsylvania, Philadelphia, PA.
epartment of Anesthesiology, David Geffen School of Medicine at Univer-
sity of California-Los Angeles, Los Angeles, CA.
ress reprint requests to Bernd Driessen, DVM, PhD, University of Pennsyl-
ain: From Sign to Disease
rnd Driessen, DVM, PhD, Dipl. ACVA, ECV
Pain is a subjective and complex multidimen
as a result of tissue trauma. It is generated
within the brain following the activation of
(nociceptors), which send nerve impulses from
Pain resulting from stimulation of nociceptor
enon as it helps minimizing further tissue da
nisms and increasing behavioral, autonomica
at maintaining body integrity, preventing f
However, if persistent, mechanisms describ
alter the pain experience in the patient, tran
pain, which is dissociated from the origina
maladaptive pain must be considered a path
responsible for persistent discomfort and str
behaviors, reduced quality of life and, if un
destruction of the animal. This article intends
well as physiological and pathophysiologica
duction, and integration of nociceptive signa
that is more indicative of the neural mecha
me
eq
vania, Department of Clinical Studies-New Bolton Center, 382 W. Street
Road, Kennett Square, PA 19348. E-mail: driessen@vet.upenn.edu
1534-7516/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1053/j.ctep.2007.05.004
sensory experience that usually occurs
extensive neuronal signal processing
eral high-threshold sensory receptors
eriphery to the central nervous system.
be considered a physiological phenom-
by activating reflex withdrawal mecha-
neurohumeral responses that are aimed
tissue injury and promoting healing.
peripheral and/or central sensitization
ing physiological pain into maladaptive
ious stimuli or healing process. Thus,
al condition in and of itself. It is often
the horse, which can lead to abnormal
olled, distress and eventually humane
e an overview of the anatomic sides as
esses involved in the generation, con-
presents a pain classification scheme
underlying pain phenomena and thus
nt to become an integral part of veterinary care in the
uine species.
A
P
Kn
inv
no
the
an
ica
an
no
pri
the
car
of
eli
res
du
Physiology and pathophysiology of pain 121
natomy and
hysiology of Nociception
owledge of the anatomic sides and physiological processes
olved in the generation, conduction, and integration of
ciceptive signals (Fig. 1) is essential for us to understand
many forms of how animals perceive and express pain
d how we can provide analgesia using both pharmacolog-
l and nonpharmacological approaches. In principle, four
atomic structures participate in the production of pain:
ciceptors (mechanical, thermal, chemical, or polymodal),
mary afferent neuronal pathways (ascending nerve fibers),
spinal cord, and finally the brain. Nociceptive signaling is
ried from the affected peripheral region to the dorsal horn
the spinal cord through small myelinated (A�) and nonmy-
nated (C) afferent nerve fibers (primary afferents) that are
Figure 1 Ascending pathways of nociceptive impulses ge
response to noxious stimulation. Once generated, impulses
fibers (primary afferents) to the dorsal horn of the spinal co
arriving at the spinal terminals of sensory afferents in the sp
which chemically convey the nociceptive input to spinal ne
the brain. In the brain a complex integration of these signals
The inflammatory process associated with tissue injury cau
peripheral nociceptors, production of inflammatory media
which collectively sensitize nociceptors toward noxious an
signals involving both inhibition and amplification takes p
originating in the brain and terminating in the dorsal horn
nociceptive signals from the peripheral nerve fibers to
peptide; NE, Norepinephrine; 5-HT, serotonin, DA, dopa
ponsive only to high-threshold stimuli. The faster con-
cting A� fibers carry information from specialized nerve
spi
hig
dings (nociceptors) responsive to high-threshold thermal
t or cold) or high-threshold mechanical stimuli. Slower
ducting C fibers transmit signals from free nerve endings
t are polymodal, ie, they are responsive to both high-
eshold mechanical and thermal stimulation as well as
emical stimuli (eg, products of cellular damage, cytokines,
tacoids, hydrogen ions, and various inflammatory media-
s).
Primary afferent nociceptive pathways terminate in the
rsal horn of the spinal cord, primarily in laminae I, II, and
onto several classes of second-order neurons.6 Neural ac-
ity evoked in the spinal cord dorsal horn by noxious stim-
projects via multiple ascending pathways (secondary af-
ents) to supraspinal sites, from where it eventually reaches
cerebral cortex as final destination. In addition, many
lateral fiber branches ascend and descend over several
d by peripheral sensory receptors (nociceptors) in
gate along small-diameter (C and A�) ascending nerve
tion potentials from activated peripheral nociceptors
rd dorsal
horn elicit the release of neurotransmitters,
(secondary afferents) that transmit the information to
orms the nociceptive input into the sensation of pain.
and electrolyte changes in the close environment of
d up-regulation of pro-inflammatory enzymes, all of
noxious stimuli. Extensive processing of nociceptive
thin the spinal cord. Descending neuronal pathways
ll as spinal interneurons modulate the conduction of
ing spinal neurons. CGRP, calcitonin gene-related
ABA, gamma aminobutyric acid.
en
(ho
con
tha
thr
ch
au
tor
do
V, 
tiv
uli
fer
the
col
nerate
propa
rd. Ac
inal co
urons
transf
ses pH
tors, an
d non
lace wi
as we
ascend
mine; G
nal segments before terminating on neurons projecting to
her centers, which provides a mechanism for input from
on
gu
asc
pro
the
affe
reg
cri
or 
sev
res
of
pa
suc
ule
am
au
pe
ten
ori
vid
sig
pla
me
wh
the
cic
eli
ma
(SP
ne
ary
ter
sal
rec
on
fee
of
dia
tor
rec
gly
ing
pa
ret
cor
ter
flu
pre
get
flo
sam
po
refl
do
tric
sen
the
bin
im
ha
dis
ma
cic
cei
cen
mi
no
spi
wh
tar
col
P
Pa
in
pa
an
thi
dif
mo
nis
tro
ph
an
da
sue
era
cau
alg
en
tra
tur
pro
an
lat
ph
cic
stim
are
cau
com
lev
aff
tiss
Ce
pu
ma
mi
in
nis
D-
tim
en
of
com
122 B. Driessen
e spinal segment to advance reflexive responses (eg, muscle
arding) over several segments. Key elements of secondary
ending pathways are direct projections to the thalamus, and
jections to the reticular and homeostatic-control regions of
medulla and brain stem. Direct spino-thalamic nociceptive
rent projections are relayed to the cortical somatosensory
ions and to limbic systems for appropriate immediate dis-
minative/cognitive and affective responses necessary to avoid
prevent further injury.7 Spino-bulbar projections involve
eral important regions for the appropriate homeostatic
ponse to nociceptive activity as well as for the modulation
afferent signaling to higher structures (through ascending
thways). Those and reciprocal interconnections between
h regions as the periaqueductal gray (PAG), locus cer-
us, and subventricular regions with limbic systems, thal-
us, and hypothalamus may serve for the integration of
tonomic, neuroendocrine, emotional, and behavioral as-
cts of the pain experience.8,9
The observation in humans that the experienced pain in-
sity often does not correlate well with the strength of the
ginal noxious stimulus and varies from individual to indi-
ual only indicates that extensive processing of nociceptive
nals involving both inhibition and amplification takes
ce once they are perceived by peripheral nociceptors.10 As
ntioned before, the spinal cord is the first relay station
ere significant modulation of the nociceptive input from
periphery occurs. Impulses from activated peripheral no-
eptors arriving at the spinal terminals of sensory afferents
cit the release of fast-acting neurotransmitters (eg, gluta-
te, ATP) and slower acting neuropeptides [substance P
), calcitonin gene-related peptide (CGRP), neurotensin,
urokinin], which conduct the nociceptive input to second-
afferents that convey the information to supraspinal cen-
s.11 Simultaneously, afferent nociceptive input to the dor-
horn activates local inhibitory interneurons, which form
iprocal synapses on primary afferents and in certain cases
ascending secondary neurons, thereby creating a type of
dback inhibition on afferent input. Segmental modulation
afferent impulse trafficking is through various neural me-
tors including opioids (acting primarily via� and � recep-
s), adrenergic neurotransmitters (acting primarily via �2
eptors), serotonin, gamma aminobutyric acid (GABA),
cine, and gonadotropic steroids (estrogen).9,10 Descend-
adrenergic, serotoninergic, and dopaminergic neuronal
thways arriving from supraspinal sites (eg, raphe nuclei,
icular formation, and other brain stem nuclei) as well as
ticofugal pathways originating in the cerebral cortex and
minating in the spinal cord exhibit strong modulating in-
ences and act on segmental interneurons as well as on
synaptic primary-afferent nerve terminals (Fig. 1).10 To-
her these mechanisms act to control as “gate keepers” the
w of nociceptive information to the brain, while at the
e time modulating the activation of simple mono- and
lysynaptic spinal reflex responses (eg, withdrawal reflexes,
ex muscle spasms) to noxious stimulation.
Involvement of the cerebral cortex in pain processing was
ubted for many decades. The historical finding that elec-
al stimulation of the cerebral cortex rarely elicited painful
sations was taken as evidence against the participation of
 cerebral cortex in pain processing.12 However, the com-
ation of data from neurophysiological experiments in an-
an
cas
als and recent functional neuroimaging studies in man
ve conclusively demonstrated the involvement of widely
tributed cerebral areas in pain processing with the so-
tosensory cortex representing the anatomic site where no-
eption finally acquires the quality of awareness, ie, is per-
ved as pain.13 All the components of the peripheral and
tral nervous system that are involved in generation, trans-
ssion, and integration of nociceptive signals (peripheral
ciceptors, ascending peripheral and spinal nerve fibers,
nal cord dorsal horn, and brain) should be considered
en prescribing a pain therapy plan as they represent the
get sides at which both pharmacological and nonpharma-
ogical interventions can exert their effects.
athophysiology of Nociception
in management strategies currently propagated by experts
both human and veterinary medicine are largely based on
in prevention (ie, preemptive analgesia/antinociception)
d/or multimodal analgesic therapy as early as possible, and
s for good reasons. The nociceptive system operates over
ferent time ranges spanning milliseconds to weeks or
nths or even years, and different neurobiological mecha-
ms are relevant over the different time scales. If left uncon-
lled, nociceptive signaling triggers a cascade of neuro-
ysiological processes that eventually lead to persistence
d exacerbation of the pain experience.2,3 Within hours to
ys following the initial noxious stimulation caused by tis-
injury, surgery, or infection, processes known as periph-
l and central sensitization are activated that eventually
se hyperalgesia. Peripheral sensitization or primary hyper-
esia occurs as a result of changes in the local chemical
vironment of peripheral nociceptors following tissue
uma and subsequent inflammation. Changes in tempera-
e, tissue pH and local electrolyte (K�) concentrations, the
duction of cytokines (TNF�), chemokines (bradykinin),
d growth factors by inflammatory cells, and the up-regu-
ion of enzyme systems (cyclooxygenase, protease, phos-
olipase) collectively activate both expressed and silent no-
eptors and sensitize them to noxious and nonnoxious
uli.4,9 As a result, in and around the originally affected
a even low-intensity stimuli, which normally would not
se pain, are perceived as painful.
Centrally mediated or secondary hyperalgesia is a more
plex and not yet completely understood process at the
el of the spinal cord and maybe supraspinal sites that
ects primarily the surrounding noninjured, noninflamed
ues and is initiated as early as primary hyperalgesia.14,15
ntral sensitization is caused by continuous nociceptive in-
t to the spinal cord triggered by tissue injury and inflam-
tion and includes up-regulation of excitatory neurotrans-
tter release and mediators within the dorsal horn. Studies
laboratory animals have demonstrated that a key mecha-
m of central hyperalgesia is the activation of the N-methyl-
aspartate (NMDA)/Ca2� channel complex, which over
e becomes increasinglymore sensitive for glutamate as the
dogenous neurotransmitter ligand.16,17
Under conditions
repetitive nociceptive afferent stimulation, the channel
plex is increasingly more frequently activated to permit
increase in intracellular Ca2�. This initiates a facilitatory
cade: posttranslational NMDA receptormodification facil-
ita
tor
cyc
ita
an
ne
im
act
stim
ch
ne
ch
en
im
rep
nal
tor
pa
sal
ran
ing
am
no
rec
cic
thr
tra
de
ica
in
gli
tur
ho
thr
sub
gro
qu
en
tra
occ
inj
the
ch
be
ou
ma
tre
pa
an
age
era
cep
C
Sy
ph
mi
its
vis
(ac
litt
inf
gre
ch
Th
kn
IAS
mo
nit
pa
acc
ina
III
ina
ers
to
of
is i
con
no
pa
ma
be
Ty
Ty
rep
sig
int
tiss
me
ten
an
nie
cel
rel
tio
occ
(eg
tid
fec
the
fib
tha
pri
he
stim
fea
no
du
to
lay
me
ess
Physiology and pathophysiology of pain 123
tes activation and increases in open-time duration, excita-
y receptor expression is up-regulated, and expression of
looxygenase (COX) products and nitric oxide (NO) facil-
tes excitatory transmitter release from primary afferents
d adjacent interneurons.7,16,18 As a result, the dorsal horn
urons become increasingly more responsive to nociceptive
pulses (hyperalgesia or winding-up) and eventually can be
ivated by normally nonpainful stimuli, ie, by subthreshold
uli and by impulses conducted via low-threshold me-
anically sensitive nerve fibers (allodynia).14
As part of the central sensitization process, the neuronal
twork within the spinal cord is undergoing morphological
anges in response to persistent high-level barrage of affer-
t nociceptive signaling, highlighting dynamic plasticity as an
portant property of neuronal structures within the CNS and
resenting a morphological correlate of “pain memory.”15 Spi-
remodeling may include alterations in the ratio of facilita-
y and inhibitory interneurons and descending neuronal
thways, thereby altering the bidirectional control over dor-
horn nociceptive transmission neurons. Physical rear-
gement of the dorsal horn circuitry by abnormal sprout-
of neurons and formation of new synaptic contacts
ong nerve cells can transform areas of the spinal cord
rmally involved in transmission of low thresholdmechano-
eptor signals (touch) into areas transmitting exclusively no-
eptive input, thus producing the sensation of painwhen low-
eshold pressure (touch) receptors are activated. 19 After
uma-associated peripheral nerve injury and subsequent
generation of neuronal axons, a complex pathophysiolog-
l condition arises where increasing spontaneous activity
peripheral afferents leads to continuous dorsal root gan-
on cell (DRG) activation and central facilitation, which in
n triggers sprouting of low-threshold afferents into dorsal
rn laminae that normally transmit only signals from high-
eshold afferents, loss of dorsal horn interneurons with
sequent loss of local and supraspinal inhibition, in-
wth of sympathetic innervation of the DRG with subse-
ent sympathetically mediated activation of primary affer-
t activity.15 As a result of these changes, nociceptive signal
nsmission to the brain is not only amplified but also can
ur in the absence of any noxious stimulation or tissue
ury, thereby further exacerbating the pain experience of
individual and causing what has been referred to as
ronic or maladaptive pain.5
Both peripheral and central sensitization processes have
en demonstrated in the horse,20,21 and often lead to fatal
tcome even if the initial disease condition, whether of trau-
tic, inflammatory, or other cause, could be successfully
ated. Therefore it is also in the horse mandatory to initiate
in treatment as early as possible by administering potent
algesics, local anesthetics, and/or other antinociceptive
nts that target different mechanisms involved in the gen-
tion, conduction, processing, and amplification of noci-
tive input.
lassification of Pain
stems of pain classification usually refer to the anatomy,
ysiology, and pathophysiology of nociceptive signal trans-
ssion and processing. Pain is generally described based on
anatomical location [superficial, musculoskeletal (deep),
de
tiv
ceral], intensity (mild, moderate, severe), and duration
ute, chronic). However, these descriptive terms provide
le clue as to the neural mechanisms involved and thus lack
ormation as to which extent nociceptive signaling has pro-
ssed with regard to neurochemical and neuroplastic
anges that eventually alter the pain sensation in the patient.
is also applies when discussing the period of pain. Un-
own to most clinicians, according to the taxonomy of the
P chronic pain is defined by duration of more than 3
nths.1 Therefore, acute pain covers several orders of mag-
ude of different durations of less than 3 months, including
in due to a brief noxious stimulus as well as pain that
ompanies the healing process.
It has recently been proposed to use also in equine veter-
ry practice a numerical taxonomy of pain (types I, II, and
).22 The classification scheme, adopted from a system orig-
lly described in human medicine by Doubell and cowork-
,18 provides the veterinarian with a better direction of how
approach pain therapeutically as it is somewhat indicative
the underlying neurobiological mechanisms. However, it
mportant to note that this scheme must be applied in the
text of the many dynamic processes that are triggered by
ciceptive signaling. Therefore, transitions from one type of
in to another (especially from type I to II) may occur in
ny cases of trauma, sometimes making a clear distinction
tween different types of pain difficult.22
pe I Pain
pe I pain occurs in the state of normal sensibility and
resents the result of physiological processes of nociceptive
nal generation, conduction, and central nervous system
egration. It is the pain associated with actual or impending
ue damage, triggered by intense hot or cold or strong
chanical stimuli that produce the typically sharp and in-
se sensation. Type I pain is generally sharp, well localized,
d temporally well defined. Trauma is commonly accompa-
d by an inflammatory response, which in part arises from
lular constituents leaking out of damaged cells or being
eased from activated inflammatory cells in the area. Addi-
nally, a neurogenic response to nociceptive stimulation
urs, resulting in the release of one ormore neural peptides
, substance P, neurokinin A, calcitonin gene-related pep-
e, bombesin, cholecystokinin, and serotonin).11,15 The ef-
t of these inflammatory response mediators is to change
excitability of sensory nerve endings and sympathetic
ers in and around the affected area, leading to a condition
t was previously described as peripheral sensitization or
mary hyperalgesia and that is characterized by locally
ightened responsiveness to both noxious and nonnoxious
uli. Thus, primary hyperalgesia is a normal and expected
ture of any tissue trauma and thus of type I pain.
Neural activity evoked in the spinal cord dorsal horn by
xious stimuli projects to supraspinal sites, including me-
lla and brain stem, for appropriate homeostatic responses
nociceptive activity. From there, nociceptive input is re-
ed to the limbic system and somatosensory cortex for im-
diate discriminative/cognitive and affective responses nec-
ary to avoid or prevent further injury.7 The previously
scribed complex neurochemical modulation of nocicep-
e signal transmission at spinal and supraspinal level (“gate
con
pla
ing
sto
to
by
tio
cu
stim
Th
pa
em
fer
wo
con
the
It t
ica
ing
mo
Ty
Ty
of
ary
hig
dif
wh
wi
aff
inh
at t
of
era
seg
na
no
con
ha
ger
res
ser
sue
ma
ha
can
tio
wh
ad
an
ext
Ty
Ty
ma
of 
res
no
mo
do
lea
an
ma
pro
cen
sig
an
Th
pa
pro
suc
inj
gen
cle
ate
pro
fib
ma
Re
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
124 B. Driessen
trol”) is also a feature of type I pain. When a horse is
ced in a situation that it perceives as potentially threaten-
(eg, being physically restrained by caregivers or in
cks), it may become unresponsive to noxious stimuli due
fear or, being a prey animal, reacts to pain by avoidance or
aggressive tactics if flight or avoidance is not an op-
n.23,24 This indicates that responses to physical or visual
es can significantly alter spinal neural responses to noxious
ulation, complicating the diagnosis and grading of pain.
us, under a normally functioning sensorium, the type I
in experience can be described as the sum of cognitive,
otional, and homeostatic responses to the modulated af-
ent nociceptive input. Type I pain, whether caused by a
und, sprain, strain, burn, or a primarily inflammatory
dition, usually disappears once the lesions have healed or
inflammation has vanished, and afferent signaling ceased.
herefore can also be referred to as adaptive or physiolog-
l pain,4 because its primary purpose is to aid in maintain-
body integrity, preventing further tissue damage and pro-
ting healing.
pe II Pain
pe II pain differs from type I in character and is the result
the processes described as central sensitization or second-
hyperalgesia. Generated and conducted primarily by
h-threshold, polymodal C fibers, the experienced pain is
fuse, poorly localized, and durable. Type II pain arises
en firing activity of secondary afferent neurons [primarily
de dynamic range neurons (WDR)] in response to primary
erent nociceptive signaling is enhanced through decreased
ibitory modulation, increased facilitatory activity, or both
he spinal level.18 Under normal conditions, WDR neurons
an affected segmental receptor are not activated by collat-
l afferent input (noxious or nonnoxious) from adjacent
ments. After central sensitization, repetitive afferent sig-
ling can lead to increased spinal receptor fields such that
nnoxious stimuli applied to intact peripheral areas can
tribute to the post traumatic sensation.18 Type II pain may
ve physiological importance. Central sensitization trig-
ed by afferent input after injury and inflammation, which
ults in discomfort or pain from low-intensity activity, may
ve to protect injured areas from further damage until tis-
healing has progressed to a degree that exposure to nor-
l mechanical, thermal, or other stressors is not causing
rm anymore. However, persistent pain and sensitization
often lead to further loss of function. Prolonged limita-
ns in movement can result in disuse atrophy of muscles,
ich further limits mobility. Abnormal posture and gait
opted to relieve discomfort may overload joints, ligaments,
d muscles, resulting in more areas of pain and even more
ensive central sensitization.10
pe III Pain
pe III pain, also referred to as neuropathic, chronic, or
ladaptive pain, represents a pathological condition in and
itself as mentioned before.4,5,15,24 Type III pain occurs as a
ult of altered neuronal plasticity. Damage to peripheral
ciceptive nerve fibers and/or morphological (plastic) re-
deling within the neuronal circuitry of the spinal cord’s
rsal horn and potentially other supraspinal centers can
d to altered firing patterns in primary afferent pathways
d abnormal conveyance and processing of sensory infor-
tion. Neurophysiological studies in laboratory animals
vided evidence for spontaneous discharge activity in as-
ding WDR pathways, causing uncontrolled nociceptive
naling to supraspinal centers in the absence of tissue injury
d painful responses to normally innocuous stimuli.4,10
us, type III pain distinguishes itself from any other form of
in by its persistence in the absence of any inflammatory
cess or any evidence of a detectable injury.24
In the horses, type III pain may arise from various conditions
h as surgical or traumatic injury resulting in sensory nerve
ury, equine fibromyalgia syndrome (EFMS) manifested as
eral body soreness or preferentially pain in the gluteal mus-
s and hamstrings, arthritis, spondylosis of the spine associ-
d with dorsal root radiculopathy, tumor growth leading to
gressive compression of adjacent tissue and thus sensory
ers, or compartment syndromes where chronic sompression
y interfere with sensory fiber function.22,24
ferences
Merskey H: Classification of chronic pain. Descriptions of chronic pain
syndromes and definitions of pain terms. Pain 3:S1-S225, 1986 (suppl)
Craig AD: Interoception: the sense of the physiological condition of the
body. Curr Opin Neurobiol 13:500-505, 2003
Murrel JC, Johnson CB: Neurophysiological techniques to assess pain
in animals. J Vet Pharmacol Ther 29:325-335, 2006
Muir WW: Pain therapy in horses. Equine Vet J 37:98-100, 2005
Siddall PJ, Cousins MJ: Persistent pain as a disease entity: implications
for clinical management. Anesth Analg 99:510-520, 2004
Light AR, Perl ER: Spinal terminations of functionally identified pri-
mary afferent neurons with slowly conducted myelinated fibers.
J Comp Neurol 186:133-150, 1979
Yaksh TL: Anatomical systems associated with pain processing, inWin-
nie A (ed): The 15th Annual Review of Pain and its Management (Vol
1). San Antonio, TX, Dannemiller Memorial Education Foundation,
2005, pp 1-16
Craig AD, Dostrovsky JO: Medulla to thalamus, in Wall PD, Melzak R
(eds): Textbook of Pain (ed 4). New York, NY, Churchill-Livingstone,
1999, pp 183-214
Giordano J: The neurobiology of pain, in Weiner RS (ed): Pain Man-
agement: A Practical Guide for Clinicians (ed 6). Boca Raton, FL, CRC
Press, 2001, pp 1089-1100
Cousins M, Power I: Acute and postoperative pain, in Wall PD, Melzak
R (eds): Textbook of Pain (ed 4). New York, NY, Churchill-Livingstone,
1999, pp 447-491
Levine JD, Fields HL, Basbaum AI: Peptides and the primary afferent
nociceptor. J Neurosci 13:2272-2286, 1993
Kenshalo D, Willis W (eds): The Role of the Cerebral Cortex in Pain
Sensation (Vol. 9). New York, NY, Plenum Press, 1991
Schnitzler A, Ploner M: Neurophysiology and functional neuroanat-
omy of pain perception. J Clin Neurophysiol 17:592-603, 2000
Stubhaug A, Breivik H, Eide PK, et al: Mapping of hyperalgesia around
a surgical incision demonstrates that ketamine is a powerful suppressor
of central sensitization to pain following surgery. Acta Anaesthesiol
Scand 41:1125-1132, 1997
Woolf CJ, Salter MW: Neuronal plasticity: increasing the gain in pain.
Science 288:1765-1768, 2000
Rison RA, Stanton PK: Long-term potentiation and N-methyl-D-aspar-
tate receptors: foundations of memory and neurologic disease? Neuro-
sci Biobehav Rev 19:533-552, 1995
Menigaux C, Fletcher D, Dupont X, et al: The benefits of intraoperative
small-dose ketamine on post-operative pain after anterior cruciate lig-
ament repair. Anesth Analg 90:29-135, 2000
Doubell TP, Mannion RJ, Wolf CJ: The dorsal horn: state dependent sen-
sory processing, plasticity, and the generation of pain, inWall PD, Melzak
R (eds): Textbook of Pain (ed 4). New York, NY, Churchill-Livingstone,
1999, pp 165-182
19. Woolf CJ, Wiesenfeld-Hallin Z: The systemic administration of local
anaesthetics produces a selective depression of C-afferent fibre evoked
activity in the spinal cord. Pain 23:361-374, 1985
20. Spadavecchia C, Andersen OK, Arendt-Nielsen L, et al: Investigation of
the facilitation of the nociceptive withdrawal reflex evoked by repeated
transcutaneous electrical stimulations as a measure of temporal sum-
mation in conscious horses. Am J Vet Res 65:901-908, 2004
21. Livingston A: Physiological basis of pain management, in Doherty T,
Valverde A (eds): Manual of Equine Anesthesia & Analgesia. Oxford,
UK, Blackwell, 2006, pp 293-300
22. Tomasic M: Pain: what it is, where it is, and what it could be, in: 2005
Proceedings of the 51st Annual Convention of the American Associa-
tion of Equine Practitioners. Seattle, WA, American Association of
Equine
Practitioners (AAEP), 2005, pp 395-397
23. Fanselow MS: The midbrain periaqueductal gray as a coordinator of
action in responses to fear and anxiety, in Depaulis A, Bandler R (eds):
The Midbrain Periaqueductal Gray Matter: Functional, Anatomical and
Immunohistochemical Organization. New York, NY, Plenum Publish-
ing Corp, 1991, pp 151-173
24. Ridgway KJ: Diagnosis and treatment of equine musculo-skeletal pain.
The role of complementary modalities: acupuncture and chiropractic,
in 2005 Proceedings of the 51st Annual Convention of the American
Association of Equine Practitioners. Seattle, WA, American Association
of Equine Practitioners (AAEP), 2005, pp 403-408
Physiology and pathophysiology of pain 125
	Pain: From Sign to Disease
	Anatomy and Physiology of Nociception
	Pathophysiology of Nociception
	Classification of Pain
	Type I Pain
	Type II Pain
	Type III Pain
	References