Allodynia and hyperalgesia within dermatomes caudal to a spinal cord injury in primates and rodents.

Full text

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J. Sandkiitrler, B. Bromm and GE Gebhat
Progress in Brain Research, Vol. 129
0 2000 Elsevier Science B.V. All rights reserved
(Eds.)
CHAF’TER 3 1
Allodynia and hyperalgesia within dermatomes caudal to
a spinal cord injury in primates and rodents
Charles J. Vierck, Jr. I,* and Alan R. Light 2
’ Department
of Cellular
of Neuroscience,
and Molecular
University of Florida Brain Institute,
Carolina,
Gainesville.
School
FL 32610-0244,
of Medicine,
USA
Hill, NC 27599, ’ Department Physiology, University of North Chapel USA
Categories of central pain following spinal cord
injury
Despite the common occurrence of pain of central
origin that is referred to dermatomes supplied by
segments below the level of a spinal cord injury
(Botterell et al., 1953; Nepomuceno et al., 1979;
Yezierski, 1996), this disorder has not been ana-
lyzed extensively in laboratory animals. In contrast,
there are well characterized laboratory animal mod-
els that describe changes in behavior directed toward
dermatomes supplied by segments adjacent to and
directly affected by a spinal lesion (Hao et al., 1991;
Yezierski et al., 1998). These border zone phenom-
ena are probably related to (if not dependent upon)
excitatory effects of a lesion on neurons in neighbor-
ing segments (Hao et al., 1992; Yezierski and Park,
1993). However, mechanisms underlying pain that
is referred to remote caudal dermatomes are yet to
be established. The latter type of sensory disorder
is referred to as deafferentation
tent with referral of abnormal sensations to portions
of the body which have lost all or a portion of
their afferent drive of (projections to) supraspinal so-
matotopic representations. This does not imply that
deafferentation is a sufficient condition for devel-
opment of central pain. It describes the distribution
zone pain, consis-
*Corresponding author: C.J. Vierck, Jr., Department of
Neuroscience, University of Florida, College of Medicine,
Gainesville, FL. 32610-0244, USA. Fax: +l (352) 392-
8513; E-mail: vierck@ufbi.ufl.edu
of referred sensations to dermatomes with reduced
input to supraspinal levels as a result of a spinal
lesion.
Models of deafferentation zone pain
A difficulty for an animal model of deafferenta-
tion zone pain is that such pain in human beings
is referred to body regions that have been shown
to be relatively insensitive to peripheral stimulation.
In particular, sensitivity to innocuous thermal and
normally painful stimulation is reliably diminished
within the region of pain referral for patients with
post-stroke central pain (Boivie et al., 1989; Bow-
sher, 1996). These and other findings suggest that
interruption of the spinothalamic tract at any level of
the neuraxis can produce central pain (Cassinari and
Pagni, 1969). In related experiments with laboratory
animals, investigators have noted the occurrence and
timing of overgrooming or autotomy in a region af-
fected by transection of a peripheral nerve (Wall et
al., 1979) or interruption of the spinothalamic tract
(Levitt and Levitt, 1981). An assumption behind this
approach is that an animal excessively grooms or
inflicts damage on tissue in an attempt to elimi-
nate pain referred to that region. When the region
is analgesic or anesthetic, autotomy would not be
discouraged, because pain would not be produced by
the animal’s actions.
Problems with autotomy as a measure of deaf-
ferentation zone pain are that self-destructive behav-
ior may or may not be driven by an abnormal sen-

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412
sation, and the quality, intensity and timing of such
a sensation that might be experienced by the animal
are unknowable (Rodin and Kruger, 1984). One pos-
sibility is that autotomy results from an absence of
sensation. However, this is an unlikely explanation
in all cases, because autotomy is susceptible to mod-
ulation (Coderre et al., 1986; Kauppila, 1998). Al-
ternatively, an animal could be responding to a non-
painful dysesthetic sensation (e.g., tingling, itching).
Substantial deafferentation regularly produces some
form of dysesthesia, either painful or not. For exam-
ple, limb amputation produces phantom sensations
in virtually all cases, but referred pain of sufficient
intensity to seek treatment occurs at some point in
time for an estimated 10% of amputees (Jensen and
Rasmussen, 1984). Similarly, spinal cord injury reg-
ularly produces phantom sensations; some form of
pain occurs later for most patients, and an estimated
25% develop severe deafferentation zone pain (Bot-
terell et al., 1953; Nepomuceno et al., 1979). Clearly
it is important to distinguish between painful and
non-painful sensations experienced in a region of
deafferentation, but this distinction cannot be made
on the basis of autotomy alone. Furthermore, auto-
tomy is not reliably produced by anterolateral spinal
lesions (Vierck and Luck, 1979; Saade et al., 1990;
Vierck et al., 1990a, 1995; Vierck and Light, 1999).
Autotomy is more prevalent among animals housed
singly in a confined space (Rodin and Kruger, 1984)
and social isolation predisposes animals to repetitive
autotomous behaviors in the absence of neural injury.
If we cannot rely upon observation of spontaneous
behaviors to indicate the presence of deafferentation
zone pain, and if nociceptive sensitivity is dimin-
ished for stimulation in the region of presumed
pain, then an appropriate laboratory animal model
of deafferentation zone pain is problematic. How-
ever, extensive observations of humans who have
received surgical lesions of the anterolateral spinal
column for relief of chronic pain in a limited distri-
bution suggest otherwise. This procedure is seldom
utilized at present, because surgical interruption of
the spinothalamic tract at any level of the neuraxis
often results in ‘recovery’ of contralateral pain sensi-
tivity over time. The functional restoration usually is
associated with dysesthetic pain within the region of
early postoperative relief of clinical pain and reduced
sensitivity to nociceptive stimulation (Horax, 1929;
Hyndman and Van Epps, 1939; Cassinari and Pagni,
1969; White and Sweet, 1969). Thus, clinical experi-
ence with surgical interruption of the spinothalamic
pathway strongly reinforces findings from studies of
post-stroke pain. Central pain occurs in the distribu-
tion of sensory deficits that implicate damage to the
spinothalamic tract as a causal factor.
After recovery from interruption of the spinotha-
lamic tract, pain elicited within contralateral regions
affected by the lesion is qualitatively distinct from
similarly evoked pain in intact individuals (Wycis
and Spiegel, 1962; White, 1968; Eide et al., 1996).
Also, regions with input contralateral and caudal
to a cordotomy can be abnormally responsive to
certain forms of stimulation (e.g., repetitive stimula-
tion; Walker, 1943; King, 1957; Nathan and Smith,
1979; Eide et al., 1996). These findings are impor-
tant for modeling of deafferentation
an extensive study of sensory capacities following
anterolateral cordotomy for clinical pain, Lahuerta et
al. (1994) reported that “Most patients (with central
pain) noted disagreeable abnormal sensations on cu-
taneous stimulation within the analgesic area.” Thus,
tests of cutaneous sensitivity could be appropriate for
detection of aversive dysesthesias referred to regions
affected by interruption of the spinothalamic tract.
zone pain. In
Effects of anterolateral
escape responses of monkeys
cordotomy on operant
Several studies with
changes in sensitivity to nociceptive stimulation of
the legs over time after interruption of the spinothala-
mic tract at a thoracic level (Vierck and Luck, 1979;
Vierck et al., 1990a). The monkeys were trained pre-
operatively to terminate (escape) electrocutaneous
stimulation of either lateral calf by pulling on a ma-
nipulandum with either hand. Following interruption
of pathways in one lateral spinal column, substan-
tial contralateral decrements in sensitivity (reduced
escape frequencies and elevated latencies) were ob-
tained for a wide range of stimulus intensities. Post-
operative sensitivity to contralateral stimulation was
clearly less than for preoperative testing, in contrast
to postoperative sensitivity to ipsilateral stimulation,
which did not differ from preoperative performance
or was enhanced. The contralateral deficit was ob-
served for escape responses to previously nociceptive
monkeys have evaluated

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stimulus levels but not for detection of innocuous
stimulation, as determined by a testing paradigm
involving food reinforcement for responses to low
levels of stimulation (Greenspan et al., 1986). These
results established an important first component of an
animal model of spinothalamic tractotomy. Consis-
tent with evidence from human beings, there should
be a diminution in nociceptive sensitivity and a spar-
ing of non-nociceptive sensitivity contralateral to a
lesion involving one anterolateral spinal column.
Our working assumption for the primate model
was that nociceptive sensitivity would return over
time following anterolateral cordotomy for at least
some of the animals (Vierck, 1991). In an initial study
with new-world Cebus albifrons monkeys (Vierck and
Luck, 1979), recovery to preoperative levels of re-
sponsivity occurred for each animal. A subsequent
study with old-world Macaca nemestrina monkeys
(Vierck et al., 1990a) produced a result consistent
with reports involving long-term clinical observations
of human patients with chronic pain (i.e., delayed re-
covery in approximately 50% of the cases; White and
Sweet, 1969). More generally, regardless of whether
recovery occurred and was sustained, sensitivity con-
tralateral to the lesion was exceedingly variable over
long postoperative testing periods. To illustrate this
lability, different patterns of change in contralateral
sensitivity over months of testing after cordotomy are
depicted in Fig. 1 for four monkeys; two that were
classified as recovered and two that were categorized
as unrecovered, based upon their level of sensitivity
to contralateral stimulation.
Fig. 1 shows the time course of changes in op-
erant response speed for electrocutaneous stimula-
tion of the left (contralateral) and right (ipsilateral)
legs following anterolateral cordotomy on the right
side. Escape speed for each trial consisted of the
maximum trial duration minus the operant response
latency, so that high speeds represent short trial du-
rations and a high level of aversion. For these plots,
response speeds were averaged across four stimulus
intensities presented in each testing session (0.1, 0.4,
1.1 and 2.5 mA/mm2). These graphs reveal over-
all levels of aversion for stimulus intensities that
ranged for normal animals (preoperatively) from a
level near threshold for escape (eliciting escape on
50% of the trials) to an intensity that produced
minimal response latencies on each trial (near 200
ms). The horizontal lines represent average response
speed over the last 4 weeks of preoperative testing.
Each data point for postoperative testing represents a
cascaded average over 10 testing sessions (week 2)
or 20 sessions (all subsequent points). That is, the
first postoperative value is averaged over weeks 1-2;
subsequent points are averaged over weeks l-4,3-6,
5-8, etc. This reveals gradual changes in contralat-
era1 sensitivity over biweekly periods but obscures
day-to-day variability. Despite the eventual catego-
rization as recovered or unrecovered, contralateral
sensitivity (large symbols in Fig. 1) returned to or
near preoperative levels for each animal at some
point in the postoperative testing period. Note that
ipsilateral sensitivity (small symbols in Fig. 1) was
relatively stable, providing a control for the possibil-
ity that the contralateral changes resulted from spon-
taneous shifts in behavioral bias toward responding.
Ipsilateral sensitivity was generally increased over
preoperative levels (reaching statistical significance
for animals eventually classified as recovered).
Methodological
nociception
considerations for evaluating
A considerable advantage of the animal model in
understanding mechanisms of recovery from cor-
dotomy is that progression of a disease process is
not a factor, as it is in clinical cases (e.g., cancer).
In addition, it is feasible to test the animals daily,
to plot changes in sensitivity with good resolution
over time. Other features of the animal model are
pertinent to evaluation of the results. Electrocuta-
neous stimulation is advantageous for training and
testing animals on an escape paradigm, because the
evoked sensation disappears abruptly when the ap-
propriate response occurs. For forms of stimulation
that offset gradually (e.g., ramped heat) and/or pro-
duce prolonged after-sensations, it is difficult for an
animal to associate occurrences of an operant re-
sponse with termination of a nociceptive sensation.
Electrocutaneous intensities ranging from levels that
do not elicit escape to levels that reliably produce
escape at minimal latencies have been evaluated by
testing human observers (e.g., Vierck et al., 1983,
1995; Vierck and Cooper, 1984; Cooper et al., 1986).
The threshold for escape by monkeys is comparable
to pain threshold for humans, and there are many

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414
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discriminable levels of nociceptive intensity (just no-
ticeable differences or JNDs) across the stimulus
range. Human beings describe sensations subthresh-
old for pain as tingling (sometimes itching). Painful
sensations elicited by higher intensities have a real-
istic thermal component for the parameters utilized
(50 ms of 60 Hz stimulation, separated by 200 ms
interstimulus intervals).
It is important to recognize that escape responses
for normal animals on this paradigm occur exclu-
sively in relationship to first pain. The animals re-
spond to the high intensities before second pain
would occur. The effects of cordotomy could differ
for methods of stimulation that preferentially activate
unmyelinated nociceptors (e.g., Cooper et al., 1986;
Yeomans et al., 1996; Lu et al., 1997). Sensations
elicited by the nociceptive stimulus intensities range
from very weak to strong pain for human observers
(Vierck et al., 1983), indicating that the shifts in
operant responsivity shown in Fig. 1 represent sub-
stantial changes in nociceptive sensitivity. Finally,
the effects of anterolateral cordotomy on escape be-
havior do not parallel effects on flexion reflexes that
are often utilized as behavioral indices of nociceptive
sensitivity. Flexion reflexes can be depressed bilat-
erally in cases of a strictly contralateral effect of
cordotomy on operant escape responses (Vierck et
al., 1990a; Vierck and Light, 1999), and alterations
of reflex sensitivity do not parallel changes in pain
sensitivity after cordotomy in humans (Garcia-Larrea
et al., 1993).
Effects of spinal lesion size and distribution
contralateral nociceptive sensitivity
on
Initial goals of the animal model were to relate alter-
ations of cellular interactions to the time course of re-
415
covery from cordotomy (e.g., Bullitt et al., 1988) and
to identify histologically the lesion configuration(s)
that permit or promote the return of contralateral
nociceptive sensitivity. For example, recovery of no-
ciceptive sensitivity could depend upon incomplete
interruption of the spinothalamic tract. Incomplete
injuries to peripheral nerves can result in exagger-
ated responses to cutaneous stimulation (Seltzer et
al., 1990; Bennett, 1993), possibly implicating par-
tial deafferentation in the generation of pathological
pain processing (Kingery and Vallin, 1989; Pale-
cek et al., 1992). If these principles apply to partial
deafferentation of rostra1 projection targets of the
spinothalamic tract in the brain stem, thalamus (see
also Dostrovsky, 2000, this volume), hypothalamus,
cerebral cortex (see also Bromm et al., 2000, this
volume; Casey, 2000, this volume) and elsewhere,
an exaggerated and qualitatively altered response to
spared input could result. That is, stimulus-response
functions for contralateral stimulation would be ex-
pected to reveal aversive responses at some point in
time to normally innocuous stimulation (allodynia)
and/or exaggerated responses to normally nocicep-
tive stimulation (hyperalgesia). Delayed appearance
of these effects could depend upon neural reorgani-
zation in response to partial deafferentation.
The lesions shown in Fig. 1 indicate that the in-
cidence of contralateral recovery of pain sensitivity
cannot be explained as the result of greater spar-
ing of spinothalamic tract axons. The largest lesion
(panel D) is associated with gradual return of no-
ciceptive sensitivity to levels of responsivity greater
than during preoperative testing. The smaller lesions
for animals shown in Fig. 1 (panels A and B) were
associated with substantial hypoalgesia after months
of postoperative testing. In general, prolonged return
of contralateral sensitivity in this study of Mucaca
Fig. 1. Average
at an upper
speeds
so that enhanced
values below
of daily
on substantial
D) were
to ipsilateral
contralateral
escape speed across
level.
are shown
postoperative
preoperative.
sessions (5 per week),
decreases
classified as recovered,
stimulation
sensitivity
stimulation
preoperative
as thick
sensitivity
In this study,
to reveal
in response
based
were generally
(e.g., panel D).
intensities is shown
are shown
Escape
by values
postoperative
changes in sensitivity.
for contralateral
upon a progressive
increased by anterolateral
for 4 monkeys
for
speeds
above
means
after surgical
and right
from
lesions
sides
escape
mean,
stimulation
(A and B) were
than a year
sensitivity
especially for
of the right
@re), and the average
latencies
and decreased
of each hindlimb
classified
of testing. Two
that was maintained
large lesions
anterolateral column
thoracic Stabilized speeds
lines.
the left
are calculated
the preoperative
were plotted
Two animals
after more
in contralateral
cordotomy,
preoperative
et al., 1990a)
is shown
across 4 weeks
as unrecovered,
other animals
over time.
associated with
for both sides horizontal
is represented
cascaded
gradual
speed
(see Vierck
sensitivity by
for
based
(C and
Responses
recovery
stimulation
increase
of

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A. LEFT SIDE FROM RIGHT THALAMUS* B. RIGHT SIDE FROM LEFT THALAMUS
60
I3 Cervical
E3 Lumbar
Silver
Sliver
60
El Cervical
El Lumbar
TMB
TMB
I, II III, IV V Ventral I, II ill, IV
V
Ventral
C. LEFT SIDE FROM LEFT THALAMUS
D. RIGHT SIDE FROM RIGHT THALAMUS
60 ; El Cervical TMB
60
13 Cervical
• I Lumbar
Silver
Silver
$ 40
d
30
a
t
*
I
20.
50
0
I, II III, IV
V Ventral
I, II
Ill, IV V Ventral
Fig.
enlargements
The number
averaged
all more ventral
T6 on the right
number
this lesion
label from
2. Cell counts
of a monkey
of cells
over four
laminae).
side)
of labeled
effect
the left thalamus
on the left (panels A and C) and right
of the left thalamus
reaction product
segments for four regions
Both injections labeled
did not appreciably
cells in laminae I-V of the left (contralateral)
were provided by cervical
to the right side (panel
sides
with HRP
or silver
of the gray
of ipsilateral
transport
lumbar
side from
(panels B and D) of spinal
and the right
grains (apo-HRP,
matter
cells
of label. The right
segments (panel
the opposite
segments
with
at the cervical
conjugated
silver
III and IV, lamina
and lumbar
to gold beads.
intensification)
after injection
HRP
or lumbar
thalamus apo-HRP
containing
cervical
(TMB) demonstrated
I and II, laminae
C and D). The anterolateral
anterolateral
A; injection in the right
thalamus (panels
with were
V and (laminae
(panels a small number
ipsilateral
spinal lesion cat
the
for
of
interrupt lesion substantially
thalamus).
reduced
Controls
transport transport on either
B).
A and B) and lumbar
nemestrina
ciated with lesions that were among the largest.
In order to more formally evaluate the sparing
of spinothalamic tract projection cells in monkeys
with an anterolateral spinal lesion, four animals re-
ceived thalamic injections of retrograde tracers in
the thalamus. Fig. 2 shows data from one animal
that satisfied criteria of complete bilateral filling of
nucleus ventralis posterolateralis (VPL) and adjacent
thalamic terminations of the spinothalamic tract. The
injections occurred 9 months after a lesion of the
monkeys (Vierck et al., 1990a) was asso-
right anterolateral column at T6. In brief, recordings
from the thalamus under surgical anesthesia were
utilized to locate VPL on each side. Horseradish per-
oxidase (HRP) was injected into the left thalamus at
the site of maximal evoked responses from the right
foot, and gold particles conjugated to apo-HRP were
injected at multiple sites in the right thalamus, in and
around the focus of evoked activity from stimulation
of the left foot. After 3 days survival, the animal was
killed, the spinal cord was processed, and cervical
and lumbar neurons were evaluated for HRP reac-

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tion product and gold particles intensified with silver
deposition. This method permitted identification of
neurons on both sides of the spinal cord that pro-
jected to the left thalamus (HRP reaction product)
and the right thalamus (silver grains). Four blocks of
tissue from segments in the cervical and lumbar en-
largements were sectioned, and the labeled neurons
in each block were counted and assigned to laminar
regions.
The principal effect of a lesion on the right side
was to virtually eliminate the projection of lamina
I, II and V neurons from the lumbar enlargement
on the left to thalamus on the opposite side. An
average of 1.3 lumbar neurons in laminae I and II
on the left projected past the anterolateral lesion to
the right thalamus, in contrast to 40 or more neurons
that transported label contralaterally from thalamus
to cervical segments and to lumbar segments on the
right. Thus, the lesion did not spare projections from
the superficial dorsal horn that shift dorsally in the
lateral spinal columns at high spinal levels (Ralston
and Ralston, 1992). Similarly, an average of 1.5 lam-
ina-V neurons on the left were labeled in lumbar
segments after thalamic injection on the right. In
contrast, 25 to 32 neurons were labeled in lamina V
on the right (cervical and lumbar sections) and on
the left side of cervical segments, after contralateral
thalamic injections. Although there was an almost
complete lack of labeled dorsal neurons in lumbar
segments on the left after injection of the right thala-
mus, an average of 11.5 ventral neurons was labeled.
Thus, there was slight sparing of spinothalamic pro-
jections to the right thalamus from ventral neurons
in lumbar segments on the left, despite the presence
of an anterolateral lesion on the right. In addition,
small numbers of spinal projections to the ipsilat-
era1 thalamus from lumbar segments were identified.
These originated predominately in the ventral gray
matter. As expected, the anterolateral lesion spared
some spinothalamic projections to the thalamus.
In addition to a slight sparing of direct spinotha-
lamic projections by anterolateral cordotomy on the
right side, input from the contralateral (left) side
projects indirectly to the right thalamus via dorsal
and ventral spinal pathways on the left (e.g., via
spinal lemniscal and spinoreticular pathways). These
pathways receive nociceptive and non-nociceptive
input (Vierck et al., 1986; Willis and Coggeshall,
1991). The partial deafferentation of the somatosen-
sory thalamus by anterolateral cordotomy (Berkley,
1980) poses a question that is pertinent to the issue
of recovery from contralateral hypoalgesia following
anterolateral cordotomy. Which pathways are re-
sponsible for rostra1 conduction of nociception after
contralateral interruption of the spinothalamic tract?
That is, which spinal pathways must be interrupted to
eliminate sensitivity to nociceptive stimulation (i.e.,
produce analgesia)?
Effects of sequential lesions to the spinothalamic
tract and then other spinal pathways have been eval-
uated in monkeys (Vierck and Luck, 1979). Follow-
ing recovery of sensitivity to nociceptive stimulation
contralateral to an anterolateral lesion, interruption
of dorsal spinal pathways did not eliminate cuta-
neous pain sensitivity that had returned after antero-
lateral cordotomy. Also, a large lesion sparing only
one anterolateral column has been reported to pre-
serve nociceptive sensitivity bilaterally in a human
patient (Noordenbos and Wall, 1976; Danziger et al.,
1996). In contrast, ventral hemisection resulted in an
enduring loss of sensitivity to nociceptive stimula-
tion in monkeys. Similarly, bilateral ventral lesions
in human beings have been reported to produce anal-
gesia (Triggs and Beric, 1992). These findings are
of particular interest in comparison to bilateral an-
terolateral cordotomy, which does not eliminate pain
sensitivity in monkeys or humans (White and Sweet,
1969; Vierck and Luck, 1979; Lahuerta et al., 1994).
It appears that axons in the ventral half of the spinal
cord, not restricted to the spinothalamic tract, are
critical for elicitation of pain by nociceptive stim-
ulation of dermatomes well below the level of the
lesion(s).
Extensive lesions of the ventral spinal cord are
not an option for control of clinical pain, because of
involvement of motor and autonomic pathways. Fur-
thermore, large bilateral lesions of the ventral spinal
cord that eliminate cutaneous nociception are asso-
ciated with severe central pain and allodynia (Triggs
and Beric, 1992). The allodynia appears to result
from interruption of ventral pathways and sparing
of dorsal spinal pathways. In addition, development
of central pain following spinal cord contusion in-
jury has been suggested to depend upon incomplete
injuries that spare some rostra1 transmission (Beric,
1993). Thus, the concept that deafferentation zone

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418
pain can develop following
section may be incorrect and related to difficulties
in discriminating complete from incomplete injuries
(Davidoff et al., 1987; Beric et al., 1988).
In contrast to large ventral spinal lesions that
can be associated with development of central pain
and allodynia, superficial lesions of the anterolateral
spinal cord that interrupt spinothalamic axons but
do not extend medially to involve the gray matter
appear to produce an enduring contralateral hypoal-
gesia for monkeys (Vierck and Luck, 1979; Vierck et
al., 1990a). Similarly, Nathan and Smith (1979) have
presented a series of patients who obtained long-term
relief of chronic pain contralateral to anterolateral le-
sions that were shown histologically to be uniformly
small and superficial. These results suggest that an-
terolateral cordotomy can be effective for long-term
attenuation of pain that is otherwise intractable, if the
lesion is appropriately placed and restricted to tran-
section of axons located superficially in the spinal
white matter.
Based upon the evidence presented above, the
following conclusions are offered regarding effects
of anterolateral cordotomy in primates. (1) As ex-
pected, unilateral interruption of the spinothalamic
tract produces a strictly contralateral hypoalgesia.
(2) Repeated measurements over time after unilat-
eral cordotomy show that there can be substantial
swings in nociceptive sensitivity for stimulation con-
tralateral to the lesion. (3) Recovery of contralateral
sensitivity is especially evident following anterolat-
era1 lesions that extend medially into the gray matter,
but recovery is not strictly dependent upon the con-
figuration of these lesions. (4) The variability in ef-
fects of cordotomy between and within animals over
time suggests that some adventitious consequence of
medially extensive lesions influences sensitivity to
contralateral stimulation.
complete spinal tran-
Effects of hemotoxicity
cordotomy on sensitivity to ipsilateral stimulation
at the site of anterolateral
The amount of bleeding into the surgical cavity
could be one determinant of the functional effects
of cordotomy. Application of blood, hemoglobin or
a ferrous compound to CNS gray matter results in
a focus of epileptic-like discharge among cortical
neurons (Willmore et al., 1986) and produces an
ischemic infarct when injected into the spinal cord
(Sadrzadeh et al., 1987). These effects are present
in models of border zone pain following ischemia
(Xu et al., 1992) or excitotoxic injury (Yezierski
et al., 1998) within spinal gray matter. In these
models, attention has been directed to overgrooming
and hypersensitivity within dermatomes supplied by
segments near the level of the spinal lesion. However,
it is quite possible that involvement of pathways in
the core spinal region (e.g., the propriospinal system
of diffuse projections) could influence sensitivity to
stimuli applied to dermatomes remote from the site
of ischemic injury (Sandktihler, 1996; Liu et al.,
1998; Wall et al., 1999). Therefore, the influence
of bleeding into anterolateral lesion cavities was
tested in a rodent model of nociceptive sensitivity
(Vierck and Light, 1999). After training Long-Evans
rats to escape electrocutaneous stimulation of either
hindlimb by pressing a lever with the right forelimb,
the rats received thoracic spinal lesions of one of two
types. Some anterolateral lesion cavities were filled
with gelfoam pledgets soaked in the animal’s blood,
and there was no intentional introduction of blood
into the lesion cavities of other animals.
Intentional introduction of blood into the lesion
cavities consistently resulted in an ipsilateral hyper-
sensitivity that was apparent as soon as the animals
could be tested after surgery (approximately 1 week)
and generally lasted for months thereafter. Signif-
icant ipsilateral hypersensitivity had been observed
after recovery of contralateral sensitivity in mon-
keys, but these effects were observed throughout
the postoperative testing interval for all rats after
introduction of blood into the lesion cavity. Ipsi-
lateral hypersensitivity was not seen consistently in
monkeys that did not show long-term recovery of
contralateral sensitivity or in rats without intentional
introduction of blood into the lesion cavity.
The occurrence of ipsilateral hypersensitivity af-
ter anterolateral cordotomy, without the presence of
a source of pathological pain in the periphery, puts
clinical observations of mirror image pain (Nathan,
1956; Bowsher, 1988; Nagaro et al., 1993) in a
new perspective. Following cordotomy for lateral-
ized chronic pain, patients sometimes develop a per-
sistent dysesthesia ipsilateral to the lesion. In these
cases, it is possible that relief of contralateral pain
has unmasked ipsilateral pain originating from the

Page 9

419
contralateral peripheral source. For example, patho-
logical involvement of a peripheral nerve produces
bilateral effects on spinal circuits that could result in
bilateral sensory abnormalities (Koltzenburg et al.,
1999). However, there was no peripheral pathology
in the monkeys or rats that became hypersensitive to
stimulation ipsilateral to anterolateral spinal lesions.
Another potential explanation for ipsilateral hyper-
sensitivity is that the anterolateral lesions interrupted
descending spinal pathways which exert inhibitory
effects on caudal spinal circuits (Jones and Light,
1992; Sandkiihler et al., 1993; Smith et al., 1995),
resulting in disinhibition
sion. However, comparing animals with and without
intentional hemotoxicity, there were no discernable
differences in configuration of white matter damage
that could account for the presence of ipsilateral al-
lodynia and hyperalgesia. These effects apparently
depended upon introduction
sion cavity, without additional destruction of spinal
white matter that could be observed with standard
histological techniques.
An implication of the ipsilateral hypersensitivity
is that hemotoxic effects on the spinal gray matter
change the excitability of distant neurons in noci-
ceptive pathways. It is apparent that responsivity
within segments near the distribution of a spinal le-
sion can be increased by excitotoxicity
et al., 1998). However, the relevance of gray matter
damage to responsivity within segments well outside
the distribution of a lesion has not been emphasized
previously. At this point, it is not clear whether re-
mote effects of gray matter involvement should be
attributed to interruption of propriospinal conduction
or to excitatory propagation rostrally and/or caudally
from the lesion site (e.g., via Lissauer’s tract).
of nociceptive transmis-
of blood into the le-
(Yezierski
Sensitivity to contralateral
anterolateral
stimulation following
cordotomy
Despite the consistent enhancement of ipsilateral
sensitivity by cordotomy plus hemotoxicity, recov-
ery from a contralateral attenuation of nociceptive
sensitivity was not obviously enhanced by inten-
tionally introducing blood into the lesion cavity. In
retrospect, however, restricting attention to sustained
recovery of nociceptive sensitivity ignores a com-
mon effect of anterolateral cordotomy on contralat-
era1 sensitivity. Even monkeys that were classified
as unrecovered on the basis of sustained late post-
operative performance had one or more periods in
which contralateral sensitivity was near preoperative
levels (e.g., Fig. lA,B). Classification of animals as
recovered would have been almost unanimous for
medially extensive lesions, if the criterion had been
contralateral sensitivity that was close to the preop-
erative level at any time in the postoperative period
of testing. Furthermore, averaging performance over
weeks to reveal long cycles of increased and de-
creased sensitivity in the monkey study obscured a
considerable day-to-day variability that is character-
istic for stimulation contralateral to an anterolateral
lesion. This is exemplified in Fig. 3, which presents
daily means of responsivity for rats after anterolat-
era1 cordotomy with hemotoxicity.
Testing for extended periods before and after
surgery provides the opportunity to regard each an-
imal as a case study and permits secure descrip-
tions of within-animal variability, in addition to the
more common comparisons between animals. Pan-
els A and B in Fig. 3 typify the operant escape
performance of rats with substantial and enduring
contralateral hyposensitivity (on the average) and ip-
silateral hypersensitivity after cordotomy plus hemo-
toxicity. As in Fig. 1, the response measure is oper-
ant escape speed, averaged across stimulus intensi-
ties. There were five intensities, ranging from below
normal escape threshold to a value that reliably
produced escape by unlesioned animals at minimal
latencies. In contrast to Fig. 1, performance during
sequential daily testing sessions is plotted, rather
than averaging across days. Contralateral sensitiv-
ity is represented by bars, and ipsilateral sensitivity
is shown as triangles. The average preoperative re-
sponse speed is depicted by a horizontal line. Notice
the extreme variability in contralateral responsivity
for both animals, ranging from apparent analgesia
on some days to levels of responsivity on other
days that were equal to or greater than the average
preoperative performance for that animal. That is,
during some sessions the animals did not terminate
stimulation during 5 s trial periods at any stimulus
intensity (or they responded only occasionally to the
highest intensity), but they responded frequently to
all intensities during other sessions. Of particular
interest is a late period (around the 80th day of post-

Page 10

420
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 65 90 95 100
Postopemtive Days
0 Contra. + Ipsi.
2.5
P
'"
m
$
g
2.0
1.5
e
,"
0
W
1.0
0.5
0.0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 60 65 90 95 100
Postoperative Days
0 Contra. --t Ipsi.
3 2.0
'Ir
00 1.5
B
(I)
0
::
::
yI
1.0
0.5
0.0
20 30 40 50
Days
60 70 60 90 100
Contra.
110 120
Ipsi.
130 140 150
Postopemtlve 0 -t
D.
Postopemtive Days
0Contra. -lpsi.

Page 11

operative testing) in which these animals (and two
others) were above normal levels of responsivity.
Because the electrocutaneous stimulus (current) was
monitored on each trial, we can be sure that these
variations in responsivity were not a consequence
of drifts in stimulation intensity. Surgery for these
animals was within several days, so that their postop-
erative testing schedules were similar. The period of
heightened contralateral responsivity overlapped for
the four rats (but was not identical in onset or dura-
tion) and was likely triggered by some environmental
event. After the fact, we determined that the timer
controlling light in the room housing the animals had
malfunctioned during this period of time, producing
24 h of light for several days. Therefore, it is pos-
sible that stress precipitated a period of heightened
sensitivity contralateral to anterolateral cordotomy
(Davis and Martin, 1947; Bowsher, 1996). Ipsilateral
sensitivity, however, was not similarly affected.
Panel C in Fig. 3 depicts a pattern of delayed and
intermittent contralateral hyposensitivity
observed for some rats following
hemotoxicity. Early in the postoperative testing pe-
riod, contralateral sensitivity appeared to be normal
for approximately half the rats, and then contralateral
hyposensitivity appeared later, for periods of vary-
ing length. The lesions for these animals tended to
include the entire lateral column on one side and ex-
tend medially to involve gray matter (as in Fig. 3C).
Other animals with similar lesions were more con-
sistently hyposensitive in the early postoperative pe-
riod. Thus, delayed appearance of contralateral hy-
posensitivity was not attributable to the distribution
of white matter damage. Some other factor - for ex-
ample, ischemic involvement of the gray matter and
associated hyperactivity of spinal neurons (Yezierski
and Park, 1993) - could have been maximal in the
early postoperative period. Furthermore, excitotoxi-
city could wax and wane over time, accounting for
that was
cordotomy with
421
periods of relative hyper- and hyposensitivity. This
is a difficult hypothesis to test, because histological
techniques give. only one point in time per ani-
mal. However, significant attenuation of functional
variability by a spinally acting treatment over an ex-
tended period would provide very useful information
concerning mechanisms of hypersensitivity.
Panel D in Fig. 3 presents a lesion that extended
through the dorsal gray matter to bilaterally involve
lateral column white matter. This is the only ani-
mal with bilaterally decreased nociceptive sensitivity
in the early postoperative interval (even though the
spinothalamic tract was largely spared on the left
side). Another unusual finding with this animal was
that nociceptive sensitivity recovered within a month
(bilaterally), indicating that extensive damage to the
spinal gray matter contributes to recovery from cor-
dotomy. The bilateral involvement of the core spinal
region is reminiscent of compression injuries, where
bilateral cellular loss within the gray matter is cer-
tain, and central pain and hypersensitivity are com-
mon (Pagni, 1984; Milhorat et al., 1996). Thus, it is
proposed that involvement of gray matter and pro-
priospinal systems contributes to the development
of dysesthesia and pain, particularly when extensive
damage to the gray matter is associated with partial
interruption of the spinothalamic pathway. This sug-
gests that prevention or attenuation of secondary cel-
lular excitotoxicity consequent to spinal cord injury
could prevent development of central pain, either by
minimizing damage to the core spinal region or by
attenuating abnormal activity among neurons near
the injury.
Episodic allodynia and hyperalgesia for segments
caudal to anterolateral cordotomy
For both monkeys and rats, anterolateral cordotomy
results in periods of apparently normal sensitivity,
Fig.
hemotoxicity.
postoperative
speed for stimulation
for contralateral
greater than preoperative
of the contralateral
3. Escape speed
Average
testing
is shown
escape
sessions
of both hindpaws
stimulation
levels.
hindpaw,
for 4 rats
for
after surgical lesions of the right
(contralateral)
anterolateral
and right
stimulus
A and B revealed
column
(ipsilateral)
intensities.
at an upper
hindpaw
The average
substantial
contralateral
preoperative
levels.
thoracic
is shown
preoperative
in escape
sensitivity
levels
level
for
with
single
escape
speed
speed
that included
stimulation
8 trials
is shown
of the left
at each of 5 electrocutaneous
as a horizontal
testing,
postoperative escape
but contralateral sensitivity
line. Animals
but there were days
speed for animals
was frequently
decreases
over 100 days of postoperative
Average
in which was near to or
for stimulation C and D was below
preoperative at or above

Page 12

422
4.0
3.5
3 3.0
f 2.5
i 2.0
0.5
0.0
l
A..
-PREOP.
PREOP. MAX.
-e-IPSI.
-e-IPSI.
MIN.
MIN.
MAX.
A
0.05 0.10
Stimulus
0.20
Intensity (mA)
0.40
0.80
3.5 ,
3.0
0.5 ,
0.0 1
l -. PREOP. MIN.
- A -. PREOP. MAX.
-E--CONTRA. MIN.
+
CONTRA. MAX.
0.05
0.10
Stimulus Intensity (mA)
0.20 0.40 0.80
Fig.
speeds
hemotoxicity.
sensitive
contralateral
was high.
4. Stimulus-response
were lowest
(S-R)
or highest
that postoperative
but the slope
stimulation were considerably
functions are averaged
for stimulation
allodynia
over 5 preoperative
of each hindpaw
and hyperalgesia
functions
(panel B). Allodynia
and 5 postoperative
of 14 animals
for ipsilateral
not altered postoperatively.
was apparent
sessions in which
unilateral
were evident
In contrast,
in which
operant escape
with (min.) (max.) that received
stimulation
spinal
during
lesions
maximally
functions
sensitivity
Panel A shows
sessions, of the ipsilateral S-R was the S-R
contralateral
for
flattened for the sessions
periods of contralateral hyposensitivity and periods
of ipsilateral hypersensitivity. The plots that were
utilized to reveal the time course of these changes
in overall sensitivity averaged performance across
all stimulus intensities delivered in a testing session
(Fig. 3) or across weeks (Fig. 1). Another way to
compare preoperative and postoperative sensitivity
is to plot stimulus-response
provides opportunities to determine whether postop-
erative changes in sensitivity are restricted to certain
stimulus intensities (e.g., indicating that allodynia
and/or hyperalgesia has occurred). Of particular in-
terest is the relative form of S-R functions during
periods of maximal and minimal sensitivity to stim-
ulation contralateral and ipsilateral to a lesion. S-R
functions for relatively sensitive and insensitive pe-
riods were obtained by sorting the average response
speeds (across stimulus intensities) for each ani-
mal, testing period (preoperative and postoperative)
and leg stimulated. Stimulus-responses functions for
each animal were then averaged across the five least
responsive and five most responsive sessions for each
leg and testing period. Minimal and maximal S-R
functions for all animals with unilateral cordotomy
plus hemotoxicity (n = 14) are shown in Fig. 4.
Panel A of Fig. 4 shows S-R functions for stim-
(S-R) functions. This
ulation of the right hindpaw (ipsilateral to cordo-
tomy). During sessions in which responsivity was
lowest for stimulation of the ipsilateral leg, there was
no difference between preoperative and postopera-
tive performance, and escape speed increased nearly
linearly for the stimulus intensities presented. In
contrast, there was a considerable difference in S-R
functions for ipsilateral stimulation during the most
responsive preoperative and postoperative sessions.
The ipsilateral hypersensitivity that was revealed by
averaging response speed across stimulus intensities
(Fig. 3) was dependent upon a subset of postoper-
ative sessions. The lowest stimulus intensity (0.05
mA) was subthreshold for escape responding during
all preoperative sessions but did elicit escape during
postoperative testing sessions in which the rats were
maximally responsive (revealing allodynia). In ad-
dition, postoperative escape speed was greater than
preoperative speed for the higher stimulus intensities
(revealing hyperalgesia) during sessions in which
responsivity was maximal.
Panel B of Fig. 4 shows minimal and maximal
S-R functions for stimulation of the left hindpaw
(contralateral to cordotomy). In contrast to ipsilateral
S-R relationships, where the slopes of preopera-
tive and postoperative functions were similar, the

Page 13

423
2.5 , / A.
LI PRE
2.0 !
POST
Contra. Ipsi.
Contra.
Ipsi.
Fig.
spinal
significantly
variability
hindpaws.
shown
any other
5. Panel
lesions
A shows
confined
increased
across
Coefficients
for the CVs).
condition.
escape
to one lateral
ipsilaterally.
the preoperative
of variability
Escape
speeds averaged
column
Between
and postoperative
(CVs)
were considerably
across
with
animal
all preoperative
hemotoxicity.
standard
testing
calculated
more
and postoperative
Nociceptive
deviations are shown
periods for
for each animal
variable for postoperative
testing
was significantly
each condition.
of the left
(between-animal
stimulation
periods for each of 14 animals
reduced contralaterally
Panel B shows
(contralateral)
standard
of the contralateral
with
and sensitivity
for within-animal
(ipsilateral)
deviations
hindpaw
stimulation
and then averaged
and right
were are
speeds than for
q PRE
POST
0.Q
1
B.
0.8 ;
contralateral slopes were smaller (flatter) postopera-
tively than preoperatively. During postoperative ses-
sions in which sensitivity was minimal, the animals
were nearly analgesic for contralateral stimulation,
responding only occasionally at the highest stimu-
lus intensity. During postoperative sessions in which
sensitivity was maximal, the animals were allodynic,
as evidenced by responses to the lowest stimulus
intensity. These animals rarely responded to the low-
est intensity during preoperative testing, even during
sessions in which they were most responsive. Thus,
for certain periods following
tomy, escape responses to low levels of contralateral
stimulation were enhanced, providing evidence for
abnormal nociceptive processing and showing that
cordotomy does not globally depresses contralateral
pain sensitivity. It is not necessary to show pro-
longed recovery of contralateral sensitivity to model
a manifestation of central pain following spinal cord
injury.
It is apparent from plots showing the time course
of changes in operant pain sensitivity after cordo-
anterolateral cordo-
tomy, such as those shown in Figs. 1 and 3, that
contralateral responsivity is labile. Dramatic changes
can occur over time, even from day to day. There are
examples of adjacent sessions in which an animal
is nearly analgesic or is allodynic for contralateral
stimulation, and there are gradual fluctuations in sen-
sitivity that occur over weeks. The simplest way to
demonstrate changes in sensitivity, regardless of the
periodicity, is shown in Fig. 5B, where coefficients
of variability (CVs) for escape speed were calculated
for each of 14 animals, before and after cordotomy
with hemotoxicity. For reference, response speeds
averaged across all preoperative and postoperative
sessions for the same group of animals are shown
in Fig. 5A. The averaged, within-animal
postoperative stimulation contralateral to anterolat-
era1 cordotomy were substantially larger than pre-
operative values (nearly tripled), and this difference
was comparable for the comparison of contralateral
with ipsilateral stimulation after cordotomy. Labile
nociceptive sensitivity was characteristic of all ani-
mals for contralateral stimulation, providing a model
CVs for

Page 14

424
of aberrant nociceptive processing for stimulation
within the deafferentation zone. Using variability as
a principal measure of abnormal processing and plot-
ting of stimulus-response functions for operant es-
cape responses provides an opportunity to evaluate a
variety of therapeutic procedures. For this purpose, it
is important to utilize methods permitting repetitive
evaluation (e.g., behavioral testing or chronic phys-
iological recording) to model deafferentation
pain sensitivity.
Extreme variability in the magnitude of pain is
well-recognized and is characteristic following
juries to peripheral nerves or to the CNS that result
in a pathological pain condition (Bowsher, 1996;
Eide et al., 1996). For example, a recent case report
documents considerable moment-to-moment
tions in pain levels in a patient with spinal cord
injury (Ness et al., 1998). Similarly, spinal lesions
involving the dorsal columns produce exaggerated
variability in motor control and in performance on
certain tests of non-nociceptive
pabilities (Vierck, 1982; Vierck et al., 1990b). That
is, interruption of the spinothalamic pathway results
in substantial variability in pain sensitivity, and in-
terruption of the dorsal column pathway produces
abnormal variability on sensory and motor tests that
depend upon transmission via that pathway. These
observations indicate that deafferentation represents
an important mechanistic component of fluctuations
in pain sensitivity following peripheral or central re-
duction of nociceptive input. After reduction of input
from the spinothalamic pathway, rostra1 networks
of partially deafferented neurons become unstable,
as demonstrated by neurophysiological recordings in
the somatosensory thalamus of humans with cen-
tral pain (Lenz et al., 1994; see also Lenz et al.,
2000, this volume) and animals with spinal lesions
(Weng et al., 2000). It is important to understand
mechanisms contributing to this instability, to iden-
tify which patterns of activity are correlated with
episodes of pain and hypersensitivity, and to develop
means of limiting or eliminating abnormal patterns
that coexist with pain. It is not sufficient to ask
whether or not abnormal activity is present among
deafferented neurons in an individual with central
pain; a more pertinent question is whether a certain
type of abnormal activity is associated with periods
in which pain (and/or hypersensitivity) is greatest.
zone
in-
varia-
somatosensory ca-
The contrast in variability of postoperative sen-
sitivity to contralateral and ipsilateral stimulation
(Fig. 5) is instructive in terms of spinal or supraspinal
sources of episodic modulation.
priospinal system is a diffusely connected system
(Nathan and Smith, 1959), it could be affected bilat-
erally by hemotoxic influences on a portion of the
core spinal region. Hemotoxicity produced an ipsi-
lateral allodynia and hyperalgesia that was episodic,
but the variability of operant responsivity to ipsi-
lateral stimulation was not substantially increased.
Also, the effect of hemotoxicity
ciceptive sensitivity continued for months, suggest-
ing that perioperative damage to the gray matter
produced an enduring ipsilateral effect. Similarly,
maximal contralateral sensitivity occurred episodi-
cally for stimulation that elicited activity in partially
deafferented rostra1 structures, and the variability in
contralateral sensitivity was extreme. Thus, allody-
nia for contralateral stimulation may depend upon
or develop as a result of trauma to the core spinal
region, but fluctuations in contralateral sensitivity
likely depend as well upon supraspinal mechanisms.
For example, partially deafferented supraspinal neu-
rons could be especially sensitive to fluctuations
in levels of abnormal activity at the spinal lesion
site, if conducted rostrally. Alternatively, levels of
arousal or stress may abnormally modulate partially
deafferented structures containing an altered intrin-
sic circuitry that normally regulates excitatory and
inhibitory influences. Surgical interruption
spinothalamic tract with hemotoxicity
results in a deficiency in GABA-ir profiles in the
somatosensory thalamus (Ralston et al., 2000), in-
cluding thalamic reticular axon terminals and local
circuit presynaptic dendritic profiles. In addition, in-
terruption of spinothalamocortical projections would
reduce inhibitory influences within the primary so-
matosensory cortex that normally result from noci-
ceptive stimulation (Tommerdahl et al., 1998). These
disinhibitory conditions could contribute to the allo-
dynia observed for stimulation contralateral to cor-
dotomy.
Because the pro-
on ipsilateral no-
of the
in primates
Conclusions
Persistent pain of central nervous system origin is
a common consequence of spinal cord injury and is

Page 15

425
highly refractory to treatment. In order to understand
mechanisms and develop treatments for this condi-
tion, an effective laboratory animal model is needed.
Clinical observations indicate that interruption of the
spinothalamic tract is a prerequisite for development
of deafferentation zone pain referred to segments
well below the site of spinal cord injury. Therefore, a
series of studies has evaluated nociceptive responses
of monkeys and rats before and after an anterolateral
spinal lesion. Attention to the variability of responses
to a wide range of stimulus intensities across test-
ing sessions has shown that contralateral sensitivity
oscillates from nearly analgesic to allodynic. All
animals cycled between these states of hyper- or
hypo-sensitivity. At different periods (either early
or late after anterolateral cordotomy), one of these
states could predominate for weeks or months, giv-
ing the impression that a given animal had recovered
or had not recovered from cordotomy. These vari-
able patterns are likely the reason that estimates of
the incidence of chronic pain from injury to periph-
eral nerves or the spinal cord injury range from 10
to nearly lOO%, depending upon applied criteria of
severity or longevity. The animal data indicate that,
after interruption of the spinothalamic tract, allody-
nia occurs episodically for each case, but persistent
allodynia occurs in a subset of cases. Thus, a mani-
festation of central pain following spinal cord injury
can be studied in an animal model by evaluating
operant escape responses that reflect cerebral pro-
cessing of nociception, and by studying factors that
increase or decrease occurrences of allodynia.
Interruption of the spinothalamic tract partially
deafferents rostra1 neurons in central pain pathways,
eventuating in abnormal sensitivity which can be
enhanced potentially by a variety of influences, in-
cluding input from non-nociceptive
presumed that certain patterns of activity among
neurons in pain pathways are interpreted as pain.
An important issue concerning development of these
abnormal patterns of activity is whether interruption
of the spinothalamic tract is sufficient. Information
from our animal model and observations of hu-
man beings indicate that superficial lesions of lateral
spinal cord white matter that do not extend into
the gray matter produce an enduring contralateral
hypoalgesia, with minimal allodynia and/or central
pain. Extension of a lesion into the core spinal region
afferents. It is
results in a higher incidence of recovery from cor-
dotomy (i.e., increased sensitivity over time). Hemo-
toxic influences at the lesion site produce ipsilateral
allodynia and hyperalgesia, suggesting that involve-
ment of the propriospinal system enhances aversion
for input to spinal segments remote from the spinal
injury. In addition, maximizing hemotoxic influences
increases the likelihood that allodynic episodes will
be observed for contralateral stimulation. Consider-
ably more investigation of remote effects of injuries
involving the core spinal region is needed. For exam-
ple, it is important to know whether damage to the
propriospinal system has effects on nociceptive sen-
sitivity as a result of (1) a loss or disruption of input
to caudal spinal neurons and/or supraspinal struc-
tures (a physiological deafferentation),
rostra1 and/or caudal inhibition,
influences that emanate from the site of damage.
(2) reduced
or (3) excitatory
Acknowledgements
The research of the authors that is summarized in
this paper was supported by NIH grants NS-14899
and NS-07261 and BSCIRTF funds from the state of
Florida.
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