Departments of 1Neurology, 2Physiology, 3Psychiatry, 4Internal Medicine, and 5Biostatistics, University of Michigan, Ann Arbor, Michigan 48109; 6Center for Sensory-Motor Interaction, Aalborg University, 9220 Aalborg, Denmark; and 7Neurology Research Laboratories, Veterans Affairs Medical Center, Ann Arbor, Michigan 48105
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ABSTRACT |
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Casey, Kenneth L.,
Peter Svensson,
Thomas J. Morrow,
Jonathan Raz,
Cyrenius Jone, and
Satoshi Minoshima.
Selective Opiate Modulation of Nociceptive Processing in
the Human Brain.
J. Neurophysiol. 84: 525-533, 2000.
Fentanyl, a µ-opioid receptor agonist, produces
analgesia while leaving vibrotactile sensation intact. We used positron
emission tomography (PET) to study the mechanisms mediating this
specific effect in healthy, right-handed human males (ages 18-28 yr).
Subjects received either painful cold (n = 11) or
painless vibratory (n = 9) stimulation before and after
the intravenous injection of fentanyl (1.5 µg/kg) or placebo
(saline). Compared with cool water (29°C), immersion of the hand in
ice water (1°C) is painful and produces highly significant increases
in regional cerebral blood flow (rCBF) within the contralateral second
somatosensory (S2) and insular cortex, bilaterally in the thalamus and
cerebellum, and medially in the cerebellar vermis. Responses just below
the statistical threshold (3.5 < Z < 4.0) are
seen in the contralateral anterior cingulate, ipsilateral insular
cortex, and dorsal medial midbrain. The contralateral primary sensory
cortex (S1) shows a trend of activation. Except for slight changes in
intensity, this pattern is unchanged following a saline placebo
injection. Fentanyl reduces the average visual analogue scale ratings
of perceived pain intensity (47%) and unpleasantness (50%), reduces pain-related cardioacceleration, and has positive hedonic effects. After fentanyl, but not placebo, all cortical and subcortical responses
to noxious cold are greatly reduced. Subtraction analysis [(innocuous
water + fentanyl) - (innocuous water + no injection)] shows that
fentanyl alone increases rCBF in the anterior cingulate cortex,
particularly in the perigenual region. Vibration (compared with mock
vibration) evokes highly significant rCBF responses in the
contralateral S1 cortex in the baseline (no injection) and placebo
conditions; borderline responses (3.5 < Z < 4.0)
are detected also in the contralateral thalamus. Fentanyl has no effect on the perceived intensity or unpleasantness of vibratory stimulation, which continues to activate contralateral S1. Fentanyl alone [(mock vibration + fentanyl) (mock vibration + no injection)]
again produces highly significant activation of the perigenual and
mid-anterior cingulate cortex. A specific comparison of volumes of
interest, developed from activation peaks in the baseline condition (no injection), shows that fentanyl strongly attenuates both the
contralateral thalamic and S1 cortical responses to noxious cold
stimulation (P < 0.048 and 0.007, respectively) but
fails to affect significantly these responses to vibrotactile
stimulation (P > 0.26 and 0.91, respectively). In
addition, fentanyl, compared with placebo, produces a unique activation
of the mid-anterior cingulate cortex during fentanyl analgesia,
suggesting that this region of the cingulate cortex participates
actively in mediating opioid analgesia. The results are consistent with
a selective, fentanyl-mediated suppression of nociceptive spinothalamic
transmission to the forebrain. This effect could be implemented
directly at the spinal level, indirectly through cingulate corticofugal
pathways, or by a combination of both mechanisms.
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INTRODUCTION |
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Despite decades of research, we have a very limited understanding
of the neural mechanisms mediating the analgesia produced by
systemically administered opioids in humans. The pharmacology of the
several opioid receptors has been elucidated (Fowler and Fraser
1994), and there is information about their relative
distribution in the human nervous system (Pfeiffer et al.
1982
). Positron emission tomography (PET) studies have revealed
high levels of opioid receptor binding in the human anterior cingulate
and prefrontal cortex (Jones et al. 1991b
).
Immunohistochemical studies have identified the µ-opioid receptor in
the cerebral cortex, hippocampus, and striatum and on primary afferent
fibers in the superficial dorsal horn of rat spinal cord
(Arvidsson et al. 1995
). Mechanistic studies using
animal models have shown that systemic opioids can attenuate the
responses of rostrally projecting spinal nociceptive neurons directly
and, through the activation of descending supraspinal pathways,
indirectly (Jensen 1997
; Yaksh 1997
).
The development of functional brain imaging now provides the
opportunity to study the physiological action of opioids in the human
CNS. Firestone et al. (1996) used PET imaging and
Schlaepfer et al. (1998)
used single photon emission
computed tomography (SPECT) to demonstrate synaptically induced
increases in regional cerebral blood flow (rCBF) in the human brain
following the systemic administration of µ receptor agonist opioids.
Both of these studies revealed increased activity in the anterior
cingulate cortex, including the perigenual region. Adler et al.
confirmed this result in an investigation of systemic analgesia induced
by the µ receptor agonist fentanyl (Adler et al.
1997
). However, none of these investigators demonstrated a
specific analgesia-related reduction in rCBF responses to painful
stimuli. Our PET study confirms the fentanyl-induced activation of
anterior cingulate cortex but also shows that, in accord with clinical
experience and psychophysical measurement, this analgesia is associated
with a marked and selective reduction in all rCBF responses to noxious
deep cold, but not vibrotactile, stimulation.
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METHODS |
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Subjects
Twenty healthy right-handed males, ages 18-28 yr, gave informed
consent to participate in this study. The consent form and the study
protocol were approved by the Human Studies Committee of the Ann Arbor
Veteran's Affairs Medical Center and by the Institutional Review Board
for Human Studies at the University of Michigan Medical Center. Females
were excluded because of evidence of gender differences in forebrain
responses to noxious stimuli (Paulson et al. 1998).
Stimulation and psychophysical procedures
All participants received instruction in estimating the magnitude of perceived stimulus intensity and unpleasantness by using a visual analog scale (VAS) in which 0 equals no sensation (vibratory stimulation) or no pain (ice-water stimulation) and 10 is the most intense vibration (or pain) imaginable. An odor analogy was described to assist the subjects in differentiating ratings of stimulus unpleasantness from stimulus intensity.
Eleven subjects participated in the cold pain component of the study.
Each immersed his left hand either in innocuous cool (29°C) or
noxious cold (1°C) water 30 s before the onset of each scan and
for the 60-s duration of the scan. Subjects were asked to remain silent
and immobile, with eyes closed during each scan and, after each scan
was completed, to describe the stimulus in their own words and to
indicate their rating of stimulus intensity on the VAS. After each scan
in the placebo and fentanyl conditions, subjects were asked to rate, on
a 0-10 scale, their subjective feelings on each of 10 items derived
from the study of Zacny et al. (1995).
Nine subjects participated in the vibratory part of the study. The hand-held vibrator (Model 91, Daito, Osaka, Japan) has a circular surface stimulation area of ~3 cm2 and oscillates at a frequency of 130 Hz at an amplitude of 2 mm. Each subject received either vibration applied to the left volar forearm or mock vibration (vibrator held above the arm) during each scan. Otherwise instructions and conditions duplicated those applied to the group receiving the cold pain stimulus.
Positron emission tomography
We used a Siemens/CTI 931/08-12 scanner with 15 tomographic
slices covering an axial field of view of 10 cm. A transmission scout
view was used to position each subject in the scanner approximately parallel to the canthomeatal line. Head position was maintained by soft
restraint and laser beam positioning on facial fiducial marks; head
motion was corrected by a computer coregistration algorithm for each
subject (Minoshima et al. 1993a,b
). At least 15 min
elapsed between each scan. For each scan, each subject received a
33-mCi intravenous bolus injection of
H215O through an indwelling
catheter in the right antecubital vein. Data acquisition began 5 s
after the estimated arrival of radioactivity in the brain and continued
for ~60 s. After normalizing each image set to whole brain counts,
mean radioactivity concentration images estimating rCBF were created
for each experimental condition by stereotactic anatomical
standardization techniques (Minoshima et al. 1992
, 1993a
,
1994
). Subtraction images were made for each subject by
subtracting the images acquired during the lower intensity stimulation
from those acquired during the highest intensity stimulation. A
voxel-by-voxel statistical subtraction analysis (Z score)
with adjustment for multiple comparisons was performed by estimating the smoothness of subtraction images following three-dimensional Gaussian filtering (FWHM = 9 mm) to enhance signal-to-noise ratio and compensate for anatomical variance (Friston et al.
1991
). Voxels showing a significantly increased CBF compared
with the average noise variance computed across all voxels (pooled
variance) were identified. The critical level of significance
(Z = 4.0) was determined by adjusting P = 0.05 using this information (Adler and Hasofer 1976
;
Worsley et al. 1992
). Only those voxels with normalized
CBF values 60% of the global value were analyzed in this study.
To compare specifically the effect of fentanyl on the activation of the
contralateral ventral posterior thalamus and the primary (S1)
somatosensory cortex, an additional separate volume of interest (VOI)
analysis was performed. We developed these VOIs from the coordintates
of peak pain and vibratory activations obtained before either the
placebo or fentanyl injections and applied them to the analysis of the
placebo and fentanyl conditions of each experimental group (painful ice
water or vibration). The size and shape of each VOI was determined
separately for each of the above structures by employing a method
similar to that described by Burton et al. (1993). The
volume defined by these voxels was then progressively expanded in three
dimensions to include only those contiguous voxels that showed rCBF
increases that were significantly greater than the global mean change
(P < 0.05, uncorrected for multiple comparisons). For
purposes of comparison, the responses within each VOI are expressed as
the average increase in rCBF within the volume of that VOI. To
determine the statistical significance of rCBF increases, a paired
t statistic was computed for each VOI from the average
percentage increase in CBF across all subjects in each of the studies.
Procedure
Four scans, two during mock vibration or neutral water and two
during vibration or ice water, were acquired during each of three
conditions in the following order: baseline (stimulation only), placebo
(intravenous saline injection), and fentanyl (1.5 µg/kg iv bolus).
The order of stimulus presentation was randomized across subjects.
Automated sphygmomanometric recordings of blood pressure were taken
immediately after each of the placebo and fentanyl scans; heart rate,
and percentage oxygen saturation were monitored continuously (Propac
Encore Model 206EL, Protocol Systems, Beaverton, OR). Subjects were
informed that two drugs were being tested. The injection of "drug
1" was announced before the set of placebo scans and "drug 2"
before the set of fentanyl scans. Each injection was administered
through an indwelling catheter in the left antecubital vein ~10 min
before the first of the set of four scans (placebo or fentanyl). Venous
blood samples (~7 ml) were taken from this catheter before the
fentanyl injection and immediately after each fentanyl scan for
radioimmune assay analysis of fentanyl plasma levels (Research
Diagnostics, Flanders, NJ). (Chapman et al. 1990). To
assure accuracy of the blood sample, 5 ml of blood was drawn and
discarded before each sample. Blood sampling was simulated during the
placebo scans by manipulating syringes attached to the sampling line
outside the subject's direct line of vision.
Statistical analysis
A repeated-measures (mixed model) ANOVA was used to determine the effect of each stimulus condition (baseline, placebo, fentanyl) on each of the autonomic variables (blood pressure, heart rate, percentage oxygen saturation) and on the VAS ratings of stimulus intensity and unpleasantness. A similar separate analysis was performed to examine the effect of fentanyl plasma level on each of the above variables. Parametric and nonparametric (Kruskall-Wallis) ANOVAs were used to determine specifically the effect of scan sequence on plasma fentanyl levels and on VAS ratings of pain intensity during the fentanyl condition. Paired t-tests were used to determine the effects of fentanyl and placebo on the S1 cortical and contralateral thalamic rCBF responses to painful ice water and vibration. The Wilcoxon signed-rank test was used to determine the significance of changes in subjective feelings. Linear correlation analysis and one-way ANOVA was used to test the relationship, across all subjects, between rCBF in each VOI and the degree of fentanyl-induced analgesia or positive hedonic effect (see following text). In this study, we could not perform enough repeated scans during identical stimulus-drug conditions to permit a within-subject correlative analysis of rCBF with other parameters.
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RESULTS |
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Effect of fentanyl alone and on pain-evoked supraspinal activity (voxel-by-voxel analysis)
Subtracting the effect of cool water from ice-water stimulation in the baseline (no injection) condition reveals highly significant rCBF increases contralaterally within the S2 and insular cortex, bilaterally in the thalamus and cerebellum, and medially in the cerebellar vermis. Responses just below the statistical threshold (3.5 < Z < 4.0) are detected in the contralateral anterior cingulate and ipsilateral insular cortex and in the dorsal medial midbrain (Table 1). A trend of activation is seen in the contralateral S1. Except for slight regional changes in the intensity of response, this overall pattern is unchanged following a saline placebo injection (Table 2 and Fig. 1). Following the fentanyl injection, however, subtraction analysis shows that, except for borderline responses in the contralateral thalamus, the ipsilateral cerebellum, and the cerebellar vermis, all cortical and subcortical pain-related activations are reduced well below statistical significance (Table 3).
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To determine if any forebrain structures are activated by fentanyl
alone in this group of subjects, we subtracted the effect of the
baseline condition (no injection) from the effect of fentanyl during
innocuous water stimulation [(innocuous water + fentanyl) - (innocuous water + no injection)]. This analysis, which eliminates interactions between fentanyl and pain or placebo effect, shows that
fentanyl alone produces highly significant responses (Z = 5.8-4.1; average 6.4% increase in rCBF) bilaterally in the
perigenual (x = ±3; y = 30;
z = 7) and mid-anterior (x = 8, 6;
y = 1, 8; z = 43, 27) cingulate cortex
during the control innocuous stimulation (Fig. 1). Activation of the
ipsilateral S2 cortex (Z = 4.7), superior temporal
gyrus (Z = 4.0), and occipital gyrus (Z = 4.8-4.5) is also observed. Similar results are obtained when the
fentanyl and baseline or placebo effects are compared during ice-water stimulation except that the S2 cortex is not activated.
Effect of fentanyl alone and on vibration-evoked supraspinal activity (voxel-by-voxel analysis)
Vibration (minus the effect of mock vibration) evokes highly significant rCBF responses in the contralateral S1 cortex in the baseline (no injection) condition. Borderline responses (3.5 < Z < 4.0) are detected also in the medial contralateral thalamus, S2 cortex, and cerebellum (Fig. 2, Table 4). Strong contralateral S1 and S2 cortical responses (Z = 4.7 and 4.5, respectively) and sub-significant (Z = 3.12) contralateral thalamic responses are present following the placebo injection. After the injection of fentanyl, contralateral S1 responses to vibratory stimulation persist (Z = 4.4, average 5.0% increase in rCBF); activation is also present in the contralateral lenticular nucleus.
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Fentanyl alone [(mock vibration + fentanyl) (mock vibration + no injection)] can again be shown to produce highly significant and
bilateral activation of the perigenual (x = 12,
6;
y = 35; z = 14, 9) and mid-anterior
(x = 10,
10; y = 8,10;
z = 34,27) cingulate cortex during, and in the absence
of, vibratory stimulation (4.1 < Z < 6.2; Fig. 2).
Plasma levels of fentanyl
Plasma fentanyl levels average 0.437 ± 0.086 (SD) ng/ml. throughout the study and range from 1.10 to 0.11 ng/ml for the 9th-12th scan across all subjects. Neither intra- nor intersubject variations in plasma fentanyl levels can be shown to affect any outcome variable. The average plasma fentanyl level declines during the four scans obtained during hypoalgesia, but the VAS pain ratings of the subjects in the ice water part of this study are unaffected (Fig. 3).
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Differential effect of fentanyl on forebrain mechanisms mediating noxious and innocuous sensations (VOI analysis)
To compare directly the effect of fentanyl on the forebrain
processing of painful cold and vibrotactile stimuli, it is necessary to
examine the rCBF responses within identical cerebral locations during
each experimental condition in each group of subjects. Accordingly, we developed specific VOI (Burton et al.
1993) from activation peaks in the contralateral S1 cortex and
thalamus of each group of subjects during the baseline condition (cold
pain or vibration but no injection). These VOIs were then applied to the subtraction images of individuals in each group during the placebo
and fentanyl conditions. Paired t-tests (2-tailed) were used
to detect significant differences in the rCBF responses within these
VOIs. As shown in Fig. 4, painful ice
water and vibration each produces rCBF responses within these VOIs.
However, fentanyl strongly attenuates both the contralateral thalamic
and S1 cortical responses to noxious cold stimulation
(P < 0.048 and 0.007, respectively) but fails to
affect significantly these responses during vibrotactile stimulation
(P > 0.26 and 0.91, respectively).
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To determine which supraspinal structures might participate actively in
mediating the analgesic effect of fentanyl, we developed specific VOIs
(Burton et al. 1993) based on the results of our previous pain activation studies (Casey et al. 1994
,
1996
) and identified from peaks of activation
(Z > 3.4) produced by painful, as compared with
painless, cold water during the baseline condition (no placebo or
fentanyl; see coordinates, Table 1). We applied these pain-activated
VOIs to the placebo and fentanyl conditions during painful ice-water
immersion to reveal those structures activated specifically by fentanyl
during fentanyl analgesia. Only 1 of 11 VOIs, located in the
mid-anterior cingulate cortex, showed an increased rCBF during fentanyl
analgesia (Fig. 5). All other structures
analyzed had reduced rCBF, compared with placebo in this condition. No
VOI response (% change from placebo) correlated with the analgesic
effect of fentanyl (measured as % change in VAS score; linear
correlation analysis across subjects). However, a one-way ANOVA
revealed a significant difference among these responses
(P < 0.001). Post hoc multiple pair-wise comparisons revealed that this anterior cingulate response was different from all others (P: 0.01-0.001) except for the bilateral insula,
contralateral S2 cortex, and the medial dorsal midbrain.
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Subjective effects of fentanyl
Fentanyl reduces the average VAS ratings of perceived pain intensity (mean ± SD) from 6.26 ± 1.41 (baseline) and 6.40 ± 1.31 (placebo) to 3.36 ± 1.15. Perceived unpleasantness is similarly affected (baseline: 6.63 ± 1.33; placebo: 6.54 ± 1.31; fentanyl: 3.30 ± 1.14). A repeated-measures ANOVA (mixed model) of the intensity and unpleasantness rating differences between ice and neutral water reveals highly significant effects of the fentanyl, but not of the placebo, on both measures (P = 0.0001). Fentanyl has no effect on the ratings of perceived vibratory intensity (baseline: 3.42 ± 2.22; placebo: 3.30 ± 2.05; fentanyl: 3.07 ± 2.14) or unpleasantness (baseline: 1.35 ± 1.30; placebo: 1.51 ± 1.49; fentanyl: 1.23 ± 1.68).
Compared with the placebo condition, fentanyl produces increases in pleasant body sensations and thoughts; feelings of being carefree, sedated, and a loss of body control during all stimulation conditions (0.002 < P < 0.03) (Fig. 6). We again performed a comparison of responses within the 11 previously identified VOIs to determine if any structures were activated by fentanyl, compared with placebo, during innocuous stimulation and thus possibly related to the positive hedonic effects of fentanyl rather than the analgesia. No VOI response (% change from placebo) correlated with the positive hedonic effect of fentanyl (total fentanyl-placebo feeling state score increase across the above 4 categories; linear correlation analysis across subjects). Moreover, a one-way ANOVA failed to reveal any significant differences among the responses within VOI in this condition.
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Autonomic effects of fentanyl
Immersion of the hand in the ice water increases the average (± SD) heart rate from 59.1 ± 2.9 to 71.2 ± 2.6 beats/min. Following the fentanyl injection, ice-water stimulation causes the average heart rate to increase from 59.1 ± 3.2 to 63.1 ± 3.3 beats/min. A repeated-measures ANOVA (mixed model) of the individual responses reveals a significant heart rate response to ice-water stimulation over all conditions (P = 0.014) and a highly significant effect of fentanyl in reducing this response compared with the baseline or placebo conditions (P = 0.001).
Blood pressure readings were obtained from the arm used for stimulation and therefore could be obtained only before and after stimulation periods. Nonetheless, we detected significant increases in both systolic and diastolic average blood pressures (mmHg) across all conditions following ice water, but not neutral water, stimulation (baseline: 132/57 increasing to 143/63; placebo: 135/58 increasing to 139/65; fentanyl: 134/56 increasing to 138/61). A repeated-measures ANOVA (mixed model) of the individual responses does not reveal an effect of fentanyl on these blood pressure increases. Vibratory stimulation has no effect on blood pressure.
A comparison of optical transcutaneous measurements of the percentage of blood oxygen saturation taken before and after the administration of fentanyl reveals a slight but statistically significant decrease across all subjects (average ± SD) 99.32 ± 0.34% to 97.27 ± 0.66%. (P = 0.0039) immediately following the administration of fentanyl.
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DISCUSSION |
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The cortical and thalamic responses to noxious cold stimulation
are similar to those observed in our previous studies (Casey et
al. 1994, 1996
) except that premotor and prefrontal activation is below the statistical significance level in this study. Fentanyl, a
µ-opioid receptor agonist, suppresses these pain-evoked responses during hypoalgesia. Presumably, the mild pain sensation that remains following fentanyl is mediated by the activity of cortical and thalamic
neurons that falls below the level of significance established for this
study (Fig. 1; Table 3).
Our experiment demonstrates a neural basis for the selective
hypoalgesic effect of fentanyl because the cortical and thalamic responses to painless vibratory stimulation are spared following hypoalgesic doses of this drug (Fig. 4). This finding is in accord with
the observation that opioid analgesia spares vibrotactile perception
(Wikler et al. 1945). The mechanism for achieving this selective analgesic effect is unknown. Fentanyl may have a relatively selective effect on cortical, as compared with thalamic, nociceptive responses. Although the S1 responses were nearly equal, fentanyl eliminated the S1 response to painful cold while sparing completely the
S1 response to vibration. Compared with this highly selective cortical
action, the effect of fentanyl on thalamic responses was similar during
both stimulus conditions. The thalamic responses were slightly smaller
and more variable, so the effect of fentanyl was statistically
different but of comparable magnitude. However, it is likely that given
the density of modality representations in the thalamus and the spatial
resolution of functional brain imaging we are better able to observe
modality-specific effects at the cortical level.
Given the background of available evidence, our results suggest at
least three major possibilities for the hypoalgesic effect of fentanyl:
a direct and selective attenuation of the nociceptive responses of
spinothalamic tract neurons in the dorsal horn of the spinal cord,
selective suppression of spinothalamic neuronal responses by the
excitation of corticofugal neurons in the anterior cingulate cortex,
and a combination of the first and second mechanisms. Yaksh
(1997) has recently reviewed evidence that the systemic administration of opiates directly and selectively suppresses the
nociceptive excitation of spinal cord dorsal horn neurons in
experimental animals and humans. Overall, the observations leave little
doubt that at least some of the analgesia produced by systemically
administered opioids is due to a direct and selective suppression of
nociceptive excitation at the spinal cord level. Our results are
consistent with this mechanism because fentanyl selectively suppresses
the nociceptive activation of those brain stem, thalamic, and cortical
regions that have been shown to respond differentially to noxious
stimuli (Casey et al. 1994
, 1996
; Coghill et al.
1994
; Craig et al. 1996
; Jones et al.
1991a
; Talbot et al. 1991
) while sparing the
physiologically and anatomically distinct vibrotactile pathways
(Coghill et al. 1994
).
There is also compelling evidence that supraspinal mechanisms could
mediate the analgesia produced by systemically administered opioids
(Jensen 1997; Yaksh 1997
). In rodents,
morphine-induced antinociception is attenuated by lesions or local
anesthetic injections within the medial medulla (Proudfit
1980
; Proudfit and Anderson 1975
) or lesions in
the central nucleus of the amygdala (Manning and Mayer
1995a
,b
). In addition, microinjection of the opioid receptor
antagonist naloxone into the midbrain periaqueductal gray (PAG) or
posterior hypothalamus reverses the analgesia of systemic morphine as
measured in the rat formalin test (Manning and Franklin
1998
). Our results also support the possibility that supraspinal structures participate in mediating opioid analgesia because we found that, among the VOIs we examined, the mid-anterior cingulate was unique in showing an increased rCBF during fentanyl analgesia (Fig. 5).
There is anatomical (Mantyh 1982; Room et al.
1985
) and neuropharmacological (Jones et al.
1991b
; Lewis et al. 1983
) evidence that the PAG,
which has long been considered an important mediator of analgesia
(Basbaum and Fields 1984
), could be excited by
corticobulbar neurons in the anterior cingulate cortex. The evidence
suggests that the fentanyl-induced activation of the cingulate cortex
could excite, by disinhibition or direct excitation, a descending
cascade of analgesic mechanisms mediated through the PAG. However,
although we detect activation of the dorsomedial midbrain (in the
region of the PAG) during ice-water stimulation, we detect only very weak dorsomedial midbrain activity (Z = 1.5; rCBF
increase of 1.9%) at nearly the same stereotactic coordinates
(x,
3; y,
28; z,
7) when the
effect of fentanyl alone is assessed during innocuous stimulation. No
response is detected in this region during nociceptive stimulation in
the fentanyl condition or when the effect of fentanyl alone is assessed
during noxious stimulation. Even when the combined effect of fentanyl
and ice-water stimulation is assessed by subtraction analysis [(ice
water + fentanyl) -(innocuous water + no injection)], we cannot
detect dorsomedial midbrain activity. Overall, the results suggest that
the activation of descending brain stem mechanisms may not be as
important a component of opioid analgesia in humans as it is in the
rodent. Perhaps the activation of corticospinal projections from the
anterior cingulate gyrus could attenuate spinothalamic responsiveness
directly without involving brainstem structures (Hutchins et al.
1988
; Luppino et al. 1994
; Ralston and
Ralston 1985
). However, it is possible that the PET methods we
used cannot detect a synaptically induced rCBF response to fentanyl in
the dorsomedial midbrain. An additional possibility is that the dorsal
midbrain activation we have seen in these and in other PET studies
reflects the activity of nociceptive neurons in the superior colliculus
(Redgrave et al. 1996a
,b
).
Comparing the cingulate cortical activity during pain with that during
fentanyl alone may provide some insight into the physiological significance of the cingulate response to fentanyl. The mid-cingulate region is activated during both fentanyl alone and during pain (Figs. 1
and 2). However, one obvious difference is the intense activation of
the most rostroventral perigenual cingulate during innocuous water
stimulation (Fig. 1) or mock vibratory stimulation (Fig. 2) in the
fentanyl condition. Anatomical and physiological studies suggest that
mid-cingulate cortical activity is associated with higher order motor
functions, such as response selection, while the rostroventral
perigenual cortex may mediate autonomic responses and their associated
affective experiences (Derbyshire et al. 1998;
Ketter et al. 1996
; Vogt et al. 1992
,
1993
). Our investigation now suggests further that the
mid-anterior region of the cingulate cortex participates actively in
mediating opioid analgesia.
The fentanyl-activated rostroventral perigenual region and the
pain-activated mid-cingulate cortex are each adjacent to the rostral
anterior cingulate region recently identified as encoding degrees of
pain unpleasantness (Rainville et al. 1997). Taken together, these observations suggest that the reduced
cardioacceleratory responses and pleasurable feelings experienced by
all our subjects during the fentanyl condition are mediated through the
activation of opiate-responsive mechanisms in the perigenual cingulate
cortex. Whether these effects are independent accompaniments or
contributing components of systemic opioid analgesia in humans remains
to be determined.
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ACKNOWLEDGMENTS |
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The authors gratefully acknowledge the support and encouragement of David E. Kuhl, M.D. The expert technical assistance of J. Rothley, T. Hauser, L. Houe, P. Kison, E. McKenna, and A. Weeden was essential for the conduct of this study and is greatly appreciated.
Support for this work was provided by grants from the Department of Veterans Affairs (Merit Review), the Department of Health and Human Services (National Institute of Child Health and Human Development Grant P01 HD-33986), and the Department of Energy (DE-FG02-87-ER60561).
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FOOTNOTES |
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Address for reprint requests: K. L. Casey, Neurology Service, V.A. Medical Center, 2215 Fuller Rd., Ann Arbor, MI 48105.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 15 September 1999; accepted in final form 9 March 2000.
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REFERENCES |
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