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The Journal of Neurophysiology Vol. 84 No. 1 July 2000, pp. 525-533
Copyright ©2000 by the American Physiological Society
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
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.
Deceased 23 February 2000.
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