Selective opiate modulation of nociceptive processing in the human brain

Fentanyl, a mu-opioid receptor agonist, produces analgesia while leaving vi brotactile sensation intact. We used positron emission tomography (PET) to study the mechanisms mediating this specific effect in healthy, right-hande d human males (ages 18-28 yr). Subjects received either painful cold (n = 1 1) or painless vibratory (n = 9) stimulation before and after the intraveno us injection of fentanyl (1.5 mu g/kg) or placebo (saline). Compared with c ool water (29 degrees C), immersion of the hand in ice water (1 degrees C) is painful and produces highly significant increases in regional cerebral b lood flow (rCBF) within the contralateral second somatosensory (S2) and ins ular cortex, bilaterally in the thalamus and cerebellum, and medially in th e cerebellar vermis. Responses just below the statistical threshold (3.5, < Z< 4.0) are seen in the contralateral anterior cingulate, ipsilateral insul ar cortex, and dorsal medial midbrain. The contralateral primary sensory co rtex (S1) shows a trend of activation. Except for slight changes in intensi ty, this pattern is unchanged following a saline placebo injection. Fentany l reduces the average visual analogue scale ratings of perceived pain inten sity (47%) and unpleasantness (50%), reduces pain-related cardioacceleratio n, and has positive hedonic effects. After fentanyl, but not placebo, all c ortical and subcortical responses to noxious cold are greatly reduced. Subt raction analysis [( innocuous water + fentanyl) - (innocuous water + no inj ection)] shows that fentanyl alone increases rCBF in the anterior cingulate cortex, particularly in the perigenual region. Vibration (compared with mo ck vibration) evokes highly significant rCBF responses in the contralateral S1 cortex in the baseline (no injection) and placebo conditions; borderlin e responses (3.5 <Z< 4.0) are detected also in the contralateral thalamus. Fentanyl has no effect on the perceived intensity or unpleasantness of vibr atory stimulation, which continues to activate contralateral S1. Fentanyl a lone [( 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 f rom activation peaks in the baseline condition (no injection), shows that f entanyl strongly attenuates both the contralateral thalamic and S1 cortical responses to noxious cold stimulation (P< 0.048 and 0.007, respectively) b ut fails to affect significantly these responses to vibrotactile stimulatio n (P> 0.26 and 0.91, respectively). In addition, fentanyl, compared with pl acebo, produces a unique activation of the mid-anterior cingulate cortex du ring fentanyl analgesia, suggesting that this region of the cingulate corte x participates actively in mediating opioid analgesia. The results are cons istent with a selective, fentanyl-mediated suppression of nociceptive spino thalamic transmission to the forebrain. This effect could be implemented di rectly at the spinal level, indirectly through cingulate corticofugal pathw ays, or by a combination of both mechanisms.