Fig. 6. Model illustrating the proposed neuronal pathways that mediate the bidirectional effects on nociception produced by isoflurane. (A ) Isoflurane pronociceptive effect is mediated by activation of pontine noradrenergic neurons (PNN), causing the release norepinephrine from brainstem projections, which act on supraspinal α¹adrenoceptors to activate descending spinal pathways that facilitate the tail-flick reflex in the spinal cord. (B ) Isoflurane antinociceptive effect is partially mediated by activation of PNN, causing the release norepinephrine from spinal cord projections, which act on spinal α^2Aadrenoceptors to inhibit the tail-flick reflex in the spinal cord. (C ) Isoflurane antinociceptive effect is also partially mediated by a direct inhibitory effect on spinal neurons that does not require PNN or intact spinal pathways.