• Ryosuke Ishida, Tetsuro Nikai, Tatsuya Hashimoto, Toshiko Tsumori, and Yoji Saito.
• Department of Anesthesiology, Shimane University Faculty of Medicine, Japan. r-ishida@med.shimane-u.ac.j
• Anesth. Analg.. 2012 Jan 1;114(1):224-9.

BackgroundRecent studies suggest that remifentanil, similar to other μ-opioid agonists, may induce hyperalgesia. We performed animal experiments to determine whether IV remifentanil infusion, the mode of administration used in clinical practice, induces hyperalgesia and the conditions in which this phenomenon occurs. We also determined whether remifentanil-induced hyperalgesia is related to extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation.MethodsRemifentanil was administered through a catheter in the tail vein of male Sprague-Dawley rats for 10 minutes (30 μg · kg(-1) · min(-1)), 30 minutes (0.1, 1, and 10 μg · kg(-1) · min(-1)), or 120 minutes (0.1, 1, 3, and 10 μg · kg(-1) · min(-1)). The von Frey test and a tail-flick test were performed, followed by ERK1/2 immunohistochemistry. We examined whether intrathecal preadministration of the mitogen-activated protein kinase inhibitor U0126 suppresses hyperalgesia.ResultsRemifentanil had a dose-dependent antinociceptive effect that rapidly diminished. Ten- or 30-minute remifentanil infusion did not induce hyperalgesia. However, tail-flick latency and mechanical pain threshold after infusion termination were significantly lower in the 120-minute remifentanil administration group than those in the control group, regardless of dose. Hyperalgesia duration was no longer than 60 minutes. Significantly more phospho-ERK1/2-immunoreactive neurons in the superficial spinal dorsal horn were observed in the remifentanil 120-minute groups with hyperalgesia than in the 30-minute remifentanil groups without hyperalgesia, although U0126 did not suppress hyperalgesia.ConclusionsIV remifentanil induces transient withdrawal hyperalgesia soon after its termination. This hyperalgesia is strongly associated with the duration of exposure to remifentanil. Contrary to our hypothesis, ERK1/2 by itself was not the essential factor involved in the induction of the hyperalgesia.

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