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Melatonin Analogs as a Novel Chemical Class of General Anesthetic
Mohamed Naguib, M.D., F.F.A.R.S.C.I.; Max T. Baker, Ph.D.; Gilberto Spadoni, Ph.D.; Johann Cutkomp, B.S.; Marc Gregerson, B.S.
Anesthesia, University of Iowa, Iowa City, Iowa
The hypnotic, analgesic, and anticonvulsant properties of melatonin endow this substance with the profile of a novel hypnotic-anesthetic. Indeed, we have demonstrated for the first time that melatonin has anesthetic-hypnotic effects in the rat. Recently, more potent analogs of melatonin have become available. Of particular note is 2-bromomelatonin which has higher affinities for melatonin receptors. This analog allowed us to further test the hypothesis that melatonin agonists have anesthetic-hypnotic activities.

Methods:These studies were approved by the University of Iowa Animal Care and Use Committee. Male Sprague-Dawley rats were randomly assigned to receive single i.v. bolus doses of 2-bromomelatonin or propofol. Other rats were injected with the solvents in which these drugs were dissolved. Loss of the righting reflex was scored on a four-point scale (1 = immediate/brisk, both feet under the rat; 2 = complete, but slower than normal; 3 = slow, feet not placed under body; and 4 = absent). The threshold pressure (mm Hg) at which the rat withdrew or vocalized after pinch of one hindpaw was determined as a measure of nociceptive threshold. Application of pinch pressure of 60 mmHg evoked a vigorous escape response in awake rats and was judged to be very painful when applied to a fold of the investigator's skin. The cutoff value was 60 mmHg. Nocifensive stimuli were tested by application of a 2-cm serrated alligator clip to the middle third of the tail.

Results: Intravenous bolus injection of propofol or 2-bromomelatonin caused a dose-dependent loss of righting reflex, increased in paw withdrawal threshold and inhibition of nocifensive responses. The peak effect was noted after 1 min and resolved within 5 min for both propofol and 2-bromomelatonin. The estimated ED90 for loss of righting reflex for propofol and 2-bromomelatonin were 7.9 (SE 1.3) and 55.8 (1.2) mg/kg, respectively. Corresponding values for loss of response to a paw pressure of 60 mmHg were respectively 5.5 (1.2) and 58.3 (1.3) mg/kg. The estimated ED50 for loss of response to tail clamp (figure 1) for propofol and 2-bromomelatonin were 5.3 (1.2) and 50 (1.1) mg/kg, respectively. Intravenous injection of the vehicle or Intralipid did not affect righting reflex, paw withdrawal threshold or tail clamp response.

Conclusion: This report is the first to demonstrate that 2-bromomelatonin can induce anesthesia with a profile similar to that induced by propofol with respect to onset and duration of action. The potency ratio of propofol to bromomelatonin observed in this study varied from 1:7-1:10 depending on the endpoint used.

Anesthesiology 2002; 96: A816
Figure 1