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Anesth Analg 2003;97:763-768
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Hypnotic and Analgesic Effects of 2-Bromomelatonin

Mohamed Naguib, MB BCh, MSc, FFARCSI, MD*, Max T. Baker, PhD*, Gilberto Spadoni, PhD{dagger}, and Marc Gregerson, BS*

Departments of Anesthesia, *University of Iowa College of Medicine, Iowa City, Iowa; and {dagger}Institute of Medicinal Chemistry and Toxicology, University of Urbino, piazza Rinascimento, Italy

Address correspondence and reprint requests to Mohamed Naguib, MB, BCh, MSc, FFARCSI, MD, Department of Anesthesia-6JCP, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, 200 Hawkins Dr., Iowa City, IA 52242-1009. Address e-mail to mohamed-naguib{at}uiowa.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
2-Bromomelatonin is an analog of melatonin with a higher melatonin receptor affinity. We tested the hypnotic and analgesic properties of 2-bromomelatonin and compared them with those of propofol. Sprague-Dawley rats were assigned to receive 2-bromomelatonin or propofol IV, or morphine intraperitoneally. Righting reflex and response to tail clamping were assessed. Both 2-bromomelatonin and propofol caused a dose-dependent increase in the percent of rats displaying loss of both the righting reflex and the response to tail clamping. 2-Bromomelatonin was comparable to propofol in terms of its rapid onset and short duration of hypnosis. The 50% effective dose (95% confidence interval) for loss of righting reflex for propofol and 2-bromomelatonin were 3.7 (3.4–4.0) and 38 (35–41) mg/kg, respectively. Corresponding values for loss of response to tail clamp were 2.9 (3.5–4.0) and 21 (15–30) mg/kg, respectively. 2-Bromomelatonin is approximately 6–10 times less potent than propofol depending on the end-point used. Intraperitoneal 30 mg/kg morphine did not affect the righting reflex, but resulted in loss of response to tail clamping in all animals. 2-Bromomelatonin can exert hypnotic and antinocifensive effects similar to that observed with propofol. Unlike propofol, the reduced nocifensive behavior persisted after the animals had regained their righting reflex. This study provides evidence that 2-bromomelatonin has properties that are desirable in anesthetics or anesthetic adjuvants.

IMPLICATIONS: The IV administration of 2-bromomelatonin can exert both hypnotic and antinocifensive effects.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Accumulating evidence indicates that the pineal hormone melatonin (N-acetyl-5-methoxytryptamine) regulates several physiologic processes including circadian, cardiovascular, reproductive, and neuroendocrine functions (1,2). Melatonin promotes sleep and aids in relieving the symptoms of jet lag (3–5). We recently demonstrated that IV administration of large doses of melatonin to rats resulted in hypnotic effects similar to that observed with equipotent doses of thiopental and propofol in regard to onset, but was associated with a slightly longer duration of action (6). Melatonin also exhibited antinociceptive effects, but was not as effective as propofol and thiopental in abolishing the response to tail clamping (6).

Several melatonin analogs have been synthesized and shown to be significantly more potent than melatonin in binding to and activating the melatonin receptors, MT1 and MT2 (7–10). From qualitative and quantitative structure-affinity studies, various chemical substituents, particularly lipophilic substituents at the 2-position of the indole moiety of melatonin, enhanced the binding affinity of the compound for melatonin receptors (11). For example, binding studies performed with isolated melatonin receptors demonstrated that the relative binding affinity of 2-bromomelatonin was about 10 times higher than that of melatonin (7).

The pharmacologic effects of IV 2-bromomelatonin have not been reported. Because of its higher melatonergic activity as well as the fact that increased lipophilicity correlates with increased potency of many general anesthetics (12,13), it is hypothesized that 2-bromomelatonin will exert significant analgesia and anesthetic properties. In this study, we examined the hypnotic and analgesic properties of IV 2-bromomelatonin in rats and compared it with those of the general anesthetic propofol.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
2-Bromomelatonin (MW 311) was synthesized by reacting melatonin with phenyltrimethylammonium tribromide in tetrahydrofuran as described by Fourtillan et al. (14). 2-Bromomelatonin was purified from the reaction mixture on a silica gel column with ethyl acetate-cyclohexane as the mobile phase. The fraction containing 2-bromomelatonin was collected and dried under a stream of nitrogen. The identity and purity (>98%) of 2-bromomelatonin fraction was confirmed by gas chromatographic/mass spectral analysis. 2-Bromomelatonin was stored in crystalline form at -22°C until use. 2-Bromomelatonin was not sufficiently soluble in conventional nonanesthetic-inducing vehicles such as soybean oil emulsion or propylene glycol containing solutions; therefore, it was prepared for IV injection by dissolving it in a mixture of 1 part N-methyl-2-pyrrolidinone (NMP), 1 part propylene glycol, and 2 parts sterile water (NMP vehicle).

Melatonin (MW 232) (99.5%), propofol (2,6-diisopropylphenol, 97%), 1-methyl-2-pyrrolidinone, and propylene glycol were purchased from (Aldrich Chemical Co., Milwaukee, WI). Propofol (1%) in 10% soybean oil emulsion was obtained from AstraZeneca Pharmaceuticals; LP (Wilmington, DE). Soybean oil emulsion (10%) was from Fresenius-Kabi Clayton (Clayton, NC). Morphine sulfate powder (product M-8777) was obtained from Sigma (St. Louis, MO).

The animal studies were performed under a protocol approved by the University of Iowa Animal Care and Use Committee. All experiments were done in male Sprague-Dawley rats (300–350 g) (Harlan, Indianapolis, IN). Rats were maintained on a 12-h light/12-h dark cycle with free access to food and water. Before experimentation, all animals were cannulated under aseptic conditions. In this procedure, rats were anesthetized with isoflurane and weighed. The right jugular vein was cannulated with a heparinized (20 U/mL) saline-filled (PE-50) catheter. The free end of the tubing was tunneled subcutaneously to exit posterior to the occiput, trimmed to remove excess length, and capped. All wound edges were infiltrated with bupivacaine. After recovery from anesthesia, the animals were placed in individual plastic cages and were returned to the Animal Care Unit for routine care. Each subsequent day, laboratory personnel inspected and weighed the rats, and flushed the catheters with 0.2 mL of heparinized saline. Animals that failed to resume weight gain after 3–5 days were not used for subsequent experiments. Studies were performed 5–7 days after surgery.

Unanesthetized rats were randomly assigned to receive a single IV bolus of 15, 30, or 45 mg/kg 2-bromomelatonin, 3 or 5 mg/kg propofol in either soybean oil emulsion or in NMP vehicle. An additional group of rats received 30 mg/kg morphine intraperitoneally (i.p.). The maximal volume of drug formulation injected did not exceed 0.6 mL.

Measurements of loss of righting reflex and loss of response to tail clamp were made before (baseline) and after IV administration of the drug (or the vehicle) at fixed intervals for 20 min. In the morphine group, these measurements were made before and 15, 20, 30, and 60 min after i.p. administration. For righting reflex, the animals were placed on their back and attempts to reassume the prone position within 15 s were noted. Tail-clamp response was tested by application of a rubber-clad vascular clamp (22-cm DeBakey) across the proximal third of the tail. The location of the stimulus was marked to avoid previously used portions of the tail. Purposeful movement of the hind limbs and/or the head was noted as a positive response. To minimize excessive stimulation, once a negative response was attained, it was assumed to be present at subsequent measurements (15).

Data were analyzed using two-way analysis of variance with repeated measures. If these analyses of variance were significant, then Dunnett’s post hoc test was used to compare the vehicle or emulsion group to their respective study groups. All statistical analyses were performed using BMDP Dynamic statistical package (University of California Press, Berkeley, CA, 1994). Analysis of the dose-response curves was obtained by the pharmacologic software programs of Tallarida and Murray (16) and included calculation of the 50% effective dose (ED50) values and their 95% confidence intervals (CIs). Results were expressed as means and SE or 95% CI, and were considered significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Intravenous bolus injection of up to 0.6 mL of soybean oil emulsion or 0.6 mL of NMP vehicle did not affect animal righting reflex or response to tail clamp.

Bolus injection of 45 mg/kg 2-bromomelatonin resulted in an immediate loss of righting reflex in 86% of the animals. This response was maximal at 1 min and resolved within 5 min (Fig. 1). Doses of 15 and 30 mg/kg 2-bromomelatonin did not result in loss of righting reflex in any animal. Bolus injection of 5 mg/kg propofol in either soybean oil emulsion or NMP vehicle resulted in an immediate loss of righting reflex in 100% of animals. This response was maximal at 1 and 2 min (P < 0.01) and resolved within 5 min (Fig. 1). There were no significance differences in response to propofol when propofol was administered in soybean oil emulsion or NMP vehicle.



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  		Figure 1. Time course of the loss of righting reflex after bolus IV doses of 15, 30, and 45 mg/kg 2-bromomelatonin (2Br-Mel) in N-methyl-2-pyrrolidinone (NMP) vehicle (A), 3 and 5 mg/kg propofol in soybean oil emulsion (B), 3 and 5 mg/kg propofol in NMP vehicle (C), or their respective vehicles (n = 7 rats in the study groups and n = 5–6 in the vehicle groups). The percent of animals in each group losing their righting reflex is presented on the y axis. *P < 0.01; +P < 0.05 versus the respective vehicle.

 
Bolus injection of 45 mg/kg 2-bromomelatonin resulted in loss of response to tail clamping in 100% of rats at 1 and 2 min (P < 0.01) and in 71% and 43% of rats at 3 and 5 min, respectively (P < 0.05) (Fig. 2). 2-Bromomelatonin 30 mg/kg, a dose that did not cause loss of righting reflex, resulted in a significant antinocifensive effect at 1 min that was significantly different from its vehicle (Fig. 2). Administration of 5 mg/kg propofol in either soybean oil emulsion or NMP vehicle, a dose that caused loss of righting reflex in 100% of the animals for 2 min, resulted in loss of response to tail clamping in 100% of rats at 1 and 2 min and in 14% of rats at 5 min (P = not significant).



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  		Figure 2. Time course of the loss of response to tail clamp after bolus IV doses of 15, 30, and 45 mg/kg 2-bromomelatonin (2Br-Mel) in N-methyl-2-pyrrolidinone (NMP) vehicle (A), 3 and 5 mg/kg propofol in soybean oil emulsion (B), 3 and 5 mg/kg propofol in NMP vehicle (C), or their respective vehicles (n = 7 rats in the study groups and n = 5–6 in the vehicle groups). The percent of animals in each group losing their response to tail clamp is presented on the y axis.*P < 0.01; +P < 0.05 versus the respective vehicle.

 
The estimated ED50 values and their 95% CIs for loss of righting reflex for propofol and 2-bromomelatonin (1 min after drug administration) were 3.7 (3.4–4.0) and 38 (35–41) mg/kg, respectively (Fig. 3). Corresponding values for loss of response to tail clamp were 2.9 (3.5–4.0) and 21 (15–30) mg/kg, respectively. For both propofol and 2-bromomelatonin, the ED50 values for loss of response to tail clamp were significantly different (P < 0.05) from those for loss of the righting reflex (the 95% CI did not overlap). The relative potencies of propofol to 2-bromomelatonin for the doses producing a 50% loss of the righting reflex and tail-clamp response were, respectively, 10.2 ± 0.05 and 6 ± 0.06. The slopes of the dose-response curves for 2-bromomelatonin and propofol for tail clamp and loss of righting reflex were statistically indistinguishable.



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  		Figure 3. Log dose-response curves for the 2-bromomelatonin (2Br-Mel), propofol in soybean oil emulsion or in N-methyl-2-pyrrolidinone (NMP) vehicle, and their vehicles for (A) loss of righting reflex and (B) loss of nocifensive motor activity (n = 7 rats in the study groups and n = 5 in the vehicle groups). Con = vehicle dose-response data. Dose-effect curves were generated with data obtained 1 min after drug administration.

 
The administration of 30 mg/kg morphine i.p. did not affect the righting reflex but resulted in loss of response to tail clamping in 100% of rats at 20, 30, and 60 min.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
These data demonstrate that the IV administration of 2-bromomelatonin can exert both hypnotic and antinocifensive effects with a profile similar to that induced by propofol in that it exerts a rapid onset and short duration of action. Unlike propofol, the reduced nocifensive behavior persisted for a longer period. However, 2-bromomelatonin is approximately 6–10 times less potent than propofol depending on the end-point used.

We have recently reported that the ED50 for melatonin for loss of righting reflex was 178 ± 1.1 mg/kg (mean ± SEM) using cumulative dose technique (6). The potency ratio of propofol/melatonin for the doses producing a 50% loss of the righting reflex was 1:14 (6). The current study demonstrates that 2-bromomelatonin is 4.7 ± 0.03 times more potent than melatonin for loss of righting reflex. The increased potency of 2-bromomelatonin was associated with shorter duration of action than melatonin (6).

In contrast to melatonin (6), we noted that 2-bromomelatonin was effective in abolishing the response to tail clamping even in some animals that did not lose their righting reflex. A tail clamp is considered to be supramaximal stimulus. This indicates that 2-bromomelatonin has analgesic effects because analgesia is an integral component of the tail-clamp response. The latter is a well established measure of inhaled anesthesia in rodents, originally introduced by Eger et al. (17) for their minimum alveolar anesthetic concentration studies of inhaled anesthetics. Loss of righting reflex (hypnosis) and abolition of purposeful movement response to tail clamp (immobilization) are used for determination of anesthetic potencies of volatile anesthetics (18,19). We have demonstrated in this study that, with the use of IV anesthetic, the response to tail clamping was absent even though the rat had regained his righting reflex. This was true for both i.p. morphine and IV 2-bromomelatonin.

Loss of the righting reflex is used solely as an index for the anesthetic effect for different IV anesthetics (20–24). The sites underlying the minimum alveolar anesthetic concentration end-point (tail clamp) appear to lie in the spinal cord, but the righting reflex involves both spinal and supraspinal regions (25,26). Koblin et al. (27) stated that "The righting reflex requires a sustained and coordinated muscular activity, whereas the response to a noxious stimulus requires only a brief and minimally coordinated movement." Unlike inhalational anesthetics, opioids block movement response to painful stimuli before the onset of hypnosis. In accordance with our results, others noted with various anesthetics, that the ratios of ED50 values for loss of response to tail clamp to ED50 values for loss of the righting reflex in rats were slightly (but significantly) different (18,19). This also confirms that separate elements of the anesthetic state are produced by different mechanisms.

Cloning of several G-protein-coupled melatonin receptor genes revealed at least three melatonin receptor subtypes, two of which (MT1 and MT2) have been found in mammals (28). These receptor subtypes are coupled to Gi/o proteins associated with inhibition of adenylyl cyclase (29,30). Whether the anesthetic effect of 2-bromomelatonin was caused by a direct effect on melatonin receptors is largely unknown. There is, however, evidence to suggest that the central effects of melatonin, at least in part, involve facilitation of gamma-aminobutyric acid (GABA)ergic transmission by modulating the GABA receptor (31,32). Also, significant dose-dependent increases in GABA concentrations were noted in the central nervous system after the administration of melatonin (33).

In conclusion, our data provide insight into the anesthetic properties of 2-bromomelatonin. Substitution with a lipophilic substituent, bromine, at the 2-indole position of N-acetyl-5-methoxytryptamine increases the hypnotic and antinociceptive, as well as the melatonergic properties of this molecule. 2-Bromomelatonin was comparable to propofol in terms of its rapid onset of effect and short duration of action at equipotent doses. Unlike propofol, the reduced nocifensive behavior persisted for a longer period. These properties are desirable in anesthetics or anesthetic adjuvants.


   Acknowledgments
 
Supported by the Carver Collaborative Grant from the College of Medicine, University of Iowa.


   Footnotes
 
Presented in part at the American Society of Anesthesiologists annual meeting, Orlando, FL, October 12–16, 2002.


   References
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 Introduction
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 Discussion
 References
 

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Accepted for publication April 16, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press