Background: Numerous agents have been demonstrated to potentiate morphine analgesia, including clonidine (α2-adrenergic and I1-imidazoline receptor agonist) and BMS182874 (endothelin-A, ETA, receptor antagonist). ET has been shown to affect pharmacological actions of clonidine. The present study was conducted to determine whether α2-adrenergic and/or I1-imidazoline receptors are involved in the augmentation of morphine and oxycodone analgesia by clonidine and BMS182874. Methods: Analgesic tail flick latencies were measured in rats at various time intervals, and were converted to AUC₀→360 min. Results: It was found that clonidine produced mild analgesia, while BMS182874 did not have any analgesic effect. Clonidine (p = 0.015) and BMS182874 (p = 0.009) enhanced the analgesic action of morphine and oxycodone. Clonidine- or BMS182874-induced increases in the analgesic effect of morphine were not inhibited by idazoxan (I1-imidazoline receptor antagonist), while increases in the analgesic effect of oxycodone were blocked by idazoxan. Yohimbine (α2-adrenergic receptor antagonist) blocked the clonidine-induced potentiation of analgesic effect of morphine (p = 0.036) and oxycodone (p = 0.0167), while yohimbine did not affect BMS182874-induced potentiation of the analgesic effect of morphine or oxycodone. Conclusions: This is the first report showing that clonidine and BMS182874 augment oxycodone analgesia. Results suggest that α2-adrenergic receptors are involved in clonidine-induced, but not in the BMS182874-induced, potentiation of the analgesic effects of morphine or oxycodone, and that I1-imidazoline receptors are involved in the potentiation of oxycodone analgesia, but not morphine analgesia, by clonidine and BMS182874.
Clonidine, an alpha2-adrenergic agonist, has been demonstrated to produce significant analgesia and potentiate morphine analgesia. Endothelin (ETA) receptor antagonists have also been found to potentiate the antinociceptive response to morphine. Clonidine and ET have been reported to have cardiovascular interactions involving the sympathetic nervous system, but it is not known whether ETA receptor antagonist affects clonidine analgesia. This study examined the influence of sulfisoxazole (ETA receptor antagonist) on clonidine analgesia. Male Swiss Webster mice were used to determine antinociceptive response of drugs by measuring tail-flick latency. The effect of clonidine (0.3, 1.0, and 3.0 mg/kg, i.p.) alone or in combination with sulfisoxazole (25, 75, and 225 mg/kg, p.o.) on analgesia and body temperature was determined. Clonidine produced a dose-dependent analgesia and hypothermia. Sulfisoxazole (25, 75, and 225 mg/kg), when administered with clonidine (0.3 mg/kg), significantly potentiated (31% increase in area under the curve (AUC)) the analgesic effect of clonidine. Yohimbine (alpha2-adrenergic receptor antagonist) did not affect analgesic effect of clonidine plus sulfisoxazole. Idazoxan (I1-imidazoline and alpha2-adrenergic receptor antagonist) reduced (47% decrease in AUC) the analgesic effect of clonidine plus sulfisoxazole. Treatment with naloxone reduced (46% decrease in AUC) the analgesic effect of clonidine plus sulfisoxazole. The effect of another ETA receptor antagonist, BMS-182874 (2, 10, and 50 microg, i.c.v.) was studied, and it was found that the dose of 10 microg significantly potentiated (26% increase in AUC) the analgesic effect of clonidine. These results indicate that sulfisoxazole, an ETA receptor antagonist, potentiates the analgesic effect of clonidine, which could be mediated through I1-imidazoline receptors and opioid receptors.
We have reported that functionalized amino acids 1 display potent anticonvulsant activities in mice and rats, and that the activity resides primarily in the D-isomer. In this study we investigated whether selectively replacing the C(2) tetrahedral atom with a trivalent nitrogen provides compounds with comparable activity. Six functionalized N(2)-substituted semicarbazides (3) were prepared. X-ray crystallographic analysis of 1-acetyl-4-benzyl-2-(thiazol-2-yl)semicarbazide (13) showed that it lost asymmetry and adopted a configuration midway between the corresponding D- and L-amino acid derivatives. Evaluation of 3 in both mice (ip) and rats (po) showed that the compounds exhibited significant anticonvulsant activities but in most cases at levels lower than their amino acid counterparts. One of the semicarbazides, 13, displayed excellent activity in mice and rats that compared favorably to that of phenytoin.
Objectives: The potentiation of morphine or oxycodone analgesia by endothelin-A (ETA) receptor antagonists and imidazoline/α2-adrenergic agonists is well documented. However, the effect of morphine or oxycodone in combination with an ETA receptor antagonist or an imidazoline/α2 adrenergic agonist on body temperature is not known. The present study was carried out to study the role of ETA and imidazoline/α2 adrenergic receptors in body temperature effects of morphine, oxycodone, and clonidine in rats. Methods: Body temperature was determined in male Sprague-Dawley rats treated with morphine, oxycodone, or clonidine. Yohimbine, idazoxan, and BMS182874 were used to determine the involvement of α2-adrenergic, imidazoline, and ETA receptors, respectively. Key Findings: Morphine and oxycodone produced hyperthermia which was not affected by α2-adrenergic antagonist yohimbine, imidazoline/α2-adrenergic antagonist idazoxan, or ETA receptor antagonist BMS182874. Clonidine alone produced hypothermia that was comparable to the hypothermia observed with clonidine plus morphine or oxycodone. The hypothermic effect of clonidine was blocked by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared to yohimbine. Clonidine hypothermia was not affected by BMS182874. Conclusions: This is the first report demonstrating that ETA receptors do not influence morphine- and oxycodone- induced hyperthermia or clonidine-induced hypothermia. Imidazoline receptors and α2-adrenergic receptors are involved in clonidine-induced hypothermia, but not in morphine- and oxycodone-induced hyperthermia.
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