Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA.
Fundam Clin Pharmacol. 2013 Oct;27(5):498-509. doi: 10.1111/j.1472-8206.2012.01046.x. Epub 2012 Jun 11.
Potentiation of opioid analgesia by endothelin-A (ET(A)) receptor antagonist, BMS182874, and imidazoline receptor/α₂-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂-adrenoceptors, imidazoline, and ET(A) receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂-adrenoceptors, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂-adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET(A) receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ET(A) receptors may be involved in blockade of oxycodone hypothermia by agmatine.
阿片类镇痛药的增强作用内皮素-A (ET(A)) 受体拮抗剂，BMS182874 和咪唑啉受体/α₂-肾上腺素能受体激动剂，如可乐定和胍丁胺是众所周知的。胍丁胺还可阻断吗啡引起的大鼠发热。然而，胍丁胺对吗啡或羟考酮引起的小鼠体温过低的影响尚不清楚。本研究旨在研究α₂-肾上腺素能受体、咪唑啉和 ET(A) 受体在吗啡和羟考酮引起的小鼠体温过低中的作用。雄性瑞士 Webster 小鼠给予吗啡、羟考酮、胍丁胺以及胍丁胺与吗啡或羟考酮联合用药后，6 小时内测定体温。使用育亨宾、伊索唑和 BMS182874 分别确定 α₂-肾上腺素能受体、咪唑啉和 ET(A) 受体的参与。吗啡和羟考酮均引起明显的体温过低，α₂-肾上腺素能受体拮抗剂育亨宾、咪唑啉受体/α₂肾上腺素能受体拮抗剂伊索唑或 ET(A) 受体拮抗剂 BMS182874 均不影响。胍丁胺本身不引起体温过低；然而，它可阻断羟考酮但不阻断吗啡引起的体温过低。胍丁胺诱导的羟考酮体温过低阻断被伊索唑和育亨宾抑制。与育亨宾相比，伊索唑的阻断作用更为明显。BMS182874 和胍丁胺联合给药并未引起小鼠体温变化。然而，当 BMS182874 与胍丁胺和羟考酮一起给药时，它阻断了胍丁胺诱导的羟考酮体温过低逆转。这是首次报道胍丁胺不影响小鼠吗啡引起的体温过低，但可逆转羟考酮引起的体温过低。咪唑啉受体和 α₂-肾上腺素能受体参与胍丁胺诱导的羟考酮体温过低逆转。我们的研究结果还表明，内皮素-A (ET(A)) 受体可能参与胍丁胺阻断羟考酮体温过低。
