Millan M J, Morris B J
Department of Neuropharmacology, Max-Planck-Institut für Psychiatrie, Planegg-Martinsried, F.R.G.
Brain Res. 1988 May 31;450(1-2):247-58. doi: 10.1016/0006-8993(88)91564-8.
Chronic subcutaneous infusion with a low dose (0.5 mg/kg/h) of naloxone via minipumps blocked the antinociceptive action of the mu-agonist, morphine, without affecting that of the kappa-agonist, U50488H. This dose resulted in a transient suppression in the rate of body weight gain and a sustained reduction in daily food intake (FI) and water intake (WI): this decrease was seen in both the light and dark phases. Naloxone also resulted in a reduction in resting core temperature (TC) in the light but not the dark phase. It did not affect the weight loss or hypothermia which accompanied 24 h food and water deprivation. Naloxone did, however, suppress FI and WI following deprivation and inhibited the recovery of body weight thereafter. The influence of naloxone upon FI, WI, TC and body weight was dose-dependent over 0.05-0.50 mg/kg/h. Increasing the dose to 3.0 mg/kg/h eliminated the antinociceptive action of U50,488H revealing a blockade of kappa- (in addition to mu-) receptors. This higher dose was not more effective in reducing FI, WI, body weight and TC than 0.5 mg/kg/h. Further, treatment with MR 2266, an antagonist (or weak partial agonist) with a higher activity at kappa-receptors than naloxone, was not more effective than naloxone in reducing FI, WI and body weight: further, it did not affect TC. Moreover, chronic infusion of bremazocine, (a kappa-agonist and mu-antagonist) reduced WI, FI, body weight and TC by a magnitude comparable to that of naloxone. Finally, chronic infusion of the mu-agonist, sufentanyl, led to a sustained rise in TC. It is concluded, that: (1) mu-opioid receptors may play a major role in the modulation of daily FI and WI and of body weight in freely behaving rats: this action is expressed in both the light and dark phases of the cycle and maintained following deprivation. The data provide no evidence for (but do not exclude) a particular role of kappa-receptors. (2) mu-Receptors play a physiological role in the modulation of TC in the light but not the dark phase of the daily cycle.
通过微型泵以低剂量（0.5毫克/千克/小时）慢性皮下输注纳洛酮，可阻断μ激动剂吗啡的抗伤害感受作用，而不影响κ激动剂U50488H的抗伤害感受作用。该剂量导致体重增加速率出现短暂抑制，每日食物摄入量（FI）和饮水量（WI）持续减少：在明相和暗相均可见这种减少。纳洛酮还导致明相而非暗相的静息核心体温（TC）降低。它不影响伴随24小时食物和水剥夺出现的体重减轻或体温过低。然而，纳洛酮确实抑制了剥夺后的FI和WI，并在此后抑制了体重恢复。在0.05 - 0.50毫克/千克/小时范围内，纳洛酮对FI、WI、TC和体重的影响呈剂量依赖性。将剂量增加到3.0毫克/千克/小时消除了U50,488H的抗伤害感受作用，显示κ（除μ外）受体被阻断。该较高剂量在降低FI、WI、体重和TC方面并不比0.5毫克/千克/小时更有效。此外，用MR 2266（一种在κ受体上比纳洛酮具有更高活性的拮抗剂（或弱部分激动剂））进行治疗，在降低FI、WI和体重方面并不比纳洛酮更有效：此外，它不影响TC。而且，慢性输注布瑞马佐辛（一种κ激动剂和μ拮抗剂）使WI、FI、体重和TC降低的幅度与纳洛酮相当。最后，慢性输注μ激动剂舒芬太尼导致TC持续升高。得出以下结论：（1）μ阿片受体可能在自由活动大鼠的每日FI和WI以及体重调节中起主要作用：这种作用在昼夜周期的明相和暗相均有表现，且在剥夺后仍维持。数据未提供κ受体有特定作用的证据（但不排除）。（2）μ受体在每日周期的明相而非暗相对TC调节起生理作用。
