Bhalla Shaifali, Matwyshyn George, Gulati Anil
Department of Biopharmaceutical Sciences (M/C 865), University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
Brain Res. 2005 Dec 7;1064(1-2):126-35. doi: 10.1016/j.brainres.2005.09.054. Epub 2005 Nov 14.
Long-term use of morphine leads to development of antinociceptive tolerance. We provide evidence that central endothelin (ET) mechanisms are involved in development of morphine tolerance. In the present study, we investigated the effect of ET(A) receptor antagonists, BQ123 and BMS182874, on morphine antinociception and tolerance in mice. Mechanism of interaction of ET(A) receptor antagonists with morphine was investigated. BQ123 (3 microg, i.c.v.) and BMS182874 (50 microg, i.c.v.) significantly enhanced antinociceptive effect of morphine (P < 0.05), through an opioid-mediated effect. Treatment with a single dose of BQ123 (3 microg, i.c.v.) reversed tolerance to morphine antinociception in morphine-tolerant mice. BQ123 or BMS182874 did not affect naloxone binding in the brain. Therefore, ET(A) receptor antagonists did not bind directly to opioid receptors. [35S]GTPgammaS binding was stimulated by morphine and ET-1 in non-tolerant mice. Morphine- and ET-1-induced GTP stimulation was significantly lower (P < 0.05) in morphine-tolerant group (33% and 42%, respectively) compared to control group. BQ123 and BMS182874 did not activate binding in non-tolerant mice. BQ123 and BMS182874 significantly increased G protein activation in morphine-tolerant mice (96% and 86%, respectively; P < 0.05). These results provide evidence that uncoupling of G protein occurs in morphine-tolerant mice, and ET(A) antagonists promote coupling of G protein to its receptors, thereby restoring antinociceptive effect. These findings indicate that ET(A) receptor antagonists potentiate morphine antinociception and reverse antinociceptive tolerance in mice, through their ability to couple G proteins to opioid receptors.
长期使用吗啡会导致抗伤害感受性耐受的产生。我们提供证据表明，中枢内皮素（ET）机制参与了吗啡耐受的形成。在本研究中，我们研究了ET(A)受体拮抗剂BQ123和BMS182874对小鼠吗啡镇痛及耐受的影响。研究了ET(A)受体拮抗剂与吗啡相互作用的机制。BQ123（3微克，脑室内注射）和BMS182874（50微克，脑室内注射）通过阿片类介导的效应显著增强了吗啡的抗伤害感受作用（P < 0.05）。单次注射BQ123（3微克，脑室内注射）可逆转吗啡耐受小鼠对吗啡抗伤害感受的耐受。BQ123或BMS182874不影响脑内纳洛酮的结合。因此，ET(A)受体拮抗剂不直接与阿片受体结合。在未耐受的小鼠中，吗啡和ET-1刺激了[35S]GTPγS结合。与对照组相比，吗啡耐受组中吗啡和ET-1诱导的GTP刺激显著降低（分别为33%和42%；P < 0.05）。BQ123和BMS182874在未耐受的小鼠中未激活结合。BQ123和BMS182874显著增加了吗啡耐受小鼠中的G蛋白激活（分别为96%和86%；P < 0.05）。这些结果提供证据表明，在吗啡耐受小鼠中发生了G蛋白解偶联，而ET(A)拮抗剂促进了G蛋白与其受体的偶联，从而恢复了抗伤害感受作用。这些发现表明，ET(A)受体拮抗剂通过其将G蛋白与阿片受体偶联的能力，增强了小鼠的吗啡镇痛作用并逆转了抗伤害感受耐受。
