Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice.
Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice.
复制标题
小鼠中吗啡和 delta 9-四氢大麻酚之间存在双向交叉耐受性的证据。
DOI：
10.1016/0014-2999(94)90003-5
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发表时间：
1994
影响因子：
5
通讯作者：
Bhargava,HN
中科院分区：
文献类型：
--
作者：
Thorat,SN;Bhargava,HN
雄性Swiss-Webster小鼠通过皮下植入吗啡丸（每个含有75 mg吗啡碱）3天，使其对吗啡耐受。植入安慰剂颗粒的小鼠作为对照。对不同剂量吗啡的镇痛反应下降证明了对吗啡镇痛作用的高度耐受性。Δ 9-四氢大麻酚（5、10和20 mg/kg ip）在植入安慰剂颗粒的小鼠中产生剂量依赖性镇痛和低体温作用。与安慰剂对照组相比，在吗啡耐受小鼠中观察到四氢大麻酚的镇痛作用显著降低。通过每天两次注射药物（5、10或20 mg/kg ip）持续4天，使小鼠对Δ 9-四氢大麻酚耐受。注射溶媒的小鼠作为对照。在长期注射药物的小鼠中对Δ 9-四氢大麻酚的镇痛和低温作用的耐受性通过与在注射媒介物的对照中观察到的那些相比时这些反应的强度的降低来证明。吗啡在长期注射媒介物的小鼠中产生剂量依赖性镇痛和低体温作用，但这些作用的强度在长期注射Δ 9-四氢大麻酚的小鼠中显著较低。这些结果表明，Δ 9-四氢大麻酚和μ-阿片受体之间可能存在相互作用，并且在Δ 9-四氢大麻酚耐受小鼠中对吗啡的镇痛和低温作用产生了实质性耐受。为了研究Δ 9-四氢大麻酚的长期给药是否改变中枢神经系统（CNS）中的μ-阿片受体，在Δ 9-四氢大麻酚耐受性动物中测定选择性μ-阿片受体激动剂[3 H][D-Ala 2，MePhe 4，Gly-ol 5]脑啡肽（[3 H] DAMGO）与全脑和脊髓μ-阿片受体的结合。Δ 9-tetrahydrocannabinol耐受小鼠脑或脊髓中[3 H] DAMGO的B max和Kd值未发生改变。因此，有证据表明，在小鼠中吗啡和Δ 9-四氢大麻酚之间存在双向交叉耐受，而中枢神经系统的μ-阿片受体没有变化。
Abstract Male Swiss-Webster mice were rendered tolerant to morphine by subcutaneous implantation of a morphine pellet, each containing 75 mg morphine base, for 3 days. Mice implanted with placebo pellets served as controls. A high degree of tolerance to the analgesic effect of morphine developed as evidenced by decreased analgesic response to various doses of morphine. Δ 9-Tetrahydrocannabinol (5, 10 and 20 mg/kg ip) produced dose-dependent analgesic and hypothermic effects in mice implanted with placebo pellets. A significant decrease in the analgesic effects of tetrahydrocannabinol was observed in morphine-tolerant mice as compared to placebo controls. Mice were rendered tolerant to Δ 9-tetrahydrocannabinol by injecting the drug (5, 10, or 20 mg/kg ip) twice daily for 4 days. Vehicle-injected mice served as controls. Tolerance to the analgesic and hypothermic effects of Δ 9-tetrahydrocannabinol in mice injected chronically with the drug was evidenced by the decreases in the intensity of these responses when compared to those observed in vehicle-injected controls. Morphine produced dose-dependent analgesic and hypothermic effects in mice injected chronically with vehicle but the intensity of these effects was significantly lower in mice injected chronically with Δ 9-tetrahydrocannabinol. These results indicate that a possible interaction exists between Δ 9-tetrahydrocannabinol and the μ-opioid receptors and that a substantial tolerance to analgesic and hypothermic effects of morphine develops in Δ 9-tetrahydrocannabinol-tolerant mice. To investigate whether the chronic administration of Δ 9-tetrahydrocannabinol alters the μ-opioid receptors in the central nervous system (CNS), the binding of a selective μ-opioid receptor agonist,[3 H][D-Ala 2, MePhe 4, Gly-ol 5] enkephalin ([3 H] DAMGO), to whole brain and spinal cord μ-opioid receptors was determined in Δ 9-tetrahydrocannabinol-tolerant animals. The B max and K d values of [3 H] DAMGO in brain or the spinal cord of Δ 9-tetrahydrocannabinol-tolerant mice were not altered. Thus, evidence is presented for the existence of bidirectional cross-tolerance between morphine and Δ 9-tetrahydrocannabinol in the mouse without changes in μ-opioid receptors of the central nervous system.