Potentiation of morphine-induced antinociception by harmaline: involvement of μ-opioid and ventral tegmental area NMDA receptors
Potentiation of morphine-induced antinociception by harmaline: involvement of μ-opioid and ventral tegmental area NMDA receptors
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DOI：
10.1007/s00213-019-05389-8
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发表时间：
2020-02-01
影响因子：
3.4
通讯作者：
Zarrindast, Mohammad-Reza
中科院分区：
文献类型：
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作者：
Alijanpour, Sakineh;Zarrindast, Mohammad-Reza
Rational 吗啡是最知名、最有效的镇痛剂之一；然而，它也会引起各种副作用。因此，寻找可以增强低剂量吗啡镇痛作用的药物和机制将是疼痛管理的一个很好的策略。目的探讨mu阿片受体和腹侧被盖区（VTA）谷氨酸能系统在骆驼蓬碱与吗啡合用时对伤害性反应的影响。此外，我们还检查了药物后的奖励功效和耐受性表达。方法采用立体定位仪对动物双侧腹侧被区插管。甩尾（TF）装置和条件位置偏好（CPP）范式分别用于测量雄性 NMRI 小鼠的伤害性反应和奖励效应。结果 吗啡（2 mg/kg，腹腔注射）对 TF 测试没有影响。此外，骆驼蓬碱（1.25 和 5 mg/kg，腹腔注射）不能改变痛阈。无效剂量的骆驼蓬碱（5 mg/kg）和吗啡（2 mg/kg）的组合产生了镇痛作用，也防止了吗啡耐受，但对 CPP 的获得没有影响。在骆驼蓬碱（5 mg/kg）加吗啡（2 mg/kg）之前全身给予纳洛酮（0.5和1 mg/kg）并在VTA内显微注射NMDA（0.06和0.1 μg/小鼠）可防止药物引起的镇痛作用。 D-AP5（0.5和1μg/小鼠，VTA内）增强低剂量骆驼蓬碱（1.25mg/kg）和吗啡（2mg/kg）的作用并诱导镇痛。单独将相同剂量的 NMDA 或 D-AP5 显微注射到 VTA 中对痛阈没有影响。结论 研究结果表明，骆驼蓬碱增强吗啡的镇痛作用并降低吗啡耐受性。 VTA 中的谷氨酸能和 mu-阿片能系统相互作用似乎在骆驼蓬碱联合吗啡诱导的镇痛中具有调节作用。
Rational Morphine is one of the most well-known and potent analgesic agents; however, it can also induce various side effects. Thus, finding drugs and mechanisms which can potentiate the analgesic effects of low doses of morphine will be a good strategy for pain management. Objective The involvement of mu-opioid receptors and ventral tegmental area (VTA) glutamatergic system in harmaline and morphine combination on the nociceptive response were investigated. Also, we examined reward efficacy and tolerance expression following the drugs. Methods Animals were bilaterally cannulated in the VTA by stereotaxic instrument. A tail-flick (TF) apparatus and conditioned place preference (CPP) paradigm were used to measure nociceptive response and rewarding effects in male NMRI mice respectively. Results Morphine (2 mg/kg, i.p.) had no effect in TF test. Also, harmaline (1.25 and 5 mg/kg, i.p.) could not change pain threshold. Combination of a non-effective dose of harmaline (5 mg/kg) and morphine (2 mg/kg) produced antinociception and also prevented morphine tolerance but had no effect on the acquisition of CPP. Systemic administration of naloxone (0.5 and 1 mg/kg) and intra-VTA microinjection of NMDA (0.06 and 0.1 mu g/mouse) before harmaline (5 mg/kg) plus morphine (2 mg/kg) prevented antinociception induced by the drugs. D-AP5 (0.5 and 1 mu g/mouse, intra-VTA) potentiated the effect of low-dose harmaline (1.25 mg/kg) and morphine (2 mg/kg) and induced antinociception. Microinjection of the same doses of NMDA or D-AP5 into the VTA alone had no effect on pain threshold. Conclusion The findings showed that harmaline potentiated the analgesic effect of morphine and reduced morphine tolerance. Glutamatergic and mu-opioidergic system interactions in the VTA seem to have a modulatory role in harmaline plus morphine-induced analgesia.