Inhibition of the morphine-induced rewarding effect by direct activation of spinal protein kinase C in mice
Inhibition of the morphine-induced rewarding effect by direct activation of spinal protein kinase C in mice
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DOI：
10.1007/s00213-004-1929-0
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发表时间：
2004-06
影响因子：
3.4
通讯作者：
K. Oe;M. Narita;S. Imai;M. Shibasaki;Chiharu Kubota;A. Kasukawa;Mami Hamaguchi;Y. Yajima;M. Yamazaki;Tsutomu Suzuki
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文献类型：
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作者：
K. Oe;M. Narita;S. Imai;M. Shibasaki;Chiharu Kubota;A. Kasukawa;Mami Hamaguchi;Y. Yajima;M. Yamazaki;Tsutomu Suzuki
基本原理我们之前证明，在啮齿类动物部分坐骨神经结扎后，吗啡诱导的奖赏效应在神经性疼痛样状态下减弱。此外，脊髓中蛋白激酶C（PKC）活性的上调被认为是坐骨神经结扎后诱发痛觉过敏的关键因素。然而，很少有直接证据表明脊髓中激活的PKC参与了慢性疼痛样状态下吗啡引起的奖赏效应的减少。目的本研究旨在探讨通过鞘内（IT）注射特定的PKC激活剂佛波醇12,13-二丁酸酯（PDBu）直接激活脊髓PKC是否可以产生痛觉过敏并抑制由吗啡引起的位置偏好 方法采用条件位置偏好法研究吗啡诱导的奖赏效应。 IT 注射 PDBu 或盐水后 24 小时开始调节疗程（吗啡 3 次，盐水 3 次），每天进行一次，持续 6 天。在最后调节疗程后的第二天，进行了后调节测试。结果IT施用的PDBu产生了持久的热痛觉过敏。在这些条件下，吗啡诱导的位置偏好通过 PDBu 的单次 IT 预处理被消除。通过同时使用特异性 PKC 抑制剂 Ro-32-0432 进行 IT 治疗，可以逆转该效应。相比之下，IT给药的PDBu未能影响吗啡引起的过度运动和脊髓上的镇痛作用。结论目前的研究结果表明，慢性疼痛样痛觉过敏的脊髓中激活的PKC可能在抑制吗啡诱导的慢性疼痛样痛觉过敏小鼠的奖赏效应中发挥重要作用。
RationaleWe previously demonstrated that the morphine-induced rewarding effect was attenuated under a neuropathic pain-like state following partial sciatic nerve ligation in rodents. Furthermore, the up-regulation of protein kinase C (PKC) activity in the spinal cord is considered to be the key factor for induction of hyperalgesia following sciatic nerve ligation. However, little direct evidence is available for the involvement of activated PKC in the spinal cord in reduction of rewarding effects induced by morphine under chronic pain-like state.ObjectiveThe present study was to investigate whether direct activation of spinal PKC by intrathecal (IT) administration of a specific PKC activator, phorbol 12,13-dibutyrate (PDBu) could produce hyperalgesia and suppress the place preference induced by morphine in mice.MethodThe morphine-induced rewarding effect was investigated using the conditioned place preference method. Conditioning sessions (three for morphine, three for saline) were started 24 h after IT injection of PDBu or saline and conducted once daily for 6 days. On the day after the final conditioning session, a post-conditioning test was performed.ResultsIT-administered PDBu produced a long-lasting thermal hyperalgesia. Under these conditions, the place preference induced by morphine was abolished by a single IT pretreatment with PDBu. The effect was reversed by concomitant IT treatment with the specific PKC inhibitor Ro-32-0432. In contrast, IT-administered PDBu failed to affect the hyperlocomotion and supraspinal antinociception induced by morphine.ConclusionThe present findings suggest that activated PKC in the spinal cord with chronic pain-like hyperalgesia may play a substantial role in the suppression of the morphine-induced rewarding effect in mice with chronic pain-like hyperalgesia.