Narita M, Oe K, Kato H, Shibasaki M, Narita M, Yajima Y, Yamazaki M, Suzuki T
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Neuroscience. 2004;125(3):545-51. doi: 10.1016/j.neuroscience.2004.02.022.
We previously demonstrated that spinal protein kinase C (PKC) is involved in the development of a neuropathic pain-like state induced by sciatic nerve ligation, and the morphine-induced rewarding effect is attenuated by sciatic nerve ligation in rodents. Here we first investigated whether sciatic nerve injury could change the activity of a conventional PKC (cPKC) and an atypical PKC isoform PKCzeta in the mouse spinal cord. The second experiment was to investigate whether direct inhibition of spinal PKC by intrathecal (i.t.) administration of a specific PKC inhibitor, 2-[8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl]-3-(1-methyl-1H-indole-3-yl)maleimide (RO-32-0432), could affect the rewarding effect induced by morphine following sciatic nerve ligation in mice. We found here that the activities of both cPKC and PKCzeta in the spinal cord were clearly increased following sciatic nerve ligation. Furthermore, i.t. administration of RO-32-0432 reversed a long-lasting pain-like syndrome as indicated by thermal hyperalgesia following sciatic nerve ligation in mice. These data provide direct evidence that activated cPKC and PKCzeta in the spinal cord may contribute to the development and maintenance of neuropathic pain. In the present study, we confirmed that the morphine-induced place preference was significantly suppressed by sciatic nerve ligation. It should be mentioned that i.t. pretreatment with RO-32-0432 significantly reversed the attenuation of morphine-induced rewarding effect following sciatic nerve ligation. These results suggest that activation of PKCs, including cPKC and PKCzeta, within the spinal cord is directly responsible for the attenuation of the morphine-induced rewarding effect under a neuropathic pain-like state following sciatic nerve ligation in mice.
我们之前证明，脊髓蛋白激酶C（PKC）参与坐骨神经结扎诱导的神经性疼痛样状态的发展，并且在啮齿动物中，坐骨神经结扎会减弱吗啡诱导的奖赏效应。在此，我们首先研究坐骨神经损伤是否会改变小鼠脊髓中传统PKC（cPKC）和非典型PKC亚型PKCζ的活性。第二个实验是研究通过鞘内（i.t.）注射特异性PKC抑制剂2-[8-[(二甲氨基)甲基]-6,7,8,9-四氢吡啶并[1,2-a]吲哚-3-基]-3-(1-甲基-1H-吲哚-3-基)马来酰亚胺（RO-32-0432）直接抑制脊髓PKC，是否会影响小鼠坐骨神经结扎后吗啡诱导的奖赏效应。我们在此发现，坐骨神经结扎后脊髓中cPKC和PKCζ的活性均明显增加。此外，i.t.注射RO-32-0432可逆转小鼠坐骨神经结扎后热痛觉过敏所表明的长期疼痛样综合征。这些数据提供了直接证据，表明脊髓中活化的cPKC和PKCζ可能促成神经性疼痛的发展和维持。在本研究中，我们证实坐骨神经结扎显著抑制了吗啡诱导的位置偏爱。应当提及的是，i.t.用RO-32-0432预处理可显著逆转坐骨神经结扎后吗啡诱导的奖赏效应的减弱。这些结果表明，在小鼠坐骨神经结扎后的神经性疼痛样状态下，脊髓内包括cPKC和PKCζ在内的PKC的激活直接导致吗啡诱导的奖赏效应减弱。
