Inhibition by spinal μ- and δ-opioid agonists of afferent-evoked substance P release
Inhibition by spinal μ- and δ-opioid agonists of afferent-evoked substance P release
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DOI：
10.1523/jneurosci.0252-05.2005
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发表时间：
2005-04-06
影响因子：
5.3
通讯作者：
Yaksh, TL
中科院分区：
文献类型：
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作者：
Kondo, I;Marvizon, JCG;Yaksh, TL
阿片样物质μ-和δ-受体存在于初级传入神经的中枢末端，在那里它们被认为抑制神经递质的释放。这种机制可能介导脊髓阿片类药物产生的镇痛作用;然而，当他们使用神经激肽1受体（NK 1 R）内化作为P物质释放的指标时，Trafton等人（1999）指出，在脊髓节段S1-S2鞘内注射吗啡仅适度改变了这种诱发的内化。我们通过研究阿片类药物对脊髓切片和体内NK 1 R内化的影响来重新研究这个问题。在切片中，在C纤维强度下刺激背根诱发的NK 1 R内化被mu激动剂[D-Ala（2），N-Me-Phe（4），Gly-ol（5）]-脑啡肽（DAMGO）（1 μ M）消除，并被δ激动剂[D-Phe（2，5）]-脑啡肽（DPDPE）（1 μ M）降低。在体内，后爪压迫诱导同侧椎板I-II中的NK 1 R内化。吗啡（60 nmol）、DAMGO（1 nmol）和DPDPE（100 nmol）可显著降低这种诱发的内化，但K-激动剂反式-（1 S，2S）-3，4-二氯-N-甲基-N-[2-（1-吡咯烷基）环己基]-苯乙酰胺盐酸盐（200 nmol）（使用鞘内导管在脊髓节段L2处给药）不会降低这种诱发的内化。这些剂量的μ和δ激动剂是等效镇痛的，如通过热逃逸试验所测量的。较低剂量既不产生镇痛作用，也不抑制NK 1 R内化。相比之下，吗啡通过经皮注射在S1-S2只有适度的热逃逸的影响，即使在较高的剂量。吗啡降低NK 1 R内化后，全身交付，但在剂量大于产生等效镇痛所需的。纳洛酮可逆转上述作用。这些结果表明，腰椎阿片类药物抑制有害刺激诱导的神经递质释放初级传入的剂量，确认行为镇痛。
Opioid mu- and delta- receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor ( NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. In slices, NK1R internalization evoked by dorsal root stimulation at C-fiber intensity was abolished by the mu agonist [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin ( DAMGO) (1 mu M) and decreased by the delta agonist [D-Phe(2,5)]-enkephalin (DPDPE) (1 mu M). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the K- agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), delivered at spinal cord segment L2 using intrathecal catheters. These doses of the mu and delta agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviourally as analgesic.