Spinal γ-Aminobutyric Acid Interneuron Plasticity Is Involved in the Reduced Analgesic Effects of Morphine on Neuropathic Pain
Spinal γ-Aminobutyric Acid Interneuron Plasticity Is Involved in the Reduced Analgesic Effects of Morphine on Neuropathic Pain
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DOI：
10.1016/j.jpain.2021.10.002
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发表时间：
2022-04-02
期刊：
影响因子：
4
通讯作者：
Obata, Hideaki
中科院分区：
文献类型：
--
作者：
Hiroki, Tadanao;Suto, Takashi;Obata, Hideaki
吗啡的全身给药增加脊髓背角（SDH）中的5-羟色胺（5-HT），其通过脊髓5-HT 3受体减弱吗啡对神经病理性疼痛的镇痛作用。我们假设，包括中脑导水管周围灰质（PAG）在内的下行多巴胺能系统的功能障碍有助于通过脊髓5-HT 3受体和GABA神经元减弱吗啡对神经病理性疼痛的疗效。PAG内注射吗啡（100 ng）对正常大鼠产生镇痛作用，但对脊神经结扎（SNL）大鼠无镇痛作用。在体微透析显示PAG吗啡增加了两组SDH 5-HT的浓度。鞘内注射5-HT_3受体拮抗剂昂丹司琼和GABA_A受体拮抗剂荷包牡丹碱可减弱PAG吗啡对正常大鼠的镇痛作用，而增强PAG吗啡对SNL大鼠的镇痛作用。用原肌球蛋白受体激酶B（Trk B）拮抗剂K252 a预处理可逆转荷包牡丹碱诱导的PAG吗啡镇痛作用。2-甲基-5-羟色胺激活脊髓5-羟色胺3受体增加GABA浓度在两组。吗啡通过激活下行的GABA能神经元来激活SDH中的GABA能中间神经元。GABA A受体的功能变化，从抑制性到促进通过激活TrkB受体可能有助于吗啡对神经性pain.Perspective的衰减的疗效：虽然吗啡提供了强大的镇痛对急性疼痛，它对神经性疼痛的疗效有限。这篇文章表明，神经损伤后脊髓背角GABA A受体的功能变化可能强烈有助于阿片类药物诱导的镇痛神经病理性疼痛的衰减。(C)2021年，任作者。爱思唯尔公司出版代表美国疼痛研究协会。
Systemic administration of morphine increases serotonin (5-HT) in the spinal dorsal horn (SDH), which attenuates the analgesic effects of morphine on neuropathic pain through spinal 5-HT3 receptors. We hypothesized that dysfunction of the descending serotonergic system, including the periaqueductal gray (PAG), contributes to attenuate the efficacy of morphine on neuropathic pain through spinal 5-HT3 receptors and GABA neurons. Morphine (100 ng) injected into the PAG produced analgesic effects in normal rats, but not in spinal nerve ligation (SNL) rats. In vivo microdialysis showed that PAG morphine increased the SDH 5-HT concentration in both groups. Intrathecal injection of the 5-HT3 receptor antagonist ondansetron and the GABA A receptor antagonist bicuculline attenuated the analgesic effects of PAG morphine in normal rats, but increased the effects in SNL rats. The increased analgesic effect of PAG morphine induced by bicuculline was reversed by pretreatment with the tropomyosin receptor kinase B (TrkB) antagonist K252a. Activation of spinal 5-HT3 receptors by 2-methyl-5-HT increased the GABA concentration in both groups. Morphine activates GABAergic interneurons in the SDH by activating descending serotonergic neurons. Functional changes in GABA A receptors from inhibitory to facilitatory through the activation of TrkB receptors may contribute to the attenuated efficacy of morphine against neuropathic pain.Perspective: Although morphine provides strong analgesia against acute pain, it has limited efficacy against neuropathic pain. This article demonstrates that functional changes in GABA A receptors in the spinal dorsal horn after nerve injury might strongly contribute to the attenuation of opioid-induced analgesia for neuropathic pain. (C) 2021 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.