Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates
Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates
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DOI：
10.1038/srep11676
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发表时间：
2015-06-29
影响因子：
4.6
通讯作者：
Ko, Mei-Chuan
中科院分区：
文献类型：
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作者：
Lee, Heeseung;Ko, Mei-Chuan
灵长类脊髓中的神经肽如何调节瘙痒和疼痛在很大程度上是未知的。在这里，我们阐明了脊髓阿片相关肽和胃泌素释放肽(GRP)在清醒的行为猴中的感觉功能。鞘内给药后，β-内啡肽(10-100nmol)和GRP(1-10nmol)可剂量依赖性地引起相同程度的强烈瘙痒，这可分别被Mu-阿片肽(MOP)受体和GRP受体(BB2)拮抗剂所抑制。与产生瘙痒和减轻炎症性疼痛的β-内啡肽不同，GRP只引起瘙痒，而不影响疼痛。相反，脑啡肽(100-1000nmol)和伤害素-孤啡肽FQ(3-30nmol)只抑制疼痛而不会引起瘙痒。更耐人寻味的是，强啡肽A(1-17)(10-100nmol)可剂量依赖性地减弱β-内啡肽和GRP引起的强烈抓挠，而不影响疼痛处理。强啡肽A的止痒作用可被kappa阿片肽(KOP)受体拮抗剂Nor-binaltorphimine逆转。这些非人类灵长类动物的行为模型与脊髓递送的配体促进了我们对神经肽调节瘙痒和疼痛的不同功能的理解。特别是，我们证明了通过β-内啡肽-MOP受体系统和GRP-BB2受体系统引起瘙痒的因果联系，以及通过强啡肽A-KOP受体系统产生的瘙痒抑制效应。这些研究将有助于将新的配体-受体系统的发现转化为未来的人类止痒和/或止痛药。
How neuropeptides in the primate spinal cord regulate itch and pain is largely unknown. Here we elucidate the sensory functions of spinal opioid-related peptides and gastrin-releasing peptide (GRP) in awake, behaving monkeys. Following intrathecal administration, beta-endorphin (10-100 nmol) and GRP (1-10 nmol) dose-dependently elicit the same degree of robust itch scratching, which can be inhibited by mu-opioid peptide (MOP) receptor and GRP receptor (BB2) antagonists, respectively. Unlike beta-endorphin, which produces itch and attenuates inflammatory pain, GRP only elicits itch without affecting pain. In contrast, enkephalins (100-1000 nmol) and nociceptin-orphanin FQ (3-30 nmol) only inhibit pain without eliciting itch. More intriguingly, dynorphin A(1-17) (10-100 nmol) dose-dependently attenuates both beta-endorphin- and GRP-elicited robust scratching without affecting pain processing. The anti-itch effects of dynorphin A can be reversed by a kappa-opioid peptide (KOP) receptor antagonist nor-binaltorphimine. These nonhuman primate behavioral models with spinal delivery of ligands advance our understanding of distinct functions of neuropeptides for modulating itch and pain. In particular, we demonstrate causal links for itch-eliciting effects by beta-endorphin-MOP receptor and GRP-BB2 receptor systems and itch-inhibiting effects by the dynorphin A-KOP receptor system. These studies will facilitate transforming discoveries of novel ligand-receptor systems into future therapies as antipruritics and/or analgesics in humans.