The Role of Nitric Oxide in the Local Antiallodynic and Antihyperalgesic Effects and Expression of δ-Opioid and Cannabinoid-2 Receptors during Neuropathic Pain in Mice
The Role of Nitric Oxide in the Local Antiallodynic and Antihyperalgesic Effects and Expression of δ-Opioid and Cannabinoid-2 Receptors during Neuropathic Pain in Mice
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DOI：
10.1124/jpet.110.167585
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发表时间：
2010-09-01
影响因子：
3.5
通讯作者：
Pol, Olga
中科院分区：
文献类型：
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作者：
Hervera, Arnau;Negrete, Roger;Pol, Olga
δ-阿片受体（DOPr）和大麻素-2受体（CB 2 R）激动剂都能减轻神经性疼痛，但这些作用的确切机制尚未完全阐明。我们研究了由神经元型（NOS 1）或诱导型（NOS 2）一氧化氮合酶合成的一氧化氮是否可以通过外周一氧化氮-cGMP-蛋白激酶G（PKG）通路激活调节DOPr和/或CB 2 R抗异常性疼痛和抗痛觉过敏作用，并影响其在神经病理性疼痛过程中的表达。在野生型（WT）小鼠坐骨神经慢性压迫后21天，我们评价了[D-Pen 2，DPen 5]-脑啡肽（DPDPE）的作用;（2-甲基-1-丙基-1H-吲哚-3-基）-1-萘基甲酮（JWH-015）;和（2-氨乙基）氨基]戊基]-N '-硝基胍三（三氟乙酸）盐; NANT]，NOS 2 [L-N（6）-（1-亚氨基乙基）-赖氨酸; L-NIL]、L-鸟苷酸环化酶[1H-[1，2，4]恶二唑并[4，3-a]喹喔啉-1-酮; ODQ]或PKG [（Rp）-8-（对氯苯硫基）鸟苷-3 '，5'-环状单硫代磷酸酯; Rp-8-pCPT-cGMP]抑制剂单独或联合给药。还评估了幼稚和神经损伤WT、NOS 1敲除（KO）和NOS 2-KO小鼠的脊髓和背根神经节中DOPr和CB 2 R mRNA的表达。足底施用NANT、L-NIL、ODQ或Rp-8-pCPT-cGMP剂量依赖性地抑制神经性疼痛并增强DPDPE或JWH-015的局部作用。此外，尽管WT和NOS-KO动物之间DOPr和CB 2 R mRNA的基础水平相似，但神经损伤仅降低（DOPr）或增加（CB 2 R）WT和NOS 2-KO小鼠背根神经节中的DOPr和CB 2 R mRNA表达，而在NOS 1-KO小鼠中则没有。结果表明，NOS 1和NOS 2引发的一氧化氮-cGMP-PKG外周通路的失活增强了DOPr和CB 2 R激动剂的外周作用，并且NOS 1合成的一氧化氮参与了神经病理性疼痛期间DOPr和CB 2 R基因转录的外周调节。
Both delta-opioid receptor (DOPr) and cannabinoid-2 receptor (CB2R) agonists attenuate neuropathic pain, but the precise mechanism implicated in these effects is not completely elucidated. We investigated whether nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric-oxide synthases could modulate DOPr and/or CB2R antiallodynic and antihyperalgesic effects through the peripheral nitric oxide-cGMP-protein kinase G (PKG) pathway activation and affect their expression during neuropathic pain. In wild-type (WT) mice at 21 days after chronic constriction of sciatic nerve, we evaluated the effects of [D-Pen2, DPen5]-enkephalin (DPDPE); (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH-015); and a NOS1 [N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N'-nitroguanidine tris(trifluoroacetate) salt; NANT], NOS2 [L-N(6)-(1-iminoethyl)-lysine; L-NIL], L-guanylate cyclase [1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one; ODQ], or PKG [(Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs] inhibitor administered alone or combined. Expression of DOPr and CB2R mRNA in the spinal cord and dorsal root ganglia of naive and nerve-injured WT, NOS1-knockout (KO), and NOS2-KO mice, also was assessed. The subplantar administration of NANT, L-NIL, ODQ, or Rp-8-pCPT-cGMPs dose-dependently inhibited neuropathic pain and enhanced the local effects of DPDPE or JWH-015. Moreover, although the basal levels of DOPr and CB2R mRNA were similar between WT and NOS-KO animals, nerve injury only decreased (DOPr) or increased (CB2R) their expression in the dorsal root ganglia of WT and NOS2-KO mice, and not in NOS1-KO mice. Results suggest that inactivation of the nitric oxide-cGMP-PKG peripheral pathway triggered by NOS1 and NOS2 enhanced the peripheral actions of DOPr and CB2R agonists and that nitric oxide synthesized by NOS1 is implicated in the peripheral regulation of DOPr and CB2R gene transcription during neuropathic pain.