Grup de Neurofarmacologia Molecular, Institut de Recerca de l'Hospital de la Sta Creu i Sant Pau & Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
Mol Pain. 2011 Apr 12;7:25. doi: 10.1186/1744-8069-7-25.
The local administration of μ-opioid receptor (MOR) agonists attenuates neuropathic pain but the precise mechanism implicated in this effect is not completely elucidated. We investigated if nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric oxide synthases could modulate the local antiallodynic effects of morphine through the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K+ (KATP) channels signaling pathway activation and affect the dorsal root ganglia MOR expression during neuropathic pain.
In wild type (WT) mice, the subplantar administration of morphine dose-dependently decreased the mechanical and thermal allodynia induced by the chronic constriction of the sciatic nerve (CCI), which effects were significantly diminished after their co-administration with different subanalgesic doses of a selective 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), PKG ((Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs) inhibitor or a KATP channel blocker (glibenclamide). The evaluation of the expression of MOR in the dorsal root ganglia from sham-operated and sciatic nerve-injured WT, NOS1 knockout (KO) and NOS2-KO mice at 21 days after surgery demonstrated that, although the basal mRNA and protein levels of MOR were similar between WT and both NOS-KO animals, nerve injury only decreased their expression in WT mice.
These results suggest that the peripheral nitric oxide-cGMP-PKG-KATP signaling pathway activation participates in the local antiallodynic effects of morphine after sciatic nerve injury and that nitric oxide, synthesized by NOS1 and NOS2, is implicated in the dorsal root ganglia down-regulation of MOR during neuropathic pain.
局部给予μ-阿片受体（MOR）激动剂可减轻神经性疼痛，但这种作用的确切机制尚未完全阐明。我们研究了神经元型（NOS1）或诱导型（NOS2）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）-ATP 敏感性钾（KATP）通道信号通路的激活来调节吗啡的局部抗痛觉过敏作用，并影响背根神经节 MOR 在神经性疼痛过程中的表达。
在野生型（WT）小鼠中，足底给予吗啡剂量依赖性地降低了慢性坐骨神经结扎（CCI）引起的机械性和热痛觉过敏，而当与不同亚镇痛剂量的选择性 NOS1（N-[(4S)-4-氨基-5-[(2-氨乙基)氨基]戊基]-N'-硝基胍三（三氟乙酸）盐；NANT）、NOS2（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[4,3-a]喹喔啉-1-酮；ODQ）、PKG（（Rp）-8-（对氯苯基硫代）鸟苷-3'，5'-环单磷酸硫代酯；Rp-8-pCPT-cGMPs）抑制剂或 KATP 通道阻滞剂（格列本脲）共同给药时，这些作用明显减弱。术后 21 天，评估 sham 手术和坐骨神经损伤 WT、NOS1 基因敲除（KO）和 NOS2-KO 小鼠背根神经节中 MOR 的表达，结果表明，尽管 MOR 的基础 mRNA 和蛋白水平在 WT 和两种 NOS-KO 动物之间相似，但神经损伤仅在 WT 小鼠中降低其表达。
这些结果表明，外周一氧化氮-cGMP-PKG-KATP 信号通路的激活参与了坐骨神经损伤后吗啡的局部抗痛觉过敏作用，并且由 NOS1 和 NOS2 合成的一氧化氮参与了背根神经节中 MOR 的下调在神经性疼痛过程中。
