Department of Medical Chemistry, Kansai Medical University, Moriguchi 570-8506, Japan.
Mol Pain. 2012 Aug 21;8:59. doi: 10.1186/1744-8069-8-59.
Postherpetic neuralgia is spontaneous pain and allodynia that persist long after the disappearance of the cutaneous lesions caused by herpes zoster. Inoculation of mice with herpes simplex virus-1 causes herpes zoster-like skin lesions and herpetic and postherpetic pain. Although NMDA receptors have been suggested to be involved in postherpetic pain as in other types of neuropathic pain, the neural mechanism remains unclear. NMDA receptor NR2B subunit is the most tyrosine-phosphorylated protein in the brain, and Tyr1472 is the major phosphorylation site of this subunit.
To elucidate the role of Tyr1472 phosphorylation of the NR2B subunit in herpetic and postherpetic allodynia, we inoculated herpes simplex virus-1 into the unilateral hind paw of knock-in mice with a mutation of Tyr1472 of the NR2B subunit to Phe (Y1472F-KI). On day 7 post-inoculation, acute herpetic allodynia was observed in more than 80% of the inoculated wild-type and Y1472F-KI mice. Y1472F-KI mice showed significantly reduced intensity and incidence of postherpetic allodynia on days 45-50 post-inoculation as compared with wild-type mice. The innervation in the skin at the postherpetic neuralgia phase was retained to a greater extent in the Y1472F-KI mice. The level of activating transcription factor-3 mRNA, a marker of axonal damage, increased much less in the dorsal root ganglia (DRGs) of Y1472F-KI mice than in those of wild-type mice; and the level of nerve growth factor mRNA significantly increased in wild-type mice, but not at all in Y1472F-KI mice on day 7 post-inoculation. Production of nerve growth factor was at the basal level in the skin of both groups of mice on day 50 post-inoculation. Nerve growth factor and glial cell-derived neurotrophic factor stimulated neurite outgrowth of cultured DRG neurons from Y1472F-KI mice, similarly or less so as they did the outgrowth of those from wild-type mice. Wild-type DRG neurons were more susceptible to glutamate neurotoxicity than Y1472F-KI ones.
Taken together, the present data suggest that phosphorylation of the NR2B subunit at its Tyr1472 is involved in the development of postherpetic allodynia due to nerve damage and that the nerve damage at the acute herpetic phase is correlated with the incidence of postherpetic pain.
带状疱疹后神经痛是一种自发性疼痛和痛觉过敏，在带状疱疹引起的皮肤损伤消失后仍持续存在。单纯疱疹病毒 1 接种小鼠会导致带状疱疹样皮肤损伤和疱疹性及带状疱疹后疼痛。尽管 NMDA 受体已被认为参与了带状疱疹后疼痛，就像其他类型的神经性疼痛一样，但神经机制仍不清楚。NMDA 受体 NR2B 亚基是大脑中酪氨酸磷酸化程度最高的蛋白，而 Tyr1472 是该亚基的主要磷酸化位点。
为了阐明 NR2B 亚基 Tyr1472 磷酸化在疱疹性和带状疱疹后痛觉过敏中的作用，我们将单纯疱疹病毒 1 接种到 NR2B 亚基 Tyr1472 突变为苯丙氨酸（Y1472F-KI）的敲入小鼠的单侧后爪中。在接种后 7 天，超过 80%的接种野生型和 Y1472F-KI 小鼠出现急性疱疹性痛觉过敏。与野生型小鼠相比，Y1472F-KI 小鼠在接种后 45-50 天的疱疹后痛觉过敏的强度和发生率显著降低。在带状疱疹后神经痛阶段，Y1472F-KI 小鼠的皮肤神经支配保留程度更大。在 Y1472F-KI 小鼠的背根神经节（DRG）中，激活转录因子-3 mRNA 的水平，一种轴突损伤的标志物，增加的幅度明显小于野生型小鼠；而神经生长因子 mRNA 的水平在接种后 7 天的野生型小鼠中显著增加，但在 Y1472F-KI 小鼠中根本没有增加。接种后第 50 天，两组小鼠皮肤的神经生长因子的产生处于基础水平。神经生长因子和胶质细胞衍生的神经营养因子刺激 Y1472F-KI 小鼠培养的 DRG 神经元的轴突生长，其作用与刺激野生型小鼠的轴突生长相似或稍弱。野生型 DRG 神经元比 Y1472F-KI 神经元更容易受到谷氨酸神经毒性的影响。
综上所述，本研究数据表明，NR2B 亚基 Tyr1472 的磷酸化参与了神经损伤引起的带状疱疹后痛觉过敏的发展，而疱疹性急性期的神经损伤与带状疱疹后疼痛的发生率有关。
