Involvement of Tyr1472 phosphorylation of NMDA receptor NR2B subunit in postherpetic neuralgia in model mice.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Medical Chemistry, Kansai Medical University, Moriguchi 570-8506, Japan.
Sawako
S
Unezaki
Atsushi
A
Sasaki
Tamaki
T
Mabuchi
Shinji
S
Matsumura
Tayo
T
Katano
Takanobu
T
Nakazawa
Naoko
N
Nishio
Tsugunobu
T
Andoh
Tadashi
T
Yamamoto
Terumasa
T
Nakatsuka
Yasushi
Y
Kuraishi
Seiji
S
Ito
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D006561:Herpes Simplex / Q000378:metabolism / Q000473:pathology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D051474:Neuralgia, Postherpetic / Q000378:metabolism* / Q000473:pathology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism*; D012867:Skin / Q000294:innervation / Q000473:pathology; D013329:Structure-Activity Relationship; D013373:Substance P / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D050505:Mutant Proteins; C121001:NR2B NMDA receptor; D009498:Neurotoxins; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D019000:Phosphotyrosine; D013373:Substance P; D016202:N-Methylaspartate; D015740:Calcitonin Gene-Related Peptide