Involvement of cyclooxygenase-2 and EP3 prostaglandin receptor in acute herpetic but not postherpetic pain in mice.
The precise mechanisms of zoster-associated pain and postherpetic neuralgia remain unknown. Inoculation of mice with herpes simplex virus type-1 elicits acute herpetic pain- and delayed postherpetic pain-related responses. We investigated the role of prostaglandins (PGs) and their synthases in both types of pain. Deficiency in EP3 but not EP1, IP or TP prostanoid receptor markedly diminished the acute herpetic pain and resulted in the decrease of the incidence of the delayed postherpetic pain. Preventive but not therapeutic administration of the EP3 antagonist ONO-AE3-240 inhibited the acute herpetic pain. The non-selective cyclooxygenase (COX) inhibitor diclofenac and the selective COX-2 inhibitors NS-398 and JTE-522 dose dependently reduced the acute herpetic pain, and NS-398 was without effect on delayed postherpetic pain. COX-2 was induced and PGE2 content was increased in the affected dorsal root ganglia at the stage of acute herpetic pain. COX-2-like immunoreactivities were found around the nuclear membrane of many dorsal root ganglion neurons that were negative for herpesvirus antigen. COX-2 mRNA expression and PGE2 content in the affected dorsal root ganglia at the stage of delayed postherpetic pain were similar to those of naive mice. The propagation of herpes virus in dorsal root ganglion may induce COX-2 and produce PGE2 in uninfected neurons. The results suggest the important roles of COX-2 induction and the PGE2-EP3 receptor system in the dorsal root ganglia in the development but not maintenance of acute herpetic pain. It was further confirmed that the PG systems do not play a key role in delayed postherpetic pain.
Takasaki
Ichiro
I
Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. takasaki@ms.toyama-mpu.ac.jp
Nojima
Hiroshi
H
Shiraki
Kimiyasu
K
Sugimoto
Yukihiko
Y
Ichikawa
Atsushi
A
Ushikubi
Fumitaka
F
Narumiya
Shuh
S
Kuraishi
Yasushi
Y
D000208:Acute Disease; D000818:Animals; D015139:Blotting, Southern; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects; D006561:Herpes Simplex / Q000150:complications*; D018259:Herpesvirus 1, Human; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000209:etiology* / Q000503:physiopathology* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism / Q000502:physiology*; D011453:Prostaglandins / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000502:physiology*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; C545647:PTGER3 protein, human; D011453:Prostaglandins; C545648:Ptger3 protein, mouse; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases