Involvement of cyclooxygenase-2 and EP 3 prostaglandin receptor in acute herpetic but not postherpetic pain in mice

Abstract

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 EP 3 but not EP 1, 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 EP 3 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 PGE 2 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 PGE 2 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 PGE 2 in uninfected neurons. The results suggest the important roles of COX-2 induction and the PGE 2–EP 3 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.