Absence of prostaglandin E 2 ‐induced hyperalgesia in NMDA receptor ε subunit knockout mice

We have previously found that intrathecal administration of prostaglandins E 2 (PGE 2 ) and D 2 (PGD 2 ) into conscious mice induced hyperalgesia by the hot plate test. The present study investigated the involvement of N ‐methyl‐ d ‐aspartate (NMDA) receptor in the prostaglandin‐induced hyperalgesia by use of mice lacking NMDA receptor ε1, ε4, or ε1/ε4 subunits. PGE 2 induced hyperalgesia over a wide range of doses from 50 pg to 500 ng kg −1 in wild‐type mice. But PGE 2 could not induce hyperalgesia in ε1, ε4, or ε1/ε4 subunit knockout mice. The NMDA receptor antagonist d ‐(−)‐2‐amino‐5‐phosphonovaleric acid ( d ‐AP5), the non‐NMDA receptor antagonist γ‐ d ‐glutamylaminomethyl sulphonic acid (GAMS), and the nitric oxide synthase inhibitor N ω ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME) inhibited the PGE 2 ‐induced hyperalgesia in wild‐type mice. PGD 2 induced hyperalgesia at doses of 25 ng to 250 ng kg −1 in both wild‐type and ε1/ε4 subunit knockout mice. The substance P receptor antagonist CP 96,345 blocked the PGD 2 ‐induced hyperalgesia in wild‐type and ε1/ε4 subunit knockout mice. These results demonstrate that the pathways leading to hyperalgesia are different between PGD 2 and PGE 2 and that both ε1 and ε4 subunits of the NMDA receptor are involved in the PGE 2 ‐induced hyperalgesia.British Journal of Pharmacology (1997) 120 , 1522–1526; doi: 10.1038/sj.bjp.0701067