Received for publication February 4, 2005.
Revised March 7, 2005.
Accepted for publication March 8, 2005.

Effects of the NMDA receptor antagonist perzinfotel (EAA-090) on chemically-induced thermal hypersensitivity

Abstract

Perzinfotel (EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid) is a selective, competitive NMDA receptor antagonist with high affinity for the glutamate site. The current study evaluated whether perzinfotel would have antinociceptive effects or block thermal hypersensitivity associated with the administration of chemical irritants in rats. Perzinfotel lacked antinociceptive effects but dose- and time-dependently blocked prostaglandin E₂ (PGE₂)- and capsaicin-induced thermal hypersensitivity in a warm-water tail withdrawal assay in rats. Doses of 10 mg/kg intraperitoneal (IP) or 100 mg/kg oral (PO) blocked PGE₂-induced hypersensitivity by 60-80%. The magnitude of reversal was greater than other negative modulators of the NMDA receptor studied, such as un-competitive channel blockers (e.g., memantine, dizocilpine and ketamine), a NR2B selective antagonist (e.g., ifenprodil), and other glutamate antagonists (e.g., selfotel, CPP, CGP-39653), up to doses that suppressed operant rates of responding. In contrast to other negative modulators of the NMDA receptor studied, which typically decreased operant rates of responding at doses that lacked antinociceptive effects, perzinfotel did not modify response rates at doses that blocked irritant-induced thermal hypersensitivity. Collectively, these studies demonstrate that perzinfotel has therapeutic ratios for effectiveness versus adverse effects superior to those seen with other competitive and un-competitive NMDA receptor antagonists studied.

Key words: NMDA, glutamate antagonist, pain, prostaglandin E2, rat, scheduled-control responding