Attenuation of hyperalgesia by LY235959, a competitive N-methyl-D-aspartate receptor antagonist.

N-methyl-D-aspartate (NMDA) receptor antagonists may be of value in the management of hyperalgesia. LY235959, a competitive NMDA receptor antagonist, at doses of 0.001 and 0.003 nmol, intrathecally (i.t.) blocked the hyperalgesia induced by 11.1 nmol of NMDA in rats prepared with a chronic i.t. cannula. However, LY235959 does not block the hyperalgesia produced by kainic acid (a non-NMDA glutamate receptor agonist) providing evidence of its selectivity for the NMDA receptor. Using the formalin nociceptive test, 0.001 nmol LY235959 (i.t.) significantly reduced the number of Phase 2 flinches by about 80%. LY235959 can also reduce the flinching in Phase 2 by 30% when given subcutaneously (s.c.) at the lowest dose which does not produce motor deficits (20 mmol/kg). Thus, LY235959 (i.t. or s.c.) has NMDA receptor antagonist activity as defined by its ability to prevent hyperalgesia and formalin-induced central sensitization. Moreover, it is a much more potent antihyperalgesic after i.t. as compared to s.c. administration.