CP-96,345, WHICH INHIBITS [H-3] SUBSTANCE-P BINDING, SELECTIVELY INHIBITS THE BEHAVIORAL-RESPONSE TO INTRATHECALLY ADMINISTERED N-METHYL-D-ASPARTATE, BUT NOT SUBSTANCE-P, IN THE MOUSE

phenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine]) (CP-96,345) noncomp etitively inhibits substance P (SP) binding at the neurokinin-l (NK-1) site and has been widely used to determine the extent of NK-1 activit y in nociception. To test the selectivity of this compound in vivo reg arding other putative nociceptive transmitters, such as excitatory ami no acids, we compared the actions of CP-96,345 to those of henyl)-meth yI]-1-azabicyclo[2.2.2]octan-3-amine]), a less active isomer, on behav ioral responses induced by SP, N-methyl-D-aspartate (NMDA) and kainic acid (KA) injected intrathecally in mice. When injected intrathecally, SP, NMDA or KA produce a caudally directed biting and scratching beha vior that lasted for approximately 60 to 90 sec. At a dose as high as 2 nmol, CP-96,345 had no effect on responses induced by a single injec tion of 22.5 pmol of SP. In contrast, NMDA-induced behaviors were inhi bited by CP-96,345 in a dose-related fashion beginning at a dose as lo w as 0.02 nmol. There was also an inhibitory effect of CP-96,345 on KA -induced activity that was not dose related. The more potent inhibitor of [H-3] SP binding, 2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidi ne (CP-99,994), was approximately 10 times more potent in inhibiting N MDA-induced activity than CP-96,345. CP-99,994 also inhibited NMDA-ind uced activity at doses that failed to inhibit SP-induced behavior. Als o attenuated by CP-96,345 was the development of sensitization to the behavioral effects produced by repeated injections of KA and desensiti zation to repeated injections of SP, phenomena linked to an action of the N-terminus of SP. NMDA-induced behaviors and sensitization to KA w ere found to be sensitive to verapamil, consistent with their mediatio n by calcium. These results indicate that either CP-96,345 and CP-99,9 94 do not inhibit NK-l-induced activity in the mouse spinal cord, or t hat exogenously administered SP does not induce behavioral responses b y an interaction with NK-1 receptors. Whether CP-96,345 acts by a mech anism that involves inhibition of calcium channels and/or SP N-termina l activity requires further testing.