Abstract
((2S,3S)-[cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine]) (CP-96,345) noncompetitively inhibits substance P (SP) binding at the neurokinin-1 (NK-1) site and has been widely used to determine the extent of NK-1 activity in nociception. To test the selectivity of this compound in vivo regarding other putative nociceptive transmitters, such as excitatory amino acids, we compared the actions of CP-96,345 to those of ((2R,3R)-[cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine]), a less active isomer, on behavioral 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 behavior 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 injection of 22.5 pmol of SP. In contrast, NMDA-induced behaviors were inhibited by CP-96,345 in a dose-related fashion beginning at a dose as low 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 [3H] SP binding, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), was approximately 10 times more potent in inhibiting NMDA-induced activity than CP-96,345. CP-99,994 also inhibited NMDA-induced activity at doses that failed to inhibit SP-induced behavior. Also attenuated by CP-96,345 was the development of sensitization to the behavioral effects produced by repeated injections of KA and desensitization to repeated injections of SP, phenomena linked to an action of the N-terminus of SP. NMDA-induced behaviors and sensitization to KA were found to be sensitive to verapamil, consistent with their mediation by calcium. These results indicate that either CP-96,345 and CP-99,994 do not inhibit NK-1-induced activity in the mouse spinal cord, or that exogenously administered SP does not induce behavioral responses by an interaction with NK-1 receptors. Whether CP-96,345 acts by a mechanism that involves inhibition of calcium channels and/or SP N-terminal activity requires further testing.
Footnotes
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Send reprint requests to: Dr. Alice A. Larson, Department of Veterinary PathoBiology, University of Minnesota, 295 Animal Science/Veterinary Medicine Building, 1988 Fitch Avenue, St. Paul, MN 55108.
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↵1 This work was supported by United States Public Health Service Grant DA04090 to A.A.L. and National Research Service Award NS09882 to R.A.V.
- Abbreviations:
- CP-96
- 344, ((2R,3R)-[cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine])
- CP-96
- 345, ((2S,3S)-[cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine])
- CP-99
- 994, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine
- DPDT-SP
- [d-Pro2,d-Phe7]-substance P
- EAA
- excitatory amino acid
- i.t.
- intrathecal
- KA
- kainic acid
- MK-801
- dizocilpine or (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
- NK-1
- neurokinin-1
- NMDA
- N-methyl-d-aspartate
- PCP
- phencyclidine
- SP
- substance P
- Received September 30, 1996.
- Accepted February 28, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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