Effects of NMDA receptor antagonists on morphine tolerance: a c-Fos study in the lumbar spinal cord of the rat

This study investigated the contribution of NMDA receptors to the developme nt of tolerance to the antinociceptive properties of morphine at the level of the spinal cord dorsal horn. The expression of c-Fos protein following i ntraplantar (i.pl.) injection of carrageenin (6 mg/150 mu l of saline) was used. In naive rats, acute intravenous (i.v.) administration of morphine (3 mg/kg) decreased the total number per section of Fos-Like-Immunoreactive ( Fos-LI) neurons by 51%, observed at 2 h after injection of carrageenin. In tolerant rats, acute morphine did not significantly modify the total number of Fos-like immunoreactive neurons/section. In rats receiving chronic morp hine and chronic injections of the non-competitive ((+)-MK 801 maleate: (SR ,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine) or the competitive (LY 235959: [3S-(3 alpha,4a alpha,6 beta,8a beta)]-Decahyd ro-6-(phosphonomethyl)-3-isoquinolinecarboxylic acid) NMDA receptor antagon ists, only partial tolerance to the acute effects of morphine were observed (decrease of 42% and 38%, respectively). Administration of an antagonist a t the strychnine-insensitive glycine site of the NMDA receptor ((+)-HA-966: R(+)-3-Amino-1-hydroxypyrrolidin-2-one) did not affect the development of morphine tolerance. These findings suggest that compounds attenuating the a ctions of the NMDA receptor via blockade of the glycine modulatory site may be substantially different from those acting at the ion channel of the NMD A receptor complex. This in vivo experiment in freely moving animals demons trates for the first time an attenuation of tolerance at the cellular level . (C) 1999 Elsevier Science B.V. All rights reserved.