Abstract
Previous reports utilizing pharmacological antagonists implicate kainate receptor (KAR) activation in the development of morphine tolerance, dependence, conditioned place preference (CPP), and locomotor sensitization, but the role of glutamate receptor (GluR) 5-containing KAR in these effects remains unclear because of limited selectivity of the inhibitors employed. Therefore, we examined responses to systemic morphine treatment in mice expressing a constitutive deletion of GluR5 [GluR5 knockout (KO)]. Unlike wild-type (WT) littermates, GluR5 KO mice do not develop tolerance after repeated morphine administration by subcutaneous injection or via subcutaneous pellet implantation. In contrast, GluR5 KO mice do not differ from WT with respect to thermal or mechanical nociceptive thresholds, acute morphine antinociception, morphine disposition in the central nervous system (CNS), morphine physical dependence as revealed by naloxone-precipitated withdrawal or development of place preference and locomotor hyperresponsiveness after chronic morphine administration. It is surprising that continuous subcutaneous infusion of the GluR2/GluR5-preferring antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid] decreased the number of naloxone-precipitated jumps to a similar extent in WT and GluR5 KO mice. We observed opioid-induced hypersensitivity in both groups during morphine withdrawal as demonstrated by equivalent reductions in thermal and mechanical thresholds; however, this hypersensitivity was not evident during continuous systemic morphine infusion. These data collectively indicate that KARs containing the GluR5 subunit contribute to the development of morphine tolerance without affecting nociceptive thresholds, morphine analgesia, or disposition in CNS of morphine and its metabolite morphine-3-glucuronide. In addition, constitutive deletion of GluR5 does not alter the morphine-induced increase in locomotor activity or the acquisition of morphine reward as measured by a CPP paradigm.
Footnotes
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This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA001457, DA000198, Training Grant DA007274, and Center Grant DA005130].
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J.J.B. and A.M.G. contributed equally to this work.
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High-performance liquid chromatography and mass spectrometry of morphine and M3G in WT and GluR5 KO mice were conducted by Drs. Rodger Foltz and David Andrenyak at the Center for Human Toxicology of the University of Utah (Salt Lake City, UT) under a services contract to NIDA and Dr. H. Singh of the Division of Neuroscience and Behavioral Research at NIDA. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.144121.
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ABBREVIATIONS: CNS, central nervous system; NMDA, N-methyl-d-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GluR, glutamate receptor; KAR, kainate receptor; AMPAR, AMPA receptor; LY293558, (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid; CPP, conditioned place preference; KO, knockout; WT, wild type; TTW, thermal tail withdrawal; CI, confidence interval; PWL, paw withdrawal latency; M3G, morphine-3-glucuronide; ANOVA, analysis of variance; LY382884, 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid; PKC, protein kinase C; SC, spinal cord.
- Received July 28, 2008.
- Accepted October 27, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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