3 research outputs found
A Conditional Deletion of the NR1 Subunit of the NMDA Receptor in Adult Spinal Cord Dorsal Horn Reduces NMDA Currents and Injury-Induced Pain
To determine the importance of the NMDA receptor (NMDAR) in pain hypersensitivity after injury, the NMDAR1 (NR1) subunit was selectively deleted in the lumbar spinal cord of adult mice by the localized injection of an adenoassociated virus expressing Cre recombinase into floxed NR1 mice. NR1 subunit mRNA and dendritic protein are reduced by 80% in the area of the virus injection, and NMDA currents, but not AMPA currents, are reduced 86–88% in lamina II neurons. The spatial NR1 knock-out does not alter heat or cold paw-withdrawal latencies, mechanical threshold, or motor function. However, injury-induced pain produced by intraplantar formalin is reduced by 70%. Our results demonstrate conclusively that the postsynaptic NR1 receptor subunit in the lumbar dorsal horn of the spinal cord is required for central sensitization, the central facilitation of pain transmission produced by peripheral injury
Deletion of the Glutamate Receptor 5 Subunit of Kainate Receptors Affects the Development of Morphine Tolerance
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