TY - JOUR
T1 - Inhibition of morphine tolerance by NMDA receptor antagonists in the formalin test
AU - Lutfy, Kabirullah
AU - Shen, Ke Zhong
AU - Woodward, Richard M.
AU - Weber, Eckard
N1 - Funding Information:
We would like to express our gratitude to Dr. Ralph E. Purdy for his comments and suggestions, Dr. James Bel-luzzi for providing us the Digiscan Activity Monitor, Dr. Sui Xiong Cai for the synthesis of ACEA-1328, Ms. Yah Ni and Dr. Ricardo Miledi at the University of California, Irvine (Irvine, CA) for the generous gift of rat cerebral cortex poly(A) ÷ RNA. We are indebted to Silvia Loyola, Minh Nguyen, Michelle Cao, Peter Doan, Ik-Sung Kwon, Phoung (Christie) Quach, Kyung Kim, Monica Trinh, Peter C. Rim, Karyn Wu, Thao Trinh, Margaret Uhm, Phong Lu, Christine Nguyen, Lisa Chen, Linh Pham, Tri Tran, Arti Shah, and Nafiseh and Neda Rahnamoon for technical assistance. This study was supported in part by NIDA Grant DA 06726 \[to E.W.\] and by Acea Pharmaceuticals, Inc. Parts of these studies were presented as preliminary data at the Society for Neuroscience, 1994.
PY - 1996/8/26
Y1 - 1996/8/26
N2 - 5-Nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328) was characterized in vitro for antagonism of excitatory amino acid receptors, and subsequently tested in vivo and compared with MK-801 for phencyclidine (PCP)-like motor stimulation, antinociception, and effects on morphine tolerance in mice. Assayed on rat cerebral cortical glutamate receptors expressed in Xenopus oocytes ACEA-1328 showed potent (K(b) ~ 40 nM) antagonism at NMDA receptor/glycine sites and moderate (K(b) ~ 3 μM) antagonism at non-NMDA receptors. In both cases inhibition was predominantly competitive. ACEA-1328 was weak, or inactive, at NMDA receptor glutamate recognition sites, metabotropic receptors and opioid binding sites. In the formalin and rotarod tests ACEA-1328 and MK-801 produced both antinociception and disturbances of motor coordination. MK-801 caused a PCP-like motor stimulatory effect, whereas ACEA-1328 was devoid of such an effect. In tolerance studies, ACEA-1328 and MK-801 each blocked morphine tolerance in the formalin test, the effect of ACEA-1328 was dose-dependent. Our data contribute to a growing body of evidence which suggests that activation of NMDA receptors is critical for the development of opioid tolerance, and that antagonism at NMDA receptor/glycine sites may have potential as a means of diminishing tolerance with no PCP-like motor stimulatory side effects.
AB - 5-Nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328) was characterized in vitro for antagonism of excitatory amino acid receptors, and subsequently tested in vivo and compared with MK-801 for phencyclidine (PCP)-like motor stimulation, antinociception, and effects on morphine tolerance in mice. Assayed on rat cerebral cortical glutamate receptors expressed in Xenopus oocytes ACEA-1328 showed potent (K(b) ~ 40 nM) antagonism at NMDA receptor/glycine sites and moderate (K(b) ~ 3 μM) antagonism at non-NMDA receptors. In both cases inhibition was predominantly competitive. ACEA-1328 was weak, or inactive, at NMDA receptor glutamate recognition sites, metabotropic receptors and opioid binding sites. In the formalin and rotarod tests ACEA-1328 and MK-801 produced both antinociception and disturbances of motor coordination. MK-801 caused a PCP-like motor stimulatory effect, whereas ACEA-1328 was devoid of such an effect. In tolerance studies, ACEA-1328 and MK-801 each blocked morphine tolerance in the formalin test, the effect of ACEA-1328 was dose-dependent. Our data contribute to a growing body of evidence which suggests that activation of NMDA receptors is critical for the development of opioid tolerance, and that antagonism at NMDA receptor/glycine sites may have potential as a means of diminishing tolerance with no PCP-like motor stimulatory side effects.
KW - Antinociception
KW - Formalin test
KW - Glycine co-agonist site
KW - NMDA receptor
KW - Tolerance
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U2 - 10.1016/0006-8993(96)00469-6
DO - 10.1016/0006-8993(96)00469-6
M3 - Article
C2 - 8883867
AN - SCOPUS:0030603088
SN - 0006-8993
VL - 731
SP - 171
EP - 181
JO - Brain research
JF - Brain research
IS - 1-2
ER -