Abstract
Previous in vitro and in vivo studies have determined that thed isomer of methadone hasN-methyl-d-aspartate (NMDA) receptor antagonist activity. The present studies examined the ability ofd-methadone to attenuate the development of morphine tolerance in mice and rats and to modify NMDA-induced hyperalgesia in rats. A decrease in the percentage of mice analgesic (tail-flick response) after 5 days of once-daily morphine (7 mg/kg s.c.) was completely blocked by coadministration of d-methadone given s.c. at 10 mg/kg. Morphine given s.c. to mice on an escalating three times per day dosing schedule resulted in a nearly 3-fold increase in the tail-flick ED50 dose of morphine which was prevented by s.c. coadministered d-methadone at 15 mg/kg. In rats, intrathecal (i.t.) morphine produced a 38-fold increase in the ED50, which was completely prevented by the coadministration of i.t. d-methadone at 160 μg/rat. A decrease in thermal paw withdrawal latency induced by the i.t. administration of 1.64 μg/rat NMDA was completely blocked by pretreatment with 160 μg/rat d-methadone. Thus, systemically coadministered d-methadone prevents systemically induced morphine tolerance in mice, i.t.d-methadone attenuates tolerance produced by i.t. morphine in rats, and i.t. d-methadone, at the same dose which modulates morphine tolerance, blocks NMDA-induced hyperalgesia. These results support the conclusion that d-methadone affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.
Footnotes
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Send reprint requests to: Dr. Charles E. Inturrisi, Pharmacology, LC-524, Cornell University Medical College, New York, NY 10021. E-mail: ceintur{at}med.cornell.edu
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↵1 This work was supported by National Institute on Drug Abuse Grant DA01457. A.M.D. is a NIDA predoctoral trainee (DA07274). C.E.I. is a recipient of a Research Scientist Award from NIDA (DA00198).
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- LY274614
- MK-801, (+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate
- TPW
- thermal paw withdrawal
- i.t.
- intrathecal
- PKC
- protein kinase C
- Received August 19, 1998.
- Accepted December 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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