Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice

Abstract

The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, vehicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.

Additive Effect of Dextromethorphan on the Inhibitory Effect of Anti-NT4 on Morphine Tolerance

“…4 ). These data are in line with other reports demonstrating reversal of morphine tolerance in rodents [16,28] . Dextromethorphan at 10 mg/kg did not affect the reversal of morphine tolerance.…”

“…In addition, doses of morphine (7 or 10 mg/kg) were selected based on our previous study [14] and other published findings [15,16] . The time separating the injections of morphine and dextromethorphan was determined based on published finding [17] .…”

Morphine Tolerance and Reward but not Expression of Morphine Dependence are Inhibited by the Selective Glutamate Carboxypeptidase II (GCP II, NAALADase) Inhibitor, 2-PMPA

“…Numerous subsequent studies revealed that coadministration of either competitive or noncompetitive NMDA receptor antagonists attenuate and/or reverse the development of tolerance to the antinociceptive effects of morphine. In the mouse, such effects have been shown for a number of NMDA receptor antagonists, including memantine (Lutfy et al, 1993;Elliott et al, 1994;Bilsky et al, 1996;Belozertseva and Bespalov, 1998;Gonzalez et al, 1997;Popik et al, 2000a). Similarly, the stimulation of presynaptic mGluRII receptors with (+)-2-aminobicyclo [3,1,0] hexane-2,6-dicarboxylic acid (LY354740) was shown to inhibit the development of morphine tolerance (Popik et al, 2000b).…”

“…Glutamate, a major excitatory neurotransmitter in the brain, stimulates both ionotropic and metabotropic glutamate receptors (Monaghan et al, 1989;Conn and Pin, 1997). Antagonists of the ionotropic N-methyl-d-aspartate (NMDA) receptor complex, including memantine, the low affinity, and highly voltage-dependent clinically available NMDA receptor antagonist, inhibit the development of morphine tolerance (Trujillo and Akil, 1991;Marek et al, 1991;Popik et al, 2000a) and reverse pre-existing tolerance so that opiatetolerant animals treated with NMDA receptor antagonists become sensitive to doses of morphine that previously did not evoke antinociception (Tiseo and Inturrisi, 1993;Popik et al, 2000a). Antagonists of this receptor complex also attenuate the development (Trujillo and Akil, 1991), expression (Cappendijk et al, 1993), and maintenance of the continuing morphine dependence.…”

Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

“…Perhaps our disparate results are attributable to differences between opiate tolerance in adult rodents (in which almost all of the NMDAR and opiate tolerance studies have been done) and the neonatal rats studied here. On the other hand, a review of the literature shows that even in adult animals only a small percentage of original studies reported experiments with NMDAR antagonists on tolerance expression (ϳ10 of 52 studies reviewed); of those, more than one-half have reported significant effects in inhibiting opiate analgesic tolerance expression with at least some doses of NMDAR antagonists (Tiseo and Inturrisi, 1993;Elliott et al, 1994;Shimoyama et al, 1996;McNally and Westbrook, 1998;Allen and Dykstra, 1999;Belozertseva et al, 2000;Popik et al, 2000). Some of these studies have been criticized because of motor (Carlezon et al, 2000) or sensory (Kozela and Popik, 2002) side effects produced by NMDAR antagonists including, in some studies, analgesia (Redwine and Trujillo, 2003) and morphine analgesia potentiation (Hoffmann and produces an inhibition of mEPSC frequency (from baseline frequency) in lamina I cells from spinal slices of opiate-naive neonatal rats that is reversed partially by removing NMDA from the bath (Wash) for 10 min.…”