Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice

Abstract

Objective: To study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice. Methods: Different doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm. Results: MRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice. Conclusion: Based on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.

REVIEW ON CPP: Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade

“…Kotlinska & Biala (2000) also showed that ACPC (50 mg/kg ip) and memantine (7.5 mg/kg ip) did not produce an effect. The glycinB‐site antagonist MRZ 2/576 (1.25, 2.5, 5 mg/kg ip) also did not produce an effect (Zhu et al . 2006).…”

“…The acquisition and expression of morphine (5 mg/kg ip)‐induced CPP were also blocked by L‐701,324 administered at 5 mg/kg po, but not at 2.5 mg/kg po (Kotlinska & Biala 1999). Likewise, both acquisition and expression of morphine (5 mg/kg ip)‐induced CPP were blocked by the glycinB‐site antagonist MRZ 2/576 (5, but not 1.25 and 2.5 mg/kg ip) (Zhu et al . 2006).…”

Endogenous opiates and behavior: 2009

“…Intra-ventral pallidal glutamate antagonists block expression of morphine-induced CPP (258). The glycine site/ NMDA receptor antagonist, MRZ2/576, reduced the acquisition and expression of CPP and locomotor activity induced by morphine in mice (1330). Ventricular administration of a neuropeptide FF agonist blocked the acquisition of a morphine CPP (724).…”

Current approaches with the glutamatergic system as targets in the treatment of neuropathic pain

“…Some of them are found to be therapeutically active, but are associated with side effects like psychomimetic symptoms, cognitive impairment, dizziness and sedation [7,48]. Newer approaches have been identified to overcome these side effects, which include, inhibiting other binding sites of NMDA receptor like the NR2B, glycine B site [49][50][51][52][53][54][55][56][57][58][59][60][61][62], targeting other receptors like AMPA [63][64][65][66][67], kainate [68][69][70][71][72] and mGluR1 -5 [73][74][75][76][77][78][79][80][81][82], enhancing the activity of glutamate transporters that sequester the extracellular glutamate [23,24,83] and inhibiting glutamate release by designing various enzyme inhibitors [84][85][86][87][88][89][90][91...…”

“…Mrz2/576 (20, Figure 4) a tricyclic pyrido-phthalazine-dione derivative has shown good analgesic activity for chronic pain and other diseases with an outstanding systemic availability and penetration of the blood-brain barrier [61]. L-701324 (21, Figure 4) and 5,7-dichlorokinurenic acid (5,7-DCK, 22, Figure 4) were studied in animal models of neuropathic pain and were found to be effective in reducing cold allodynia in CCI animals and tactile allodynia in animals with SNL [62].…”