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NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats

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Abstract

Rationale

N-Methyl-d-aspartate (NMDA) receptors have an important role in different forms of behavioral and neural plasticity. Evidence suggests that these receptors may also be involved in plasticity arising from long-term treatment with different drugs of abuse, including tolerance, sensitization, and physical dependence. There is abundant evidence demonstrating that NMDA receptors are involved in tolerance to opiate-induced antinociception; however, the role of these receptors in sensitization to the locomotor effects of opiates is more controversial.

Objective

The ability of NMDA receptor antagonists to modify the development of sensitization to the locomotor stimulant effect of three different opiates was examined. In selected studies, the ability of the antagonists to modify tolerance to the antinociceptive effects of the opiates was also examined.

Materials and methods

Adult male Sprague–Dawley rats were used to assess the effects of NMDA receptor antagonists (MK-801, memantine or LY235959) on tolerance and sensitization to three opiates: morphine, methadone, or buprenorphine. It was predicted that low, selective doses of the antagonists would inhibit the development of opiate tolerance and sensitization.

Results

Consistent with our predictions, the noncompetitive NMDA receptor antagonists MK-801 and memantine and the competitive NMDA receptor antagonist LY235959 inhibited the development of sensitization to the locomotor stimulant effect of morphine. Additionally, MK-801 inhibited the development of tolerance and sensitization to methadone and buprenorphine in a similar manner.

Conclusions

The results, together with previous research, suggest that NMDA receptors are broadly involved in opiate-induced plasticity, including the development of opiate tolerance and sensitization.

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Acknowledgment

This research was supported by the National Institute on Drug Abuse (DA 19859), the National Institute of General Medical Sciences (GM 59833), and the Office for Biomedical Research and Training at California State University San Marcos. Ian Mendez was supported by the National Institute of General Medical Sciences (GM 64783). We would like to thank Kathleen Warmoth for the expert technical assistance and Jon Athancio for the help with the graphing.

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  1. Ian A. Mendez

    Present address: Department of Psychology, Texas A & M University, TAMU 4235, College Station, TX, 77843, USA

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  1. Department of Psychology, California State University, 333 S. Twin Oaks Valley Road, San Marcos, CA, 92096-0001, USA

    Ian A. Mendez & Keith A. Trujillo

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  1. Ian A. Mendez
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  2. Keith A. Trujillo
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Correspondence to Keith A. Trujillo.

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Mendez, I.A., Trujillo, K.A. NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats. Psychopharmacology 196, 497–509 (2008). https://doi.org/10.1007/s00213-007-0984-8

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  • DOI: https://doi.org/10.1007/s00213-007-0984-8

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