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Augmented responses to morphine and cocaine in mice with a 12-lipoxygenase gene disruption

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Abstract

Rationale

Recent studies have shown that pharmacological inhibition of the 12-lipoxygenase pathway selectively blocks opioid inhibition of GABAergic synaptic currents. A similar mechanism has been shown for the regulation of glutamate release in the ventral tegmental area (VTA) during acute withdrawal from morphine, although the functional significance of these effects in vivo are not known.

Objectives

We have utilized mice with a disruption of the "leukocyte-type" 12-lipoxygenase gene (12-LO−/− mice) to examine a variety of general behavioral responses as well as several specific responses to morphine and cocaine.

Methods

Behavioral responses to morphine include sensitivity to thermal stimuli and withdrawal from chronic morphine treatment. Responses to cocaine were measured through locomotor activity.

Results

General behavioral responses in 12-LO−/− mice are not different from their wild-type controls. However, these mutant mice showed enhanced morphine-induced analgesia. However, this effect is eliminated following chronic morphine treatment. In addition, 12-LO−/− mice demonstrated enhanced somatic signs of opiate withdrawal relative to littermate controls. Lastly, cocaine-mediated increases in locomotor activity was augmented acutely but not chronically in 12-LO−/− mice.

Conclusions

Together, these results suggest a role for metabolites of arachidonic acid metabolism in morphine- and cocaine-induced behavioral responses and may reflect a utilization of this pathway following acute but not chronic drug administration.

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Acknowledgement

This work was supported by National Institute on Drug Abuse Grant DA-11649–01A2.

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Authors and Affiliations

  1. Department of Pharmacology, 125 John Morgan Building, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA

    Carrie L. Walters, Bao-Cheng Wang, Misty Godfrey, Colin D. Funk & Julie A. Blendy

  2. Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA

    Duxin Sun & Colin D. Funk

Authors
  1. Carrie L. Walters
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  2. Bao-Cheng Wang
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  3. Misty Godfrey
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  4. Duxin Sun
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  5. Colin D. Funk
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  6. Julie A. Blendy
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Correspondence to Julie A. Blendy.

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Walters, C.L., Wang, BC., Godfrey, M. et al. Augmented responses to morphine and cocaine in mice with a 12-lipoxygenase gene disruption. Psychopharmacology 170, 124–131 (2003). https://doi.org/10.1007/s00213-003-1526-7

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  • DOI: https://doi.org/10.1007/s00213-003-1526-7

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