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Role of the guanine nucleotide binding protein, Gαo, in the development of morphine tolerance and dependence

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Abstract

Rationale

The use of morphine and other opioids for chronic pain is limited by the development of analgesic tolerance and physical dependence. Morphine produces its effects by activating the μ opioid receptor, which couples to Gαi/o-containing heterotrimeric G proteins. Evidence suggests that the antinociceptive effects of morphine are mediated by Gαo. However, the role of Gαo in the development of morphine tolerance and dependence is unknown.

Objective

The objective of the study is to evaluate the contribution of Gαo to the development of morphine tolerance and dependence in mice.

Methods

129S6 mice lacking one copy of the Gαo gene (Gαo +/−) were administered morphine acutely or chronically. Mice were examined for tolerance to the antinociceptive action of morphine using the 52 °C hot plate as the nociceptive stimulus and for dependence by evaluating the severity of naltrexone-precipitated withdrawal. Wild-type littermates of the Gαo +/− mice were used as controls. Changes in μ receptor number and function were determined in midbrain and hindbrain homogenates using radioligand binding and μ agonist-stimulated [35S]GTPγS binding, respectively.

Results

Following either acute or chronic morphine treatment, all mice developed antinociceptive tolerance and physical dependence, regardless of genotype. With chronic morphine treatment, Gαo +/− mice developed tolerance faster and displayed more severe naltrexone-precipitated withdrawal in some behaviors than did wild-type littermates. Morphine tolerance was not associated with changes in μ receptor number or function in brain homogenates from either wild-type or Gαo +/− mice.

Conclusions

These data suggest that the guanine nucleotide binding protein Gαo offers some protection against the development of morphine tolerance and dependence.

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Acknowledgements

This work was supported by R01 DA035316. JTL was supported by a pre-doctoral fellowship from the PhRMA Foundation and by training grants DA007267 and GM007767. The authors wish to acknowledge Claire Meurice, Joe Guel, and Jasmine Schimmel for technical support and animal care.

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  1. Jennifer T. Lamberts

    Present address: College of Pharmacy, Ferris State University, Big Rapids, MI, 49307, USA

Authors and Affiliations

  1. Department of Pharmacology and Edward F. Domino Research Center, University of Michigan Medical School, 1150 W. Medical Center Dr., 1301 MSRB III, Ann Arbor, MI, 48109-5632, USA

    Jennifer T. Lamberts, Lisa D. Rosenthal, Emily M. Jutkiewicz & John R. Traynor

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  1. Jennifer T. Lamberts
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  2. Lisa D. Rosenthal
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  3. Emily M. Jutkiewicz
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Corresponding author

Correspondence to John R. Traynor.

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All protocols were approved by the University of Michigan Committee on the Use and Care of Animals and experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the National Institutes of Health.

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The authors declare that they have no conflict of interest.

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Highlights

• Morphine tolerance and dependence occur 129S6 mice

• Gαo heterozygous null mice develop morphine tolerance more quickly than wild type

• Withdrawal from chronic morphine is more severe in Gαo heterozygous null mice

• Chronic morphine does not alter μ-opioid agonist activation of G proteins in brain membranes

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Lamberts, J.T., Rosenthal, L.D., Jutkiewicz, E.M. et al. Role of the guanine nucleotide binding protein, Gαo, in the development of morphine tolerance and dependence. Psychopharmacology 235, 71–82 (2018). https://doi.org/10.1007/s00213-017-4742-2

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  • DOI: https://doi.org/10.1007/s00213-017-4742-2

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