Role of the guanine nucleotide binding protein, Gαo, in the development of morphine tolerance and dependence
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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.
The objective of the study is to evaluate the contribution of Gαo to the development of morphine tolerance and dependence in mice.
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.
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.
These data suggest that the guanine nucleotide binding protein Gαo offers some protection against the development of morphine tolerance and dependence.
KeywordsAntinociception G protein Morphine μ receptor Receptor binding Tolerance Withdrawal
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.
Compliance with ethical standards
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.
Conflict of interest
The authors declare that they have no conflict of interest.
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