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

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

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.

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

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.