Psychopharmacology · 2017
Role of the guanine nucleotide binding protein, Gαo, in the development of morphine tolerance and dependence.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Lamberts Jennifer T, Rosenthal Lisa D, Jutkiewicz Emily M, Traynor John R
Аннотация
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.
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.