Jennifer T Lamberts1,2, Lisa D Rosenthal1, Emily M Jutkiewicz1, John R Traynor3. 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. 2. College of Pharmacy, Ferris State University, Big Rapids, MI, 49307, USA. 3. 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. jtraynor@umich.edu.
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.
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.
Authors: Jennifer T Lamberts; Emily M Jutkiewicz; Richard M Mortensen; John R Traynor Journal: Neuropsychopharmacology Date: 2011-06-08 Impact factor: 7.853
Authors: Leon W Fyfe; Daniel R Cleary; Tara A Macey; Michael M Morgan; Susan L Ingram Journal: J Pharmacol Exp Ther Date: 2010-08-25 Impact factor: 4.030
Authors: Elmer Yu; Karen Miotto; Evaristo Akerele; Ann Montgomery; Ahmed Elkashef; Robert Walsh; Ivan Montoya; Marian W Fischman; Joseph Collins; Frances McSherry; Kathy Boardman; David K Davies; Charles P O'Brien; Walter Ling; Herbert Kleber; Barbara H Herman Journal: Drug Alcohol Depend Date: 2008-05-27 Impact factor: 4.492
Authors: Jennifer T Lamberts; Chelsea E Smith; Ming-Hua Li; Susan L Ingram; Richard R Neubig; John R Traynor Journal: J Neurosci Date: 2013-03-06 Impact factor: 6.167
Authors: Rahul S Guda; Katherine E Odegaard; Chengxi Tan; Victoria L Schaal; Sowmya V Yelamanchili; Gurudutt Pendyala Journal: Int J Mol Sci Date: 2021-06-15 Impact factor: 5.923