Studies on the Role of G Protein Alpha Subunits in Opioid Signaling and Behavior.

Opioids;Antinociception;G Proteins;Regulator of G Protein Signaling Proteins;Transgenic Mice;Dependence;Pharmacy and Pharmacology;Health Sciences;Pharmacology

Lamberts, Jennifer ThomsonJutkiewicz, Emily M. ;

University of Michigan

关键词: Opioids;    Antinociception;    G Proteins;    Regulator of G Protein Signaling Proteins;    Transgenic Mice;    Dependence;    Pharmacy and Pharmacology;    Health Sciences;    Pharmacology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/98076/jathom_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Opioids (e.g. morphine) are powerful analgesics that are used clinically to treat a variety of pain conditions. However, chronic use of opioids is associated with the development of adaptations such as tolerance and dependence, which limit their utility as long-term pain therapeutics. Opioids produce analgesia by activating mu opioid receptors that are located on both central and peripheral nerve terminals. The mu opioid receptor is a G protein-coupled receptor that activates inhibitory heterotrimeric G proteins composed of a G(alpha)i/o subunit and a (beta)(gamma) heterodimer via nucleotide exchange. Once activated, these G protein subunits modulate the activity of a number of downstream effectors, including adenylate cyclase and various ion channels. G protein signaling is terminated by the intrinsic GTP hydrolysis of the G(alpha) subunit, although this process is accelerated in vivo by regulator of G protein signaling (RGS) proteins. The goal of the work described in this thesis was to evaluate the role of G(alpha)o protein and its regulation by RGS proteins in opioid-mediated behaviors. G(alpha)o is the most abundant G(alpha)i/o subtype in the brain and has been shown to couple preferentially to the mu opioid receptor. In addition, individual RGS subtypes have been demonstrated to play important roles in opioid-mediated behaviors, but it is not known if endogenous RGS proteins exert their effects through direct binding to G(alpha)i/o subunits or by some other mechanism. To study this, opioid-mediated signaling and behaviors were measured in two different transgenic mouse models, one with a one with targeted knockout of G(alpha)o protein (G(alpha)o knockout mice) and the other with targeted knock-in of an RGS-insensitive mutant G(alpha)o protein (G(alpha)o RGSi mice). Together, these studies demonstrated that mu opioid receptor coupling to G(alpha)o is important for the production of opioid antinociception, and that RGS proteins regulate this response by directly interacting with G(alpha)o subunits. This work also showed that G(alpha)o is protective against morphine tolerance and dependence. Overall, these findings suggest that the RGS:G(alpha)o interface could be a potential target for the development of improved analgesics that are devoid of unwanted adaptations.