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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.

“The Third Person in the Room: Servants and the Construction of Identity in the Eighteenth-Century Gothic Novel” explores the eighteenth-century Gothic novelists’ use of the stock servant character device to illustrate the tenuous nature of identity construction in a novelistic world torn between an admiration for its feudalistic past and a desire to embrace rising notions of individualism. I examine representations of real and literary servants to argue that the servant figure offers a convenient avenue for the discussion of class, social expectation, and economics, for as both family members and participants in the economy of the outside world, servants bridge the gap eighteenth-century authors find between their reclusive, feudalistic past and their social, individualistic present. Further, servants’ ties to the household associate them with the feminine perspective and provide authors, particularly authors of the Female Gothic, with a means of presenting the female voice in cases where it had otherwise been silenced by male oppression. In this work, I focus specifically on usurpation in Horace Walpole’s The Castle of Otranto¸ Robert Jephson’s The Count of Norbonne, and William Godwin’s Caleb Williams, maternal history in Clara Reeve’s The Old English Baron, Ann Radcliffe’s The Italian, and Sophia Lee’s The Recess, sexual surrogacy in Ann Radcliffe’s The Mysteries of Udolpho, and aristocratic criminalization in Charlotte Smith’s The Old Manor House. I examine these works in the context of eighteenth-century realistic literature, social criticism and historical frameworks as well as through the lens of current theoretical examinations of the eighteenth-century Gothic.