AuthorWild, Kenneth Douglas.
Committee ChairPorreca, Frank
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe central hypothesis of this dissertation is that agonists acting at opioid δ or κ (but not μ) receptors may be useful for the production of effective pain relief with decreased incidence of side-effects, as well as for the possible treatment of drug-addiction. This dissertation focused on differentiating subtypes of the δ as well as the κ opioid receptor to provide selective targets for drug-development. Studies of the opioid δ receptor in vivo indicated that agonists at opioid δ receptor subtypes (δ₁ and δ₂) may produce antinociception via activation of different second messenger pathways. A study using the mouse isolated vas deferens (MVD), a bioassay in vitro for δ receptors, demonstrated that the MVD contains only one functional δ receptor which is of the δ₂ subtype. A thermodynamic study of radioligand binding in vitro demonstrated that there were fundamental differences in the way [³H]naltrindole, a δ-antagonist, bound to δ receptors in the brain compared to the spinal cord. Another study of radioligand binding using brain membranes from the ground squirrel hibernator ( C. lateralis) directly identified subtypes of δ receptor in the brain of this species, providing further evidence for the existence of δ receptor subtypes and possibly identifying a procedure which could be used to determine the selectivity of drug candidates for these subtypes. Studies of the opioid κ receptor were also performed in vitro using bioassays and radioligand binding. Studies using bioassays demonstrated that differences in efficacy among several κ-agonists could not explain examples of differential antagonism seen in studies in vivo. Radioligand binding studies made use of a non-equilibrium antagonist, though to produce differential antagonism in vivo, to demonstrate that binding of κ receptor radioligands could be differentially blocked by the non-equilibrium antagonist. These studies support the existence of κ receptor subtypes and provide a convenient way of determining the affinity of a drug-candidate at these subtypes. Taken as a whole, this dissertation has provided strong evidence for the existence of subtypes of both the opioid δ and κ receptors and described methodology for the determination of the selectivity of drug candidates for these subtypes. Hopefully, development of such compounds will allow for the production of analgesia in the absence of undesirable side-effects or for the improved treatment of drug-addiction.
Degree ProgramPharmacology & Toxicology