Work in my laboratory is directed towards testing a model of the opioid receptors sufficiently complex enough to explain varied physiological data. This model postuates a receptor complex consisting of adjacent and interacting mu, delta and kappa bindings sites, as well as distinct mu, delta and kappa receptors not associated with the receptor complex. To test this model we utilize several techniques: (1) quantitative ligand binding studies using the method of """"""""binding surface analysis"""""""" and weighted nonlinear least squares curve fitting, (2) site-directed alkylating agents such as BIT (mu-directed), FIT (delta-directed) and beta-FNA (mu-directed), (3) receptor autoradiography to provide anatomic information, (4) """"""""in-vivo"""""""" manipulations such as chronic morphine and chronic naltrexone which up-relate opiate receptors and (5) biochemical information using a technique to cross-link 125 I-beta endorphin to opiate receptors. As our work progress, not only is the model tested, but additional data is generated. Our work addresses fundamental issues of morphine tolerance and dependence. It has defined the opiate receptors labeled by (3H) cycloFOXY, a novel antagonist suitable for position emission tomography. We have developed methods for measuring rat brain kappa receptors, a subtype of the opiate receptor implicated in eating disorders and work is underway to develop a kappa-directed site-directed alyklating agent.
