.....................................................................................................................................................................3 1. Background and Significance .............................................................................................................................4 1.1. The Cannabinoid System .................................................................................................................................4 1.1.1. History of Cannabinoids ...........................................................................................................................4 1.1.2. The Endocannabioid System ....................................................................................................................5 1.1.3. Cannabinoid Receptors .............................................................................................................................5 1.1.4. Pharmacology of CB drugs.......................................................................................................................6 1.1.5. Therapeutic Potential of Cannabinoids .....................................................................................................7 1.2. The Opioid System .....................................................................................................................................8 1.2.1. History of Opioids ....................................................................................................................................8 1.2.2. The Opioid System ...................................................................................................................................8 1.2.3. Clinical uses of opioids ............................................................................................................................9 1.3. Cannabinoids, Kappa Opioids and Diuresis ..................................................................................................10 2. Specific Aims ...................................................................................................................................................13 3. Materials and Methods .....................................................................................................................................14 3.1. Animals .........................................................................................................................................................14 3.2. Measurement of Diuresis ...............................................................................................................................14 3.3. Drugs .............................................................................................................................................................16 3.4. Statistical Methods ........................................................................................................................................17 4. Rationale, Research Strategy and Study Design ..............................................................................................18 4.1. Rationale ........................................................................................................................................................18 4.2. Research Strategy ..........................................................................................................................................18 4.3. Study Design .................................................................................................................................................19 5. Results ..............................................................................................................................................................20 5.1. Validating Cannabinoid mediated diuresis in mice .......................................................................................20 5.2. Validating Kappa Opioid mediated diuresis in mice .....................................................................................22 5.3. Effects of Chronic THC dosing on the diuretic dose response of the CB1 agonist, AM4054 ......................24 5.4. Effects of Chronic THC dosing on the diuretic dose response of the kappa opioid, U50488 .......................27 5.5. Effects of Chronic THC dosing on diuretic dose response of furosemide ....................................................31 6. Discussion.........................................................................................................................................................33 7. Conclusions ......................................................................................................................................................37 8. Bibliography .....................................................................................................................................................38