? This project investigates the changes in opioid metabolism and response that are caused by sickle cell anemia (SCA). It has been observed that patients experiencing a sickle cell-related pain episode respond poorly to opioid therapy. Two murine models of SCA have been developed and will be tested to determine their utility in addressing this aspect of the disease. To determine if poor opioid response is caused by increased opioid clearance, the expression of opioid metabolizing enzymes in human and mouse liver with and without SCA will be measured with gene arrays and quantitative (real time) RT-PCR. To determine if the mouse models are appropriate for studying SCA related pain and analgesia, the baseline nociceptive thresholds of these animals will be compared with wild type mice using von Frey monofilaments, grip force reduction, and thermal sensory response. To determine if SCA mouse models display poor opioid analgesic efficacy and/or reduced potency similar to that observed in humans, a second battery of tests will be performed on SCA and wild type mice that have been dosed with an opioid analgesic. ? ? ? ?
