The overall objective of this project continues to be the elucidation of the mechanism of action of morphine and other opiate analgesics. A secondary objective is to determine the role of endogenous opioid peptides in various respiratory diseases of children and infants. We have found that children who have apnea as a part of their symptomatology have an increased level of endogenous opioid peptide in their cerebrospinal fluid. We now propose to expand our preliminary results which show that naltrexone, an opiate antagonist, is efficacious in treatment of the disease in these children. We further will explore whether other endogenous opioid peptides, such as met-enkephalin, leu-enkephalin, and dynorphin, are also elevated and a causative factor in the disease of these patients. We will continue to develop an animal model for these diseases which will be essential to evaluate the etiology of the disease and mechanism of action of naltrexone. The second portion of this proposal has to do with our demonstration that the intrathecal injection of mice with morphine produces a pronounced hypoglycemia. This was a surprising observation, since morphine administered by any other route of administration produces hyperglycemia. We will continue to investigate the mechanisms of disappearance of glucose from the blood following the intrathecal injection of opiates. Thirdly, we propose to continue our investigation into the role of intracellular calcium in the mechanism of action of morphine. It has been shown by others and ourselves that morphine alters calcium homeostasis in both the drug-naive animal as well as in the opiate-tolerant animal. These investigations will continue. The work described in this proposal has both theoretical and practical applications. The calcium and glucose experiments will add greatly to our knowledge of the effects of morphine in living organisms, while our studies with the endogenous opioid peptides will be beneficial to the treatment of children with various diseases characterized at least in part by apnea.
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