Individuals who abuse drugs by intravenous administration are prone to a variety of health problems, including the development of neoplastic diseases. Both infection by human immunodeficiency viruses (HIV) and abuse of narcotic analgesics produce decreased immune responsiveness which could ead to the ensuing health sequela. It is not clear whether direct mutagenic or carcinogenic actions of opioids might also contribute to the observed disorders, as conflicting data exist on the genotoxicity of these agents. The demonstration that opioid use results in reduced DNA repair capacity has led to the suggestion by others that heroin may play a role as a tumor promoter. The ability of opioids to alter mitogenic response and function of lymphocytes also suggests narcotic analgesics have the potential to alter the response of these cells to chemical insult. There have been, however, no studies reported which address opioid potentiation of the genotoxicity of known chemical mutagens and clastogens. I propose to assess the ability of morphine to produce cytotoxicity, chromosome damage, and gene mutations in murine splenocytes. In addition, I will determine whether morphine administration augments the cytotoxicity and genotoxicity of mutagens known to produce a spectrum of DNA lesions. The effect of morphine on the extent of mutagen binding to DNA and on the repair of those lesions will also be examined. The cell-type specificity if any observed effect will be determined in defined populations of T and B lymphocyte . Further, narcotic antagonists will be employed to determine if the effects of morphine appear to be mediated through classical opioid receptors. Tests of immune competence will also be performed to determine whether genotoxicity is accompanied by alterations of T- and B-cell function. Although there is a strong correlation between HIV infection and acquired immunodeficiency syndrome (AIDS), AIDS-related diseases also occur in individuals with other risk factors, such as drug abuse, in whom HIV infection has not been demonstrated. The goal of the proposed studies is to define the role of chronic morphine administration on the production and/or potentiation of cytotoxic and genotoxic effects which may contribute to these diseases.
