The immunomodulatory actions of opiates have been implicated as significant cofactors in the immune deficiencies of opiate addicts and their vulnerability to opportunistic infections, including AIDS. To date, no clear explanation of the mechanism for the immunomodulation has emerged although binding sites for naloxone, B-endorphin, met5-enkephalin and bremazocine have been reported to exist on lymphoid cell membranes. These binding sites are significantly different in ligand specificity and avidity from the opiate receptors of the central nervous system (CNS). To investigate the mechanism of lymphocyte/opiate interactions, three general methodologies will be employed. First, because nonactivated cells lack binding sites for such immunomodulators as morphine, human peripheral T lymphocytes will be activated to cell division with general mitogens or receptor specific agents to see if activation stimulates the presence of binding sites for morphine and naloxone. Second, the location, nature and specificity of a high affinity, naloxone reversible binding site will be studied on lymphocyte subcellular fractions obtained by centrifugation and characterized by specific enzyme and opiate binding assays, Third, the ability of T lymphocytes to take up morphine will be studied to see whether a pathway of internalization followed by binding provides the explanation for the failure to detect membrane surface binding. These three methodologies will be used to define a binding site (receptor) for morphine to parallel its naloxone reversible immunomodulatory properties. Once evidence of morphine contact is defined in terms of mitogen activated versus nonactivated cells, surface binding versus uptake, and the subcellular location of maximal binding, then the specificity and avidity of this interaction can be assessed by pharmacologic methods using ligands of known receptor specificity in the CNS. These experiments are important because no data currently exist to explain the mechanism of morphine's interaction with lymphocytes, yet morphine is the most used drug for demonstrating in vitro immune/opiate effects and the opiate most relevant to street opiate addiction. Finally, knowledge of the ligand specificity would be important in the design of anesthetics without immune effects.
| Madden, J J; Ketelsen, D; Whaley, W L et al. (1995) Mitogenic activation of human T lymphocytes induces a high affinity morphine binding site. Adv Exp Med Biol 373:37-40 |
| Madden, J J; Ketelsen, D; Whaley, W L (1993) Morphine binding sites on human T lymphocytes. Adv Exp Med Biol 335:61-6 |
| Madden, J J; Falek, A (1991) The use of nonneuronal cells as an in vitro model system for studying the genetic component of cellular response to opiates and other drugs of abuse. J Addict Dis 10:229-38 |
| Madden, J J; Falek, A; Donahoe, R et al. (1990) Opiate binding sites on cells of the immune system. NIDA Res Monogr 105:103-8 |
