Induction of micronuclei in murine lymphocytes by morphine

Abstract

Although individuals who abuse drugs are prone to an increased risk of malignancy, the mutagenic and carcinogenic potential of these agents has received relatively little attention. We report here on the potential of morphine to induce micronuclei in murine lymphocytes. Following a single intraperitoneal injection of 20 mg/kg morphine, the frequency of micronucleated binuclear (cytochalasin-blocked) murine T- and B-splenocytes was elevated from 12-36 hr after treatment. The maximum frequencies seen 24 hr after injection were 6.3- and 4.9-fold greater than the respective controls. A dose-dependent induction of micronuclei was observed from 5-20 mg/kg morphine, with no further increases in frequency produced by higher doses. In contrast, incubation of mitogen-stimulated splenocytes with 10(-7)-10(-4) M morphine in vitro produced no change in frequency of micronucleated cells relative to controls. Treatment with the narcotic antagonist naloxone (5 mg/kg) alone had no effect on the frequency of micronuclei, but reduced the clastogenic response of a subsequently administered dose of morphine (20 mg/kg). Thus, in murine lymphocytes morphine indirectly produces genetic damage, which is at least in part opioid receptor-mediated.

Genetic toxicology of abused drugs: a brief review

“…Although only limited information is available, there is evidence that in vivo administration of morphine to mice can increase the frequency of chromosome aberrations in bone marrow cells (Swain et al, 1980) and induce micronuclei in bone marrow cells and lymphocytes (Das and Swain, 1982;Sawant and Couch, 1995). In contrast, in vitro morphine treatment has failed to induce chromosome aberrations in cultured human lymphocytes (Falek et al, 1972) or micronuclei in mitogen-stimulated murine splenocytes (Sawant and Couch, 1995). It is therefore reasonable to assume that metabolic activation is involved in the induction of chromosome aberrations or micronuclei.…”

“…Furthermore, morphineinduced micronuclei in mice can be reduced by naloxone, an opioid antagonist, indicating that this genetic damage is at least in part opioid receptor mediated. Although the principal metabolite of morphine in vivo, morphine-3-glucuronide (Glare and Walsh, 1991), does not participate in receptor-mediated responses, the possibility of the involvement of other metabolites cannot be ruled out (Sawant and Couch, 1995). Mutagenic effects of morphine were not observed in Drosophila.…”

Cytogenetic Evaluation of the Genotoxicity in Cultured Lymphocytes of Some Tramadol-Dependent Egyptians

“…Moreover, administration of morphine to mice produced doserelated increases in the frequencies of micronucleated cells and sister chromatid exchanges in bone marrow cells in vivo, suggesting its genotoxic effect. The damage appears to arise by an indirect mechanism, as incubation of isolated human or mouse lymphocytes with morphine in vitro does not increase the frequency of chromosomal aberrations or micronucleated cells indicating that the genotoxic response is opioid receptor-mediated (Sawant and Couch., 1995). Moreover, results in the mouse lymphoma assay indicated an in vitro genotoxic activity for tramadol at toxic doses.…”

Scientific Opinion on the risks for public health related to the presence of opium alkaloids in poppy seeds

“…A role of glucocorticoids in these effects was strongly suggested, as plasma from morphine-treated animals (20 mg/kg i.p.) induces micronuclei formation in naïve lymphocytes in vitro, and this response is blocked by the steroid antagonist RU486 (Couch and Sawant, 1995). Shuey et al (2007) indicate that the increases induced by oxymorphone (also binding to the same μopiate receptor) in micronuclei might occurr secondary to hyperthermia, and not due to a direct genotoxic effect of morphine.…”