title: Long term effects of morphine on mesangial cell proliferation and matrix synthesis.
abstract: Since focal glomerulosclerosis is the predominant glomerular lesion in heroin nephropathy and since mesangial expansion is considered to be a precursor of glomerulosclerosis, we have evaluated the effect of opiates on mesangial cell (MC) proliferation and matrix synthesis. We showed, using a fluorometric assay, that MC are not capable of metabolizing heroin to its active metabolite morphine. Cells exposed to morphine (10(-5) M or 10(-4) M) in prolonged cultures either continuously (Group A) or intermittently (Group B) showed enhanced incorporation of [3H]thymidine when compared to control cells (control, 88600 +/- 26303 cpm/well vs. morphine 10(-4) M-Group A, 321203 +/- 52867, P less than 0.001; control vs. morphine 10(-4) M-Group B, 223126 +/- 46866 cpm/well, P less than 0.01; control, 107593 +/- 42284 cpm/well vs. morphine 10(-5) M - Group A, 267108 +/- 41866 cpm/well, P less than 0.001; control vs. morphine 10(-5) M - Group B, 202317 +/- 24325 cpm/well, P less than 0.05). However, MC incubated with a lower concentration of morphine (10(-6) M) enhanced DNA synthesis when exposed intermittently only (control, 107593 +/- 42284 cpm/well vs. Group B, 219164 +/- 15552 cpm/well, P less than 0.05). This growth stimulating effect of morphine (10(-6) M and 10(-5) M) was also observed at earlier time points, that is, one- and one-and-a-half-week old cultures. However, in one-week-old cultures. morphine in a higher concentration (10(-4) M) showed a suppressive effect (P less than 0.05) on MC proliferation (morphine, 3620 +/- 220 cpm/well vs. control, 4668 +/- 410 cpm/well). This effect not only subsided by one and a half weeks but morphine (10(-4) M) treated cells enhanced MC proliferation. An opioid antagonist, naloxone attenuated the effect of morphine in one and half week old cultures. Morphine at 10(-6) M to 10(-4) M concentrations enhanced incorporation of [3H]proline in the extracellular proline pool (a component of mesangial matrix) when compared to control (control, 309661 +/- 3992 vs. morphine 10(-4) M, 363104 +/- 10539 cpm/well, P less than 0.05 or morphine 10(-5) M, 397954 +/- 31008 cpm/well, P less than 0.001 or morphine 10(-6) M, 384630 +/- 26369 cpm/well, P less than 0.01). In addition, MC incubated with morphine (10(-6) M and 10(-4) M) also enhanced (P less than 0.001) synthesis of laminin.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York.
authors.forename: P C
authors.initials: PC
authors.lastname: Singhal
authors.forename: N
authors.initials: N
authors.lastname: Gibbons
authors.forename: M
authors.initials: M
authors.lastname: Abramovici
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced; D007797:Laminin / Q000096:biosynthesis; D008855:Microscopy, Electron, Scanning; D009020:Morphine / Q000633:toxicity*; D009270:Naloxone / Q000494:pharmacology; D011392:Proline / Q000378:metabolism
chemical_list: D007797:Laminin; D009270:Naloxone; D009020:Morphine; D011392:Proline; D015232:Dinoprostone