title: Theoretical analysis of a morphine withdrawal phenotype in a cultured cell line.
abstract: We have previously described a delta-opioid receptor-expressing cultured cell line that proliferates in a defined medium and responds to chronic morphine treatment with an inhibition of its rate of proliferation. To help provide an explanation for this behavior, we have used computer simulation of cell cycle kinetics to analyze the observed rates of proliferation of these cells in the presence and absence of morphine, and after withdrawal of morphine treatment. We questioned whether the difference in cell kinetics observed for the cell populations under the different treatments could be due to changes in the length of the cell cycle, withdrawal of cells from the cycle into a quiescent state, or differences in cell renewal. This was investigated by comparing observed cell numbers as a function of time with the results of different computer simulations using different values for these parameters. We found that we can provide a satisfactory explanation of the experimental observations on the basis of changes in a small set of parameters: Untreated cells experience a slowdown of cell proliferation at about the culture density where multiple cell-cell contacts are made and, beginning then, a large fraction are shunted from G1 into a quiescent state. Chronic morphine treatment inhibits proliferation by slowing passage through G1, but the cells remain as sensitive to cell-cell contacts as the untreated cells. After drug withdrawal following a 6 day treatment with morphine, the cells exhibit a large temporary increase in their rate of proliferation compared with control or chronically treated cells but about 48 hours after withdrawal, when cell-cell contacts just begin to be made, the cells return to almost their pre-treatment total cell cycle time and, as before, a large fraction are shunted into a quiescent state. Taken in conjunction with previously published results, the present ones indicate a possible interaction between morphine-induced and insulin-induced nuclear signaling pathways to the nucleus.
authors.affiliation: Department of Biochemistry, University of Connecticut Health Center, Farmington 06030, USA. glasel@panda.uchc.edu
authors.forename: J A
authors.initials: JA
authors.lastname: Glasel
authors.forename: D
authors.initials: D
authors.lastname: Agarwal
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle; D003198:Computer Simulation; D051379:Mice; D008954:Models, Biological; D009020:Morphine / Q000009:adverse effects*; D013375:Substance Withdrawal Syndrome
chemical_list: D009020:Morphine