title: Pioglitazone potentiates development of morphine-dependence in mice: possible role of NO/cGMP pathway.
abstract: Peroxizome proliferator-activated receptor gamma (PPARγ) is highly expressed in the central nervous system where it modulates numerous gene transcriptions. Nitric oxide synthase (NOS) expression could be modified by simulation of PPARγ which in turn activates nitric oxide (NO)/soluble guanylyl-cyclase (sGC)/cyclic guanosine mono phosphate (cGMP) pathway. It is well known that NO/cGMP pathway possesses pivotal role in the development of opioid dependence and this study is aimed to investigate the effect of PPARγ stimulation on opioid dependence in mice as well as human glioblastoma cell line. Pioglitazone potentiated naloxone-induced withdrawal syndrome in morphine dependent mice in vivo. While selective inhibition of PPARγ, neuronal NOS or GC could reverse the pioglitazone-induced potentiation of morphine withdrawal signs; sildenafil, a phosphodiesterase-5 inhibitor amplified its effect. We also showed that nitrite levels in the hippocampus were significantly elevated in pioglitazone-treated morphine dependent mice. In the human glioblastoma (U87) cell line, rendered dependent to morphine, cAMP levels did not show any alteration after chronic pioglitazone administration while cGMP measurement revealed a significant rise. We were unable to show a significant alteration in neuronal NOS mRNA expressions by pioglitazone in mice hippocampus or U87 cells. Our results suggest that pioglitazone has the ability to enhance morphine-dependence and to augment morphine withdrawal signs. The possible pathway underlying this effect is through activation of NO/GC/cGMP pathway.
authors: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
authors: Shiva
authors: S
authors: Javadi
authors: Shahram
authors: S
authors: Ejtemaeimehr
authors: Hamid Reza
authors: HR
authors: Keyvanfar
authors: Peiman
authors: P
authors: Moghaddas
authors: Atefeh
authors: A
authors: Aminian
authors: Alaleh
authors: A
authors: Rajabzadeh
authors: Ali R
authors: AR
authors: Mani
authors: Ahmad Reza
authors: AR
authors: Dehpour
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008297:Male; D051379:Mice; D009021:Morphine Dependence / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009270:Naloxone / Q000633:toxicity; D009292:Narcotic Antagonists / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger; D015398:Signal Transduction / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism; D045162:Thiazolidinediones / Q000009:adverse effects*; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D009292:Narcotic Antagonists; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D009569:Nitric Oxide; D009270:Naloxone; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D000077205:Pioglitazone