Browsing by Subject "Morphine withdrawal"

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    Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: Role of corticotropin-releasing factor (CRF) 1 receptor
    (Elsevier, 2014-01-05) Navarro Zaragoza, Javier; Martínez Laorden, Elena; Mora, L.; Hidalgo, J.; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología
    Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts.
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    Crosstalk between G protein-coupled receptors (GPCRs) and tyrosine kinase receptor (TXR) in the heart after morphine withdrawal
    (2013-12-27) Almela Rojo, Pilar; García-Carmona, Juan-Antonio; Martínez Laorden, Elena; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología
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    Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons
    (Wiley, 2013-08-08) García Pérez, Daniel; López Bellido, Roger; Hidalgo, Juana M.; Rodríguez, Raquel E.; Núñez Parra, Cristina; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultades de la UMU::Facultad de Medicina
    Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction.
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    Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius-A2 catecholaminergic neurons
    (Wiley, 2009-08-10) Martín Sánchez, María Rosario Fátima; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología
    The transcription factor cAMP response element binding protein (CREB) has been implicated in the actions of drugs of abuse in several brain areas. However, little is known about CREB regulation in the nucleus tractus solitarius (NTS)-A2 catecholaminergic cell group, one of the key regions of the brain stress system. Morphine withdrawal modulates gene expression in the NTS through various second- messenger signal transduction systems including activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase C (PKC). In the current study we used immunoblotting and immunohistochemistry to investigate changes in CREB phosphorylation in the NTS and kinases that may mediate the morphine withdrawal-triggered activation of CREB and hypothalamo- pituitary-adrenocortical (HPA) axis (another stress system circuit) response after naloxone-induced morphine withdrawal. We found an increased phosphorylation of REB (pCREB) selectively within tyrosine hydroxylase (TH) immunoreactive neurons in the NTS from morphine- withdrawn rats, which parallel elevated corticosterone levels. We also measured expression levels of TH and phosphorylated ERK1/2 (pERK1/2), and found that both are up-regulated following morphine withdrawal. SL327, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK1/2 levels, did not attenuated the rise in pCREB and TH immunoreactivity or plasma corticosterone secretion during morphine withdrawal, indicating that ERK kinase/ERK pathway was not directly needed for either activation of CREB and TH expression in the NTS or HPA axis hyperactivity. In contrast, PKC inhibitor calphostin C reduced the withdrawal-triggered rise in pCREB, pERK1/2, TH expression and corticosterone secretion. The results indicate that PKC mediates both CREB activation and HPA response by morphine withdrawal and might suggest that CREB activation in the NTS is related to TH expression associated with morphine withdrawal.
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    Naloxone-induced conditioned place aversion score and extinction period are higher in C57BL/6J morphine-dependent mice than in Swiss: Role of HPA axis.
    (Elsevier, 2021-01-02) Navarro Zaragoza, Javier; Martínez Laorden, Elena; Teruel Fernández, Francisco Javier; Gómez Murcia, Victoria; Cánovas Cabanes, Alberto; Milanés Maquilón, María Victoria; Laorden Carrasco, María Luisa; Almela Rojo, Pilar; Farmacología
    Intense associative memories develop between drug-paired contextual cues and the drug withdrawal associated aversive feeling. They have been suggested to contribute to the high rate of relapse. Our study was aimed to elucidate the involvement of hypothalamic-pituitary-adrenocortical (HPA) axis activity in the expression and extinction of aversive memory in Swiss and C57BL/6J (B6) mice. The animals were rendered dependent on morphine by i.p. injection of increasing doses of morphine (10–60 mg/kg). The negative state associated with naloxone (1 mg/kg s.c.) precipitated morphine withdrawal was examined by using conditioned place aversion (CPA) paradigm. B6 mice obtained a higher aversion score and took longer to extinguish the aversive memory than Swiss mice. In addition, corticosterone levels were increased after CPA expression. Moreover, corticosterone levels were decreased during CPA extinction in Swiss mice without changes in B6 mice. Pre-treatment with the selective CRF1 receptor antagonist CP-154,526 before naloxone, impaired morphine-withdrawal aversive memory acquisition and decreased the extinction period. CP-154,526 also antagonized the increased levels of corticosterone observed after CPA expression in Swiss mice, without any changes in B6 mice. These results indicate that HPA axis could be a critical factor governing opioid withdrawal memory storage and retrieval, but in a strain or stock-specific manner. The differences observed between Swiss and B6 mice suggest that the treatment of addictive disorders should consider different individual predisposition to associate the aversive learning with the context.