Global Changes in the Rat Heart Proteome Induced by Prolonged Morphine Treatment and Withdrawal

Abstract

Morphine belongs among the most commonly used opioids in medical practice due to its strong analgesic effects. However, sustained administration of morphine leads to the development of tolerance and dependence and may cause long-lasting alterations in nervous tissue. Although proteomic approaches enabled to reveal changes in multiple gene expression in the brain as a consequence of morphine treatment, there is lack of information about the effect of this drug on heart tissue. Here we studied the effect of 10-day morphine exposure and subsequent drug withdrawal (3 or 6 days) on the rat heart proteome. Using the iTRAQ technique, we identified 541 proteins in the cytosol, 595 proteins in the plasma membrane-enriched fraction and 538 proteins in the mitochondria-enriched fraction derived from the left ventricles. Altogether, the expression levels of 237 proteins were altered by morphine treatment or withdrawal. The majority of changes (58 proteins) occurred in the cytosol after a 3-day abstinence period. Significant alterations were found in the expression of heat shock proteins (HSP27, α-B crystallin, HSP70, HSP10 and HSP60), whose levels were markedly up-regulated after morphine treatment or withdrawal. Besides that morphine exposure up-regulated MAPK p38 (isoform CRA_b) which is a well-known up-stream mediator of phosphorylation and activation of HSP27 and α-B crystallin. Whereas there were no alterations in the levels of proteins involved in oxidative stress, several changes were determined in the levels of pro- and anti-apoptotic proteins. These data provide a complex view on quantitative changes in the cardiac proteome induced by morphine treatment or withdrawal and demonstrate great sensitivity of this organ to morphine.

Continuous High Frequency Deep Brain Stimulation of the Rat Anterior Insula Attenuates the Relapse Post Withdrawal and Strengthens the Extinction of Morphine Seeking

“…Our proteomic analysis reveals that 17 proteins are differentially expressed in the anterior insula after 8-day morphine exposure and subsequent withdrawal as compared with saline-treated rats. Previous studies have reported that the expression levels of four DEPs (CaM kinase-like vesicle-associated protein, Guanine nucleotide-binding protein G[olf] subunit alpha, Serine protease inhibitor A3K, Striated muscle-specific serine/threonine-protein kinase) are altered in the brain or heart by morphine treatment and withdrawal ( 57 – 59 ). The rest of 13 DEPs are not identified in the Morphinome Database ( addiction-proteomics.org ) which includes the morphine-regulated proteins from 29 published proteomics studies ( 60 ).…”

Comparative mRNA and MicroRNA Profiling during Acute Myocardial Infarction Induced by Coronary Occlusion and Ablation Radio-Frequency Currents

“…In the last decade, there have been several efforts to dissect out cardiac mRNA and proteome in a wide array of cardiovascular diseases (McGregor and Dunn, 2006) using different animal models or plasma samples collected from human patients (Seenarain et al, 2010; Haas et al, 2011; Silbiger et al, 2011; Drastichova et al, 2012; Chowdhury et al, 2013; Marshall et al, 2014; Petriz and Franco, 2014). While novel biomarkers were identified from some of these studies (Haas et al, 2011; Silbiger et al, 2011; Chowdhury et al, 2013), authors reported general alterations in the cardiac transcriptome and proteome profile that suggested changes in Ca2+ handling proteins (Seenarain et al, 2010), energy metabolism proteins (Jin et al, 2006; Meng et al, 2009), and mediators of apoptotic signaling (Drastichova et al, 2012; Marshall et al, 2014; Petriz and Franco, 2014). …”

Corticotropin‐releasing factor (CRF) receptor‐1 is involved in cardiac noradrenergic activity observed during naloxone‐precipitated morphine withdrawal

“…As the repeated exposure to morphine and its withdrawal induces profound and severe stress reactions that are also evidenced by over expression of Hsp27 (Almela et al ., ; Drastichova et al ., ; Martínez‐Laoden et al ., ), we evaluated Hsp27 expression and phosphorylation in the left ventricle in wild‐type and CRF 1 receptor knockout mice. In accord with previous data (Almela et al ., ; Drastichova et al ., ; Martínez‐Laoden et al ., ), the present investigation showed that both chronic morphine treatment and its withdrawal are associated with an increase of Hsp27 expression. However, chronic morphine treatment did not modify Hsp27 phosphorylation, whereas naloxone administration to morphine‐treated rats induced an enhancement of Hsp27 phosphorylation at Ser 82 .…”