The effects of acute and chronic steady state methadone on memory retrieval in rats

Rationale

Although widely prescribed to treat opioid addiction, little is known about the possible side effects of methadone on memory functions.

Objectives

The aim of this study is to compare the effects of acute and chronic methadone on memory retrieval in rats and to explore the selectivity of possible deficits.

Methods

Administration of acute (0, 1.25, 2.5, and 5?mg/kg SC) and chronic steady state methadone (0, 10, 30, and 55?mg/kg/day SC by osmotic mini-pump) was tested on recall of three different types of information: stimulus?Creward (10-arm parallel maze), stimulus?Cresponse (8-arm radial maze), and stimulus?Cstimulus (Barnes maze). Acute and steady state methadone doses were also compared on tests of locomotor activity and reactivity to aversive stimuli (i.e., swimming and acoustic startle).

Results

In the stimulus?Creward task, acute methadone impaired performance as a result of severe depression of locomotion. This motor deficit, however, was modulated by the motivational valence of environmental stimulation. In fact, acute methadone did not eliminate forced swimming behavior. In the stimulus?Cresponse and stimulus?Cstimulus tasks, accuracy was impaired independently of direct motor deficits, but rats were hyper-reactive to aversive stimulation and, in fact, 5?mg/kg enhanced acoustic startle. Importantly, chronic steady state methadone did not affect accuracy of memory retrieval, did not depress motor or swimming activity, and did not change startle reactivity.

Conclusion

Only acute methadone impaired accuracy and/or performance on three tests of memory retrieval. These findings in rats suggest that memory deficits reported in methadone-maintained individuals may not be directly attributable to methadone.     

Mechanisms of myocardial regeneration

Traditionally, the adult heart has been viewed as a terminally differentiated postmitotic organ in which the number of cardiomyocytes is established at birth and these cells persist throughout the life span of the organ and organism. However, the discovery that cardiac stem cells live in the heart and differentiate into the various cardiac cell lineages has dramatically changed our understanding of myocardial biology. Deciphering the biological processes that lead to myocyte renewal is a challenging task. Cardiac regeneration may be accomplished by (1) commitment of multipotent stem cells that generate all specialized lineages within the parenchyma, (2) activation of unipotent progenitors with restricted differentiation potential, (3) replication of pre-existing differentiated cells, (4) transdifferentiation of exogenous progenitors that undergo plastic conversion into cells different from the organ of origin, and (5) dedifferentiation of cardiomyocytes that re-enter the cell cycle and divide. These multiple mechanisms of cell growth may act in concert to regenerate complex structures and restore the function of the target organ.     

PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence

Background and aim: The PNPLA3 rs738409 C>G polymorphism has been found to be strongly associated with non‐alcoholic fatty liver disease and with alcoholic liver disease. Whether the PNPLA3 rs738409 polymorphism could be a risk factor for the development of hepatocellular carcinoma (HCC) in cirrhosis patients is unknown. Methods: This study included 483 (344 males) consecutive Italian patients of Caucasian ethnicity affected by cirrhosis, of whom 279 had undergone transplantation for end‐stage liver disease while 204 had been referred to our liver and transplant unit for the diagnosis of cirrhosis. The aetiologies were hepatitis C virus=209, hepatitis B virus=76, alcohol=166, metabolic=32. Ile148Met rs738409 transversion was genotyped using an restriction fragment length polymorphism‐based assay. Results: The genotype frequencies of the rs738409 polymorphism were distributed differently in patients with cirrhosis C/C=168, C/G=220, G/G=95 vs controls C/C=218, C/G=175, G/G=35 (P<0.0001). Among cirrhotics, the G allele was over‐represented in alcoholic/metabolic (0.505) vs viral (0.368, P<0.001) liver disease. Patients with cirrhosis complicated by HCC were more likely to be G/G homozygotes (38/141) than the remaining patients (57/342, P<0.02). At multivariate analysis, the PNPLA3 rs738409 polymorphism was confirmed to be an independent predictor of HCC occurrence (odds ratio 1.76, 95% confidence interval 1.06–2.92, P<0.05). HCC rates increased from 13/116 (11.2%; female C/^* carriers), to 97/295 (32.9%; male C/^*carriers and female G/G homozygotes), to 31/72 (43.1%; male G/G homozygotes) (P<0.0001). Conclusions: The PNPLA3 rs738409 C>G polymorphism is associated with cirrhosis. In synergy with gender, this polymorphism is a strong predictor of HCC occurrence among patients with cirrhosis.     

In CD28‐costimulated human naïve CD4+ T cells,I‐κB kinase controls the expression of cell cycle regulatory proteins via interleukin‐2‐independent mechanisms

Stimulation of naïve CD4⁺ T cells through engagement of the T‐cell receptor (TCR) and the CD28 co‐receptor initiates cell proliferation which critically depends on interleukin (IL)‐2 secretion and subsequent autocrine signalling via the IL‐2 receptor. However, several studies indicate that in CD28‐costimulated T cells additional IL‐2‐independent signals are also required for cell proliferation. In this study, using a neutralizing anti‐human IL‐2 antibody and two selective, structurally unrelated, cell‐permeable I‐κB kinase (IKK) inhibitors, BMS‐345541 and PS‐1145, we show that in human naïve CD4⁺ T cells stimulated through a short engagement of the TCR and the CD28 co‐receptor, IKK controls the expression of the cell cycle regulatory proteins cyclin D3, cyclin E and cyclin‐dependent kinase 2 (CDK2) and the stability of the F‐box protein S‐phase kinase‐associated protein 2 (SKP2) and its co‐factor CDC28 protein kinase regulatory subunit 1B (CKS1B), through IL‐2‐independent mechanisms.     

A study of the mu opioid receptor gene polymorphism A118G in patients with primary biliary cirrhosis with and without pruritus

The increase in opioidergic tone by the central administration of morphine, which binds to the mu opioid receptor, is associated with pruritus. Pruritus is a symptom of cholestasis, which appears to result, in part, from increased opioidergic tone; a central mechanism has been proposed. The single nucleotide polymorphism Al18G in exon 1 of the opioid receptor mu 1 (OPRM1) gene, which codes for the mu opioid receptor, has been associated with alterations in functions mediated by the endogenous opioid system. In this study we found A118G in heterozygosity in 29% of the DNA samples from patients with primary biliary cirrhosis from the USA and from Italy with and without pruritus. A118G was 1.5 times more frequent in the samples from patients without pruritus from the USA than in the rest of the samples. The possibility of protection from pruritus associated with A118G supports the study of genetic polymorphisms of the OPRM1 gene in patients with cholestasis.     

Hepatitis C and pregnancy

Acute hepatitis C is a rare event in pregnancy. The most common scenario is chronic hepatitis C virus(HCV) infection in pregnancy. During pregnancy in women with chronic HCV infection a significant reduction in mean alanine aminotransferase levels has been reported,with a rebound during the postpartum period. In few cases exacerbation of chronic hepatitis C has been reported in pregnancy. A cofactor that might play a role in the reduction of liver damage is the release of endogenous interferon from the placenta. Observations regarding serum HCV-RNA concentration have been variable.In some women HCV-RNA levels rise toward the end of pregnancy. In general,pregnancy does not have a negative effect on HCV infection. Conversely,chronic hepatitis does not appear to have an adverse effect on the course of pregnancy,or the birth weight of the newborn infant. The role of spontaneous abortion is approximately the same as in the general population. The overall rate of mother-to-child transmission for HCV is3%-5% if the mother is known to be anti-HCV positive.Co-infection with human immunodeficiency virus(HIV)increases the rate of mother-to-child transmission up to19.4%. Numerous risk factors for vertical transmission have been studied. In general,high viral load defined as at least 2.5 × 106viral RNA copies/mL,HIV co-infection,and invasive procedures are the most important factors. Both interferon and ribavirin are contraindicated during pregnancy. Viral clearance prior to pregnancy increases the likelihood that a woman remains nonviremic in pregnancy with a consequent reduced risk of vertical transmission.