Inhibition of C-Jun NH2-Terminal Kinase Stimulates Mu-Opioid Receptor Expression via P38 MAPK-Mediated Nuclear NF-?B Activation in Neuronal and Non-Neuronal Cells.

Inhibition of c-Jun NH2-terminal kinase stimulates mu-opioid receptor expression via p38 MAPK-mediated nuclear NF-?B activation in neuronal and non-neuronal cells.

Biochim Biophys Acta. 2013 Feb 25;
Wagley Y, Hwang CK, Lin HY, Kam AF, Law PY, Loh HH, Wei LN

Despite its potential side effects of addiction, tolerance and withdrawal symptoms, morphine is widely used for reducing moderate and severe pain. Previous studies have shown that the analgesic effect of morphine depends on mu opioid receptor (MOR) expression levels, but the regulatory mechanism of MOR is not yet fully understood. Several in vivo and in vitro studies have shown that the c-Jun NH2-terminal kinase (JNK) pathway is closely associated with neuropathic hyperalgesia, which closely resembles the neuroplastic changes observed with morphine antinociceptive tolerance. In this study, we show that inhibition of JNK by SP600125, its inhibitory peptide, or JNK-1 siRNA induced MOR at both mRNA and protein levels in neuronal cells. This increase in MOR expression was reversed by inhibition of the p38 mitogen-activated protein kinase (MAPK) pathway, but not by inhibition of the mitogen-activated protein/extracellular signal-regulated kinase (MEK) pathway. Further experiments using cell signaling inhibitors showed that MOR upregulation by JNK inhibition involved nuclear factor-kappa B (NF-?B). The p38 MAPK dependent phosphorylation of p65 NF-?B subunit in the nucleus was increased by SP600125 treatment. We also observed by chromatin immunoprecipitation (ChIP) analysis that JNK inhibition led to increased bindings of CBP and histone-3 dimethyl K4, and decreased bindings of HDAC-2, MeCP2, and histone-3 trimethyl K9 to the MOR promoter indicating a transcriptional regulation of MOR by JNK inhibition. All these results suggest a regulatory role of the p38 MAPK and NF-?B pathways in MOR gene expression and aids to our better understanding of the MOR gene regulation. HubMed – addiction


A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders.

Clin Neurophysiol. 2013 Feb 25;
Radhu N, de Jesus DR, Ravindran LN, Zanjani A, Fitzgerald PB, Daskalakis ZJ

OBJECTIVE: To evaluate transcranial magnetic stimulation (TMS) measures of inhibition and excitation in obsessive-compulsive disorder (OCD), major depressive disorder (MDD) and schizophrenia (SCZ). METHODS: Paradigms included: short-interval cortical inhibition (SICI), cortical silent period (CSP), resting motor threshold, intracortical facilitation, and motor evoked potential amplitude. A literature search was performed using PubMed, Ovid Medline, Embase Psychiatry and PsycINFO 1990 through April 2012. RESULTS: A significant Hedge’s g was found for decreased SICI (g=0.572, 95% confidence interval [0.179, 0.966], p=0.004), enhanced intracortical facilitation (g=0.446, 95% confidence interval [0.042, 0.849], p=0.030) and decreased CSP (g=-0.466, 95% confidence interval [-0.881, -0.052], p=0.027) within the OCD population. For MDD, significant effect sizes were demonstrated for decreased SICI (g=0.641, 95% confidence interval [0.384, 0.898], p=0.000) and shortened CSP (g=-1.232, 95% confidence interval [-1.530, -0.933], p=0.000). In SCZ, a significant Hedge’s g was shown for decreased SICI (g=0.476, 95% confidence interval [0.331, 0.620], p=0.000). CONCLUSION: Inhibitory deficits are a ubiquitous finding across OCD, MDD, SCZ and enhancement of intracortical facilitation is specific to OCD. SIGNIFICANCE: Provides a clear platform from which diagnostic procedures can be developed. HubMed – addiction


Post-humanism, addiction and the loss of self-control: Reflections on the missing core in addiction science.

Int J Drug Policy. 2013 Feb 25;
Weinberg D

The core criterion of addiction is the loss of self control. Ironically enough, however, neither the social nor the biomedical sciences of addiction have so far made any measurable headway in linking drug use to a loss of self control. In this essay I begin by demonstrating the limitations in this regard suffered by the social and bio-medical sciences. Whereas the social sciences have variously reduced addicted drug use to deviant, but nonetheless self-governed, behaviour or discourses thereof, the bio-medical sciences have completely failed to adequately specify, let alone empirically analyse, how we might distinguish addicted from self-governed behaviour. I then show how these limitations can be very easily overcome by the adoption of a post-humanist perspective on self control and the various afflictions, including addiction, to which it is regarded heir. This argument provides occasion to acquaint readers with post-humanist scholarship concerning a spectrum of relevant topics including the human body, disease, drug use and therapeutic intervention and to show how these lines of investigation can be combined to provide an innovative, theoretically robust and practically valuable method for advancing the scientific study of addiction specifically as the loss of self control. The essay concludes with a discussion of some of the more important ramifications that follow from the adoption of this post-humanist approach for drug policy studies. HubMed – addiction


Neuro-Genetics of Reward Deficiency Syndrome (RDS) as the Root Cause of “Addiction Transfer”: A New Phenomenon Common after Bariatric Surgery.

J Genet Syndr Gene Ther. 2011 Dec 23; 2012(1):
Blum K, Bailey J, Gonzalez AM, Oscar-Berman M, Liu Y, Giordano J, Braverman E, Gold M

Now after many years of successful bariatric (weight-loss) surgeries directed at the obesity epidemic clinicians are reporting that some patients are replacing compulsive overeating with newly acquired compulsive disorders such as alcoholism, gambling, drugs, and other addictions like compulsive shopping and exercise. This review article explores evidence from psychiatric genetic animal and human studies that link compulsive overeating and other compulsive disorders to explain the phenomenon of addiction transfer. Possibly due to neurochemical similarities, overeating and obesity may act as protective factors reducing drug reward and addictive behaviors. In animal models of addiction withdrawal from sugar induces imbalances in the neurotransmitters, acetylcholine and dopamine, similar to opiate withdrawal. Many human neuroimaging studies have supported the concept of linking food craving to drug craving behavior. Previously our laboratory coined the term Reward Deficiency Syndrome (RDS) for common genetic determinants in predicting addictive disorders and reported that the predictive value for future RDS behaviors in subjects carrying the DRD2 Taq A1 allele was 74%. While poly genes play a role in RDS, we have also inferred that disruptions in dopamine function may predispose certain individuals to addictive behaviors and obesity. It is now known that family history of alcoholism is a significant obesity risk factor. Therefore, we hypothesize here that RDS is the root cause of substituting food addiction for other dependencies and potentially explains this recently described Phenomenon (addiction transfer) common after bariatric surgery. HubMed – addiction



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