An Integrated Quantitative Proteomics and Systems Biology Approach to Explore Synaptic Protein Profile Changes During Morphine Exposure

Abstract

Morphine is a classic analgesic for the treatment of chronic pain. However, its repeated use is known to produce tolerance, physical dependence, and addiction; these properties limit its long-term therapeutic use and this has led to a quest for therapeutics without these unwanted side effects. Understanding the molecular changes in response to long-term use of morphine is likely to aid in the development of novel therapeutics for the treatment of pain. Studies examining the effects of chronic morphine administration have reported alterations in gene expression, synapse morphology, and synaptic transmission implying changes in synaptic protein profile. To fully understand the changes in protein profiles, proteomic techniques have been used. Studies using two-dimensional gel electrophoresis of various brain regions combined with mass spectrometry have found alterations in the levels of a number of proteins. However, neither the changes in brain regions relevant to morphine effects nor changes in the abundance of synaptic proteins have been clearly delineated. Recent studies employing subcellular fractionation to isolate the striatal synapse, combined with quantitative proteomics and graph theoryinspired network analyses, have begun to quantify morphine-regulated changes in synaptic proteins and facilitate the generation of networks that could serve as targets for the development of novel therapeutics for the treatment of chronic pain. Thus, an integrated quantitative proteomics and systems biology approach can be useful to identify novel targets for the treatment of pain and other disorders of the brain.

MicroRNAs Are Involved in the Development of Morphine-Induced Analgesic Tolerance and Regulate Functionally Relevant Changes in Serpini1

“…The direct, affective and cognitive/associative components of pain and analgesia are mediated throughout central nervous system (CNS) regions containing μ-opiate receptors including periaqueductal gray, amygdala, lateral habenula, dorsal raphe, anterior cingulate, and prefrontal cortex (PFC) (Pastoriza et al, 1996 ; Wagner et al, 2001 ; Craggs et al, 2007 ; Wager et al, 2007 ; Petrovic et al, 2010 ; Stockton and Devi, 2014 ; Zeidan et al, 2015 ). A clear consensus on specific canonical pathways altered by COA has not been reached, however complex intracellular neuroadaptations in direct response to opioid administration (Chu et al, 2008 ; Drdla et al, 2009 ; Ueda and Ueda, 2009 ; Abul-Husn et al, 2011 ; Ziolkowska et al, 2012 ; Williams et al, 2013 ) initiate complex synaptic reorganization characterized by altered neurotransmission (Abul-Husn et al, 2011 ) and synaptic architecture (Russo et al, 2010 ; Abul-Husn et al, 2011 ; Stockton and Devi, 2014 ) such as decreased spine density (Robinson et al, 2002 ), cytoskeletal structure (Hou et al, 2009 ; Li et al, 2009 ), cell size (Russo et al, 2007 ), and neurotransmitter relevant protein distribution (Xu et al, 2003 ; Mickiewicz and Napier, 2011 ). Neuroadaptations initiated by COA are additionally contingent upon context-dependent associative components (Tiffany et al, 1991 ; Cox and Tiffany, 1997 ; Mitchell et al, 2000 ; Miguez et al, 2014 ) that together underlie the behavioral effects of repeated opioid administration.…”

“…Given the significant amount of support for neuroplasticity changes following COA (Kauer and Malenka, 2007 ; Kalivas and O'Brien, 2008 ; McClung and Nestler, 2008 ; Stockton and Devi, 2014 ), altered miRNA expression is a promising candidate to coordinate the complex response. MiRNAs are a class of noncoding RNAs that regulate gene expression by targeting mRNAs for translation inhibition and/or mRNA degradation (He and Hannon, 2004 ).…”

Proteomics of the Synapse – A Quantitative Approach to Neuronal Plasticity

“…The majority of studies that compared the proteome of synapses were performed on human brain disease states (12,40,72,73,76,78,(123)(124)(125)(126) and despite significant methodological progress in recent years the resulting picture is still not representative. Apart from the problem of tissue preservation and preparation the limitations of conventional proteomic analysis lead to a situation where in several studies very different proteins where shown to be up-and downregulated in the same brain region and disease state.…”

Frontiers of Biomolecular Exploration in Brain Disorders

“…The past decade has been marked by extraordinary advances in proteomic techniques that have demonstrably increased our understanding of the composition, regulation, and function of protein complexes and pathways underlying altered neurobiological conditions. The next two papers in the issue emphasize neuroproteomics as a means to enrich our understanding of the mechanisms through which exposure to psychoactive drugs affects protein function and interactions (Stockton and Devi, 2014;Gorini et al, 2014). Stockton and Devi (2014) discuss an elegant quantitative proteomic approach and graph theory-inspired network analysis to enable our comprehension of how morphine impacts isolated presynaptic and postsynaptic functions of the striatal synapse.…”

“…The next two papers in the issue emphasize neuroproteomics as a means to enrich our understanding of the mechanisms through which exposure to psychoactive drugs affects protein function and interactions (Stockton and Devi, 2014;Gorini et al, 2014). Stockton and Devi (2014) discuss an elegant quantitative proteomic approach and graph theory-inspired network analysis to enable our comprehension of how morphine impacts isolated presynaptic and postsynaptic functions of the striatal synapse. This article emphasizes the coupling of key technologies to target synaptic sites of protein interactions and plasticity, which contribute to the enduring behavioral and physiological changes associated with opiate addiction.…”