Prodynorphin transcripts and proteins differentially expressed and regulated in the adult human brain.
ABSTRACT Transcription from multiple promoters along with alternative mRNA splicing constitutes the basis for cell-specific gene expression and mRNA and protein diversity. The prodynorphin gene (PDYN) gives rise to prodynorphin (PDYN), precursor to dynorphin opioid peptides that regulate diverse physiological functions and are implicated in various neuropsychiatric disorders. Here, we characterized PDYN transcripts and proteins in the adult human brain and studied PDYN processing and intracellular localization in model cell lines. Seven PDYN mRNAs were identified in the human brain; two of the transcripts, FL1 and FL2, encode the full-length PDYN. The dominant, FL1 transcript shows high expression in limbic-related structures such as the nucleus accumbens and amygdala. The second, FL2 transcript is only expressed in few brain structures such as the claustrum and hypothalamus. FL-PDYN was identified for the first time in the brain as the dominant PDYN protein product. Three novel PDYNs expressed from spliced or truncated PDYN transcripts either lack a central segment but are still processed into dynorphins, or are translated into N-terminally truncated proteins. One truncated PDYN is located in the cell nucleus, suggesting a novel nonopioid function for this protein. The complexity of PDYN expression and diversity of its protein products may be relevant for diverse levels of plasticity in adaptive responses for the dynorphin system.
Article: Pharmacotherapy of addictions.[show abstract] [hide abstract]
ABSTRACT: Addiction to drugs, such as heroin, cocaine and alcohol, exacts great human and financial costs on society, but the development of pharmacotherapies for addiction has been largely neglected by the pharmaceutical industry. With advances in our understanding of the underlying biology of addictions now opening the door for the development of novel pharmacotherapies, it could be time for a reassessment of involvement in this increasingly important therapeutic area. Here, we summarize the current approved and implemented pharmacotherapeutic approaches to the treatment of addiction, and then highlight the most promising areas for future drug development from the perspective of our laboratory and our National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) Research Center.dressNature Reviews Drug Discovery 10/2002; 1(9):710-26. · 33.08 Impact Factor
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ABSTRACT: Opiate addiction is a chronically relapsing disorder that is char- acterized by compulsive drug taking, an inability to limit intake, and bouts of intense drug craving that can be precipitated by the mere presence of people, places, or objects previously associated with drug use. Although knowledge of the neural mechanisms that underlie the transition from casual drug use to addiction is still incomplete, the development of animal models that enable differentiation of the various stages of the addiction process have provided new insights regarding the neural substrates on which opiates act to affect and subsequently control behavior. Data derived from these models are consistent with the hypothesis that opiates, like psychostimulants, are initially abused by virtue of their rewarding or hedonic effects. However, as will be discussed in this review, the repeated use of opiates induces alterations in neurotransmitter and neuropeptide systems that regulate incentive -motivation and stress-responsiveness. In- creasing evidence indicates that the dysregulation of these systems underlies the compulsive use and loss of control of drug-taking that characterizes opiate and other addictions. Studies examining the neural basis of drug addiction have been guided by the premise that the motivation of an addict to take drugs results from the desire to experience the hedonic (e.g., rewarding) effects of the drug as well as from the desire to avoid the anhedonia and aversive consequences of drug withdrawalJournal of Neuroscience 06/2002; 22(9):3321-5. · 6.91 Impact Factor
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ABSTRACT: The primary structure of porcine preproenkephalin B has been elucidated by cloning and sequencing cDNA: it contains neoendorphin, dynorphin and leumorphin (containing rimorphin as its amino-terminus). These opioid peptides, each having a leucine-enkephalin structure, act on the kappa-receptor. We have now cloned a human genomic DNA segment containing the preproenkephalin B gene. The structural organization of this gene resembles those of the genes encoding the other opioid peptide precursors, that is, preproenkephalin A and the corticotropin-beta-lipotropin precursor (ACTH-beta-LPH precursor). The primary structure of human preproenkephalin B has been deduced from the gene sequence. The amino acid sequence homology observed between preproenkephalin B and preproenkephalin A, together with the similarity between their gene organizations, suggests that the two genes have been generated from a common ancestor by gene duplication.Nature 01/1983; 306(5943):611-4. · 38.60 Impact Factor