The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (k)-opioid system has a role in the increased consumption of ethanol in dependent animals. The effects of three opioid receptor antagonists with different effects on opioid receptors, naltrexone, nalmefene, and nor-binaltorphimine (nor-BNI), were compared in their ability to decrease ethanol self-administration in nondependent and ethanol-dependent male Wistar rats. Nalmefene and naltrexone are both opioid receptor ligands with comparable molecular weights and pharmacokinetic profiles, but differing specificity for the three opioid receptor subtypes at low doses, while nor-BNI is a selective k-opioid receptor antagonist. Dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14 h per day. Subsequent to dependence induction, nalmefene, naltrexone, and nor-BNI were tested for their ability to modulate self-administration of ethanol in vapor-exposed and control rats. The results indicated that both nalmefene and naltrexone induced a significant dose-dependent decrease in the number of lever presses for ethanol in both groups of animals. However, in ethanol-dependent animals, nalmefene was significantly more effective in suppressing ethanol intake than naltrexone. Nor-BNI selectively attenuated ethanol-dependent self-administration while leaving nondependent ethanol self-administration intact. Because naltrexone is primarily selective for the m-opioid receptor, and nalmefene is primarily selective for the m-and k-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent animals suggests that opioid systems distinct from the m-regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that k-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/k-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats. INTRODUCTIONThe acute effects of ethanol have been shown to be both reinforcing and rewarding in animal models such as operant self-administration (Anderson and Thompson, 1974;Smith and Davis, 1974) and the conditioned place preference paradigm (Bozarth, 1990;Walker and Ettenberg, 2007). Ethanol produces its effects on the central nervous system via a variety of pharmacological mechanisms. These include alterations in the function of the cholinergic, dopaminergic, g-aminobutyric acid, glutamatergic, opioidergic, and serotonergic neurotransmitter systems (for review see Eckardt et al, 1998). In the case of the endogenous opioid system and its receptor subtypes (m, d, kFselective for the three main classes of endogenous opioids: b-endorphin, enkephalins, and dynorphins, respectively), acute ethanol has been shown to stimulate the release of b-endorphin...

Context This article describes the historical context and current developments in evidence-based practice (EBP) for medicine, nursing, psychology, social work, and public health, as well as the evolution of the seminal “three circles” model of evidence-based medicine, highlighting changes in EBP content, processes, and philosophies across disciplines. Methods The core issues and challenges in EBP are identified by comparing and contrasting EBP models across various health disciplines. Then a unified, transdisciplinary EBP model is presented, drawing on the strengths and compensating for the weaknesses of each discipline. Findings Common challenges across disciplines include (1) how “evidence” should be defined and comparatively weighted; (2) how and when the patient’s and/or other contextual factors should enter the clinical decision-making process; (3) the definition and role of the “expert”; and (4) what other variables should be considered when selecting an evidence-based practice, such as age, social class, community resources, and local expertise. Conclusions A unified, transdisciplinary EBP model would address historical shortcomings by redefining the contents of each model circle, clarifying the practitioner’s expertise and competencies, emphasizing shared decision making, and adding both environmental and organizational contexts. Implications for academia, practice, and policy also are discussed.

Interactions with ankyrin G are crucial to the localization of voltage-gated sodium channels (VGSCs) at the axon initial segment and for neurons to initiate action potentials. However, the molecular nature of these interactions remains unclear. Here we report that VGSC-␣, but not -␤, subunits bind to ankyrin G using pull-down assays. Further dissection of this activity identifies a conserved 9-amino acid motif ((V/A)P(I/L)AXXE(S/D)D) required for ankyrin G binding. This motif is also required for the localization of chimeric neurofascin/sodium channel molecules to the initial segment of cultured hippocampal neurons. The conserved nature of this motif suggests that it functions to localize sodium channels to a variety of "excitable" membrane domains both inside and outside of the nervous system.The concentration of voltage-gated sodium channels (VGSCs) 1 into excitable membrane domains is crucial to information processing and transmission in the nervous system and to excitation/contraction coupling in muscle. Localized concentrations of VGSCs at the initial segment (IS) and the nodes of Ranvier are necessary for the initiation and propagation of action potentials through myelinated axons. However, mechanisms underlying the localization of VGSCs to these excitable membrane domains remain relatively unknown. In neurons, VGSCs exist as heterotrimers composed of a large pore-forming ␣ subunit associated with two smaller accessory ␤ subunits (reviewed in Ref. 1). At least 10 genes encoding putative ␣ subunits have been identified in mammals (reviewed in Ref.2) along with three ␤ subunit genes. ␤ subunits not only modulate the activity of ␣ subunits (3, 4) but also exhibit characteristics of cell adhesion molecules (CAMs) binding to extracellular matrix molecules such as tenascin-C and -R (5) and other CAMs such as neurofascin (6).Polarized localization of VGSCs in the axonal membrane requires interactions with members of the ankyrin family of peripheral membrane proteins (reviewed in Ref. 7). Ankyrins function as membrane-cytoskeleton adaptors that immobilize integral membrane proteins to the spectrin-based membrane skeleton. Ankyrins co-purify with and directly bind to purified VGSCs (8), and specific isoforms of the ankyrin G gene are concentrated with VGSCs at the IS (9), the nodes of Ranvier (9), and the neuromuscular junction (10). The functional importance of the interaction between ankyrin G and VGSCs is demonstrated in knockouts of ankyrin G in the mouse cerebellum. Purkinje cells from knockout animals are deficient in localized VGSC concentrations at the IS (11) and are unable to initiate action potentials (12).In addition to VGSCs, ankyrins also interact with a variety of other integral membrane proteins present at the node including the CAMs neurofascin and NrCAM (13,14). Interactions of ankyrins with VGSCs (15) and other integral membrane proteins are mediated through the N-terminal 90-kDa repeat or membrane-binding (MB) domain. The interaction between the ankyrin MB domain and neurofascin/NrCAM is depende...

Altered dynorphin opioid peptide systems contribute to increased ethanol self-administration during withdrawal following chronic alcohol exposure. We previously identified that the k-opioid receptor antagonist nor-binaltorphimine (nor-BNI) selectively reduced ethanol self-administration in dependent animals. The purpose of this study was twofold:(1) determine whether peripherally administered nor-BNI could reduce dependence-induced ethanol selfadministration and (2) confirm the selective k-opioid effects of nor-BNI by administering it 24 hours prior to ethanol self-administration sessions occurring during acute withdrawal. Nor-BNI decreased ethanol self-administration in ethanol-dependent animals, with no effect in nondependent animals. Thus, the k-opioid/dynorphin system is a viable pharmacotherapeutic target for the treatment of alcoholism.

Highlights d Pain recruits the dynorphin-kappa opioid receptor system in the nucleus accumbens d Inhibitory inputs onto dynorphin cells are reduced during inflammatory pain d Increase in dynorphin tone mediates inflammatory paininduced negative affect