Alcoholism and anxiety disorders have a huge impact on society and afflict 17.6 million and 40 million people in the United States, respectively. A strong comorbidity exists between alcoholism and anxiety disorders. Indeed, alcohol withdrawal-induced anxiety is a primary contributing factor for relapse, and anxiolytics are a common adjuvant therapy prescribed for treatment-seeking alcoholics. It is thought that the use of alcohol to self-medicate and relieve anxiety contributes to the development of addiction. Treatment for anxiety disorders and alcoholism exist but are not universally effective. The delta opioid receptor (DOR) plays a role in both alcohol consumption and anxiety, making it a very interesting clinical target. Two pharmacologically distinct DORs have been described: DOR1 and DOR2. We find here that the relative specificity of DOR agonists for DOR1 or DOR2 can greatly affect the effects they exert on ethanol consumption and anxiety. The DOR1 agonist 2-methyl-4a␣-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a␣-octahydro-quinolino[2,3,30g]isoquinoline (TAN-67), although not effective in decreasing anxiety-like behavior in naive mice, has anxiolytic-like properties in ethanolwithdrawn mice. In contrast, a less subtype-selective agonist,, while also reducing anxiety-like behavior, increases ethanol consumption. In addition, we found that the conical anxiolytic diazepam [DZ; 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one] is a less effective anxiolytic in ethanol-withdrawn mice than in naive mice. Together, our findings suggest that selective DOR agonists can decrease anxiety-like behavior and are more effective than diazepam at reducing ethanol consumption. We believe the dual efficacy of DOR1 agonists makes these receptors an interesting therapeutic target for treatment-seeking alcoholics.

Background The delta opioid receptor (DOR) is a promising target to treat multiple indications, including alcoholism, anxiety, and nonmalignant pain. The potential of the DORs has been underappreciated, in part, due to relatively low functional expression of these receptors in naïve states. However, chronic exposure to stress, opioids, and inflammation can induce a redistribution of DORs to the cell surface where they can be activated. Previously, DORs were shown to be selectively/exclusively present in spinal cord circuits mediating mechanical sensitivity but not those mediating thermal nociception under naïve conditions. Methods We spinally administered DOR and mu opioid receptor (MOR) selective agonists ([D-Pen2,D-Pen5]-Enkephalin, deltorphin II, SNC80, and DAMGO) and antagonists (naltriben and CTAP) and determined thermal antinociception and mechanical sensitivity in wild-type mice or mice with a genetic disruption of DOR or MOR. Thermal antinociception was measured using a radiant heat tail-flick assay; mechanical sensitivity was measured using von Frey filaments. Dose response curves were generated in naïve mice and mice exposed to ethanol in a model of voluntary consumption. Results We show that prolonged exposure to ethanol can promote an upregulation of functional DORs in the spinal cord in thermal pain-mediating circuits but not in those mediating mechanical sensitivity. The upregulated DORs either modulate MOR-mediated analgesia through convergence of circuits or signal transduction pathways and/or interact directly with MORs to form a new functional (heteromeric) unit. Conclusions Our findings suggest that DORs could be a novel target in conditions in which DORs are redistributed.

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Few studies have evaluated the effectiveness of Zika virus (ZIKV) public health educational campaigns. Following a ZIKV educational campaign in Roatán, Honduras (October 2016), a survey was administered (March-May 2017) to residents ( = 348) and health-care professionals ([HCPs]; = 44) to evaluate ZIKV knowledge, attitudes, and preventive practices, with attention to sexual health. Knowledge scores were calculated and mapped using participants' home locations. The knowledge scores between HCPs and residents were significantly different (mean 17 versus 11; < 0.001). Only 6% of residents and 14% of HCPs knew that ZIKV was sexually transmissible. Few reported abstinence (2.6% residents; 9.4% HCPs) or condom use (1.6% residents; 12.5% HCPs) to prevent ZIKV infection. Of all subjects, 15.6% were pregnant or had a pregnant partner in the past year; 57.6% expressed concern over ZIKV. Mapping demonstrated spatial heterogeneity in knowledge. The findings suggest a need for improved public health messaging in ZIKV-affected areas.

Background Naltrexone is one of the few drugs approved by the Federal Drug Administration for the treatment of alcoholism. However, naltrexone is only effective in a subpopulation of treatment-seeking alcohol abusers, and suffers from compliance issues. The non-selective nature of this opioid antagonist likely contributes to its side effects and poor therapeutic efficacy. Drugs selectively targeting delta opioid receptor subtypes offer a potential way to treat alcohol abuse disorders. We have recently shown that delta subtype-selective agonists TAN-67 and SNC80 can have opposing effects on alcohol consumption, while having similar effects on alcohol withdrawal-induced anxiety. Methods We studied the ability of TAN-67 and SNC80 to induce place preference in naïve and ethanol exposed C57BL/6 mice and determined the effect of these agonists on the expression of ethanol place preference. Results We show that TAN-67 and SNC80 have opposing actions on ethanol place preference. However, neither of the drugs induces place preference by themselves at doses that are therapeutically effective in mice. Interestingly, SNC80, like naltrexone reduces ethanol place preference, however we have previously shown that SNC80 increases ethanol consumption at the tested dose. Similar to naltrexone, TAN-67 reduces alcohol consumption, but we show here that it may be due to an increase in ethanol place preference. Importantly, we found that chronic ethanol exposure does not increase the rewarding properties of the DOR subtype selective agonists. Conclusions Our results provide a better understanding of how DOR subtype selective drugs could potentially be used for treatment of alcohol abuse disorders.

Drugs targeting G-protein-coupled receptors (GPCRs) make up more than 25% of all prescribed medicines. The ability of GPCRs to form heteromers with unique signaling properties suggests an entirely new and unexplored pool of drug targets. However, current in vitro assays are ill equipped to detect heteromer-selective compounds. We have successfully adapted an approach, using fusion proteins of GPCRs and chimeric G proteins, to create an in vitro screening assay (in human embryonic kidney cells) in which only activated heteromers are detectable. Here we show that this assay can demonstrate heteromer-selective G-protein bias as well as measure transinhibition. Using this assay, we reveal that the d-opioid receptor agonist ADL5859, which is currently in clinical trials, has a 10-fold higher potency against d-opioid receptor homomers than d/m-opioid receptor heteromers (pEC 50 5 6.7 6 0.1 versus 5.8 6 0.2). The assay enables the screening of large compound libraries to identify heteromer-selective compounds that could then be used in vivo to determine the functional role of heteromers and develop potential therapeutic agents.

Molecular cloning has identified three opioid receptors: mu (MOR), delta (DOR) and kappa (KOR). Yet, cloning of these receptor types has offered little clarification to the diverse pharmacological profiles seen within the growing number of novel opioid ligands, which has led to the proposal of multiple subtypes. In the present study, utilizing in vitro and in vivo methods including the use of opioid receptor knockout mice, we find that certain antinociceptive effects of the KOR-1 and KOR-2 subtype-selective ligands (+)-(5α,7α,8β)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzene-acetamide (U69, 593) and 4-[(3,4-Dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazine-carboxylic acid methyl ester fumarate (GR89, 696), respectively, are potentiated by antagonism of MOR and DOR receptors. We believe that our findings can be best explained by the existence of KOR-DOR and KOR-MOR heteromers. We only find evidence for the existence of these heteromers in neurons mediating mechanical nociception, but not thermal nociception. These findings have important clinical ramifications as they reveal new drug targets that may provide avenues for more effective pain therapies.

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