- Role of mu-opioid agonist efficacy on antinociceptive interactions between mu agonists and the nociceptin opioid peptide agonist Ro 64-6198 in rhesus monkeys. [Journal Article]
- EJEur J Pharmacol 2018 Dec 12
- Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modul...
Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modulates nociception, and NOP agonists might be useful adjuncts to enhance the analgesic effects or attenuate the undesirable effects of mu-opioid agonists. The present study determined behavioral interactions between the NOP agonist (-)-Ro 64-6198 and mu-opioid ligands that vary in mu-opioid receptor efficacy (17-cyclopropylmethyl-3,14β-dihyroxy-4,5α-epoxy-6α-[(3 ́-isoquinolyl)acetamindo]morphinan (NAQ) < buprenorphine < nalbuphine < morphine = oxycodone < methadone) in male rhesus monkeys. For comparison, Ro 64-6198 interactions were also examined with the kappa-opioid receptor agonist nalfurafine. Each opioid ligand was examined alone and following fixed-dose Ro 64-6198 pretreatments in assays of thermal nociception (n=3-4) and schedule-controlled responding (n=3). Ro 64-6198 alone failed to produce significant antinociception up to doses (0.32mg/kg, IM) that significantly decreased rates of responding. All opioid ligands, except NAQ and nalfurafine, produced dose- and thermal intensity-dependent antinociception. Ro 64-6198 enhanced the antinociceptive potency of buprenorphine, nalbuphine, methadone, and nalfurafine. Ro 64-6198 enhancement of nalbuphine antinociception was NOP antagonist SB-612111 reversible and occurred under a narrow range of dose and time conditions. All opioid ligands, except NAQ and buprenorphine, produced dose-dependent decreases in rates of responding. Ro 64-6198 did not significantly alter mu-opioid ligand rate-decreasing effects. Although these results suggest that NOP agonists may selectively enhance the antinociceptive vs. rate-suppressant effects of some mu-opioid agonists, this small enhancement occurred under a narrow range of conditions dampening enthusiasm for NOP agonists as candidate "opioid-sparing" adjuncts.
- Serotonin receptors and suicide, major depression, alcohol use disorder and reported early life adversity. [Journal Article]
- TPTransl Psychiatry 2018 Dec 14; 8(1):279
- Serotonin neurotransmitter deficits are reported in suicide, major depressive disorder (MDD) and alcohol use disorder (AUD). To compare pathophysiology in these disorders, we mapped brain serotonin t...
Serotonin neurotransmitter deficits are reported in suicide, major depressive disorder (MDD) and alcohol use disorder (AUD). To compare pathophysiology in these disorders, we mapped brain serotonin transporter (SERT), 5-HT1A, and 5-HT2A receptor binding throughout prefrontal cortex and in anterior cingulate cortex postmortem. Cases and controls died suddenly minimizing agonal effects and had a postmortem interval ≤24 h to avoid compromised brain integrity. Neuropathology and toxicology confirmed absence of neuropathology and psychotropic medications. For most subjects (167 of 232), a DSM-IV Axis I diagnosis was made by psychological autopsy. Autoradiography was performed in right hemisphere coronal sections at a pre-genual level. Linear model analyses included sex and age with group and Brodmann area as interaction terms. SERT binding was lower in suicides (p = 0.004) independent of sex (females < males, p < 0.0001), however, the lower SERT binding was dependent on MDD diagnosis (p = 0.014). Higher SERT binding was associated with diagnosis of alcoholism (p = 0.012). 5-HT1A binding was greater in suicides (p < 0.001), independent of MDD (p = 0.168). Alcoholism was associated with higher 5-HT1A binding (p < 0.001) but only in suicides (p < 0.001). 5-HT2A binding was greater in suicides (p < 0.001) only when including MDD (p = 0.117) and alcoholism (p = 0.148) in the model. Reported childhood adversity was associated with higher SERT and 5-HT1A binding (p = 0.004) in nonsuicides and higher 5-HT2A binding (p < 0.001). Low SERT and more 5-HT1A and 5-HT2A binding in the neocortex in depressed suicides is dependent on Axis I diagnosis and reported childhood adversity. Findings in alcoholism differed from those in depression and suicide indicating a distinct serotonin system pathophysiology.
- Toll-like receptor 3 activation increases voluntary alcohol intake in C57BL/6J male mice. [Journal Article]
- BBBrain Behav Immun 2018 Dec 11
- Many genes differentially expressed in brain tissue from human alcoholics and animals that have consumed large amounts of alcohol are components of the innate immune toll-like receptor (TLR) pathway....
Many genes differentially expressed in brain tissue from human alcoholics and animals that have consumed large amounts of alcohol are components of the innate immune toll-like receptor (TLR) pathway. TLRs initiate inflammatory responses via two branches:  MyD88-dependent or  TRIF-dependent. All TLRs signal through MyD88 except TLR3. Prior work demonstrated a direct role for MyD88-dependent signaling in regulation of alcohol consumption. However, the role of TLR3 as a potential regulator of excessive alcohol drinking has not previously been investigated. To test the possibility TLR3 activation regulates alcohol consumption, we injected mice with the TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)) and tested alcohol consumption in an every-other-day two-bottle choice test. Poly(I:C) produced a persistent increase in alcohol intake that developed over several days. Repeated poly(I:C) and ethanol exposure altered innate immune transcript abundance; increased levels of TRIF-dependent pathway components correlated with increased alcohol consumption. Administration of poly(I:C) before exposure to alcohol did not alter alcohol intake, suggesting that poly(I:C) and ethanol must be present together to change drinking behavior. To determine which branch of TLR signaling mediates poly(I:C)-induced changes in drinking behavior, we tested either mice lacking MyD88 or mice administered a TLR3/dsRNA complex inhibitor. MyD88 null mutants showed poly(I:C)-induced increases in alcohol intake. In contrast, mice pretreated with a TLR3/dsRNA complex inhibitor reduced their alcohol intake, suggesting poly(I:C)-induced escalations in alcohol intake function are, at least partially, dependent on TLR3. Together, these results strongly suggest that TLR3-dependent signaling drives excessive alcohol drinking behavior.
- Toll-like receptor 3 dynamics in female C57BL/6J mice: Regulation of alcohol intake. [Journal Article]
- BBBrain Behav Immun 2018 Dec 11
- Although there are sex differences in the effects of alcohol on immune responses, it is unclear if sex differences in immune response can influence drinking behavior. Activation of toll-like receptor...
Although there are sex differences in the effects of alcohol on immune responses, it is unclear if sex differences in immune response can influence drinking behavior. Activation of toll-like receptor 3 (TLR3) by polyinosinic:polycytidylic acid (poly(I:C)) produced a rapid proinflammatory response in males that increased alcohol intake over time (Warden et al., 2019). Poly(I:C) produced a delayed and prolonged innate immune response in females. We hypothesized that the timecourse of innate immune activation could regulate drinking behavior in females. Therefore, we chose to test the effect of two time points in the innate immune activation timecourse on every-other-day two-bottle-choice drinking: (1) peak activation; (2) descending limb of activation. Poly(I:C) reduced ethanol consumption when alcohol access occurred during peak activation. Poly(I:C) did not change ethanol consumption when alcohol access occurred on the descending limb of activation. Decreased levels of MyD88-dependent pathway correlated with decreased alcohol intake and increased levels of TRIF-dependent pathway correlated with increased alcohol intake in females. To validate the effects of poly(I:C) were mediated through MyD88, we tested female mice lacking Myd88. Poly(I:C) did not change alcohol intake in Myd88 knockouts, indicating that poly(I:C)-induced changes in alcohol intake are dependent on MyD88 in females. We next determined if the innate immune timecourse also regulated drinking behavior in males. Poly(I:C) reduced ethanol consumption in males when alcohol was presented at peak activation. Therefore, the timecourse of innate immune activation regulates drinking behavior and sex-specific dynamics of innate immune response must be considered when designing therapeutics to treat excessive drinking.
- Prenatal alcohol exposure prevalence as measured by direct ethanol metabolites in meconium in a Native American tribe of the southwest. [Journal Article]
- BDBirth Defects Res 2018 Dec 14
- CONCLUSIONS: Results of this study on the prevalence of PAE in the Navajo Nation, obtained for the first time with an objective comprehensive panel of meconium biomarkers, indicate that the rates in the NBCS may be comparable to the general U.S. population and are in accord with recent U.S. national survey estimates. Our findings emphasize that drinking behaviors among Native American communities in the United States can vary, and generalization across all Native American populations is not warranted.
- Psychometric Properties of a Modified Moral Injury Questionnaire in a Military Population. [Journal Article]
- TTraumatology (Tallahass Fla) 2018; 24(4):301-312
- Moral injury (MI) results from perpetration of or exposure to distressing events, known as morally injurious events (MIEs), that challenge moral beliefs and values. Due to the type of involvement in ...
Moral injury (MI) results from perpetration of or exposure to distressing events, known as morally injurious events (MIEs), that challenge moral beliefs and values. Due to the type of involvement in recent military conflicts, many veterans report MIEs that may cause dissonance and, in turn, MI. Although two existing measures assess MIEs, neither currently assesses the defining characteristics of MI (i.e., guilt, shame, difficulty forgiving self and others, and withdrawal). The present study reports the initial psychometric test of a modified version (Robbins, Kelley, Hamrick, Bravo, & White, 2017) of the Moral Injury Questionnaire - Military version (MIQ-M; Currier, Holland, Drescher, & Foy, 2015) in a sample of 328 military personnel (e.g., veterans, National Guard/reservists, active duty members). The MIQ-M was modified to assess both MIEs and the defining characteristics of MI. Exploratory factor analyses suggested a three-factor model of MIEs consisting of Atrocities of war, Psychological consequences of war, and Leadership failure or betrayal. The modified MIQ-M factors were correlated with defining characteristics of MI. In addition, each MIE factor and associated defining characteristics of MI were positively correlated with symptoms of posttraumatic stress disorder, depression, and anxiety, as well as substance use. The modified MIQ-M is a reliable measure of MI that is comprised of three subscales that are associated with, but distinct from, mental health outcomes. Although findings are promising, further research evaluating the applicability of the modified MIQ-M in clinical settings is required to establish construct validity of the defining characteristics and secondary manifestations of MI.
- Website Analytics of a Google Ads Campaign for a Men's Mental Health Website: Comparative Analysis. [Journal Article]
- JMJMIR Ment Health 2018 Dec 13; 5(4):e12428
- CONCLUSIONS: A Google Ads campaign designed to direct men to the Headstrong website increased the number of user visits by more than five-fold. However, engagement by users responding to the ad campaign was substantially lower than that by users who visited the website via other acquisition methods, possibly reflecting the nonspecific online targeting of men by the ad campaign. General targeting of men online to promote men's mental health appears to have limited value.
- Machine learning selected smoking-associated DNA methylation signatures that predict HIV prognosis and mortality. [Journal Article]
- CEClin Epigenetics 2018 Dec 13; 10(1):155
- CONCLUSIONS: We demonstrated that smoking-associated DNA methylation features in white blood cells predict HIV infection-related clinical outcomes in a population living with HIV.
- From Synapse to Function: A Perspective on the Role of Neuroproteomics in Elucidating Mechanisms of Drug Addiction. [Review]
- PProteomes 2018 Dec 09; 6(4)
- Drug addiction is a complex disorder driven by dysregulation in molecular signaling across several different brain regions. Limited therapeutic options currently exist for treating drug addiction and...
Drug addiction is a complex disorder driven by dysregulation in molecular signaling across several different brain regions. Limited therapeutic options currently exist for treating drug addiction and related psychiatric disorders in clinical populations, largely due to our incomplete understanding of the molecular pathways that influence addiction pathology. Recent work provides strong evidence that addiction-related behaviors emerge from the convergence of many subtle changes in molecular signaling networks that include neuropeptides (neuropeptidome), protein-protein interactions (interactome) and post-translational modifications such as protein phosphorylation (phosphoproteome). Advancements in mass spectrometry methodology are well positioned to identify these novel molecular underpinnings of addiction and further translate these findings into druggable targets for therapeutic development. In this review, we provide a general perspective of the utility of novel mass spectrometry-based approaches for addressing critical questions in addiction neuroscience, highlighting recent innovative studies that exemplify how functional assessments of the neuroproteome can provide insight into the mechanisms of drug addiction.
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- miR-183 and miR-141 in lesion tissues are potential risk factors for poor prognosis in patients with infected abdominal aortic aneurysm. [Journal Article]
- ETExp Ther Med 2018; 16(6):4695-4699
- The expression levels of micro ribonucleic acid-183 (miR-183) and miR-141 in the lesion tissues of infected abdominal aortic aneurysm (IAAA) and their relationship with prognosis were investigated. T...
The expression levels of micro ribonucleic acid-183 (miR-183) and miR-141 in the lesion tissues of infected abdominal aortic aneurysm (IAAA) and their relationship with prognosis were investigated. Thirty-six patients with IAAA admitted and who underwent vascular surgery in People's Hospital of Shenzhen from June 2003 to June 2013 were selected. Reverse transcription polymerase chain reaction (RT-PCR) was utilized to detect the expression levels of miR-183 and miR-141 in lesion tissues and adjacent tissues 1 cm away from the aneurysm in 36 patients with IAAA. The relationship between the expression levels of miR-183 and miR-141 as well as the clinicopathological features of patients with IAAA were analyzed, and the factors influencing the prognosis of IAAA were analyzed by univariate and multiva-riate analysis. The expression levels of miR-183 and miR-141 were significantly downregulated in the lesions of patients with IAAA, and miR-183 and miR-141 levels in the lesion tissues of the IAAA patients were significantly lower than those in the adjacent tissues (P<0.05). The expression levels of miR-183 and miR-141 were not related to sex, age, history of hypertension, and alcoholism (P>0.05), but they were related to smoking history or aneurysm size (P<0.05). The overall survival rate of patients with IAAA was 41.6% (15/36). The multivariate analysis found that aneurysm size, low expression of miR-183, and low expression of miR-141 were independent factors affecting the prognosis of patients with IAAA. In conclusion, the expression levels of miR-183 and miR-141 in the lesion tissues of IAAA are low, and the lower the expression level is, the worse the prognosis gets. miR-183 and miR-141 can be used as predictors of prognosis in patients with IAAA.