40 results on '"Poklis A"'
Search Results
2. N-oleoyl alanine attenuates nicotine reward and spontaneous nicotine withdrawal in mice
- Author
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Karin, Kimberly N., Mustafa, Mohammed A., Poklis, Justin L., Buzzi, Belle, Schlosburg, Joel E., Parker, Linda, Damaj, M. Imad, and Lichtman, Aron H.
- Published
- 2024
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- View/download PDF
3. Effects of acute Δ9-tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice
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Yadav-Samudrala, Barkha J., Gorman, Benjamin L., Dodson, Hailey, Ramineni, Shreya, Wallace, E. Diane, Peace, Michelle R., Poklis, Justin L., Jiang, Wei, and Fitting, Sylvia
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- 2024
- Full Text
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4. Inactivation of fatty acid amide hydrolase protects against ischemic reperfusion injury-induced renal fibrogenesis
- Author
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Chen, Chaoling, Wang, Weili, Poklis, Justin L., Lichtman, Aron H., Ritter, Joseph K., Hu, Gaizun, Xie, Dengpiao, and Li, Ningjun
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- 2022
- Full Text
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5. The short-acting synthetic cannabinoid AB-FUBINACA induces physical dependence in mice
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Trexler, Kristen R., Vanegas, S. Olivia, Poklis, Justin L., and Kinsey, Steven G.
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- 2020
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6. Lorcaserin maintenance fails to attenuate heroin vs. food choice in rhesus monkeys
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Townsend, E. Andrew, Negus, S. Stevens, Poklis, Justin L., and Banks, Matthew L.
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- 2020
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7. Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone
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Schwienteck, Kathryn L., Blake, Steven, Bremer, Paul T., Poklis, Justin L., Townsend, E. Andrew, Negus, S. Stevens, and Banks, Matthew L.
- Published
- 2019
- Full Text
- View/download PDF
8. Identification of MDMB-FUBINACA in commercially available e-liquid formulations sold for use in electronic cigarettes
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Peace, Michelle R., Krakowiak, Rose I., Wolf, Carl E., Poklis, Alphonse, and Poklis, Justin L.
- Published
- 2017
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9. Formation of HETE-EAs and dihydroxy derivatives in mouse kidney tissue and analysis by high-performance liquid chromatography tandem mass spectrometry
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Dempsey, Sara K., Gesseck, Ashley M., Ahmad, Ashfaq, Daneva, Zdravka, Ritter, Joseph K., and Poklis, Justin L.
- Published
- 2019
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10. Postmortem tissue distribution of acetyl fentanyl, fentanyl and their respective nor-metabolites analyzed by ultrahigh performance liquid chromatography with tandem mass spectrometry
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Poklis, Justin, Poklis, Alphonse, Wolf, Carl, Mainland, Mary, Hair, Laura, Devers, Kelly, Chrostowski, Leszek, Arbefeville, Elise, Merves, Michele, and Pearson, Julia
- Published
- 2015
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11. The history, evolution, and practice of cannabis and E-cigarette industries highlight necessary public health and public safety considerations.
- Author
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Holt, Alaina K., Poklis, Justin L., and Peace, Michelle R.
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MARIJUANA industry , *PUBLIC safety , *CONSUMER confidence , *PUBLIC health , *MEDICAL marijuana , *CANNABIS (Genus) ,CHEMICAL labeling - Abstract
• In the United States, hemp and marijuana are both Cannabis sativa, differentiated only by whether the plant on dry weight basis is above or below 0.3% Δ9-tetrahydrocannabinol (Δ9-THC). • Pod-based vaping products were devised for discreet vaping and originated in the cannabis industry. • Cannabis vaping is correlated with younger age, higher education, and higher income. • Thorough and transparent labelling of chemicals present in cannabis vaping products is not widespread industry practice. • A federally unregulated cannabis industry and variable state-to-state regulations has enabled low quality products to enter the marketplace which can lead to adverse events and consumer confusion. • Unified and enforced state regulations or federal regulations supported by quality testing and robust research are needed for consumer confidence and safety in cannabis vaping products. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
12. The unexpected identification of the cannabimimetic, 5F-ADB, and dextromethorphan in commercially available cannabidiol e-liquids
- Author
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Poklis, Justin L., Mulder, Haley A., and Peace, Michelle R.
- Published
- 2019
- Full Text
- View/download PDF
13. High performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for detection and quantification of select NLRP3 inhibitors from brain tissue
- Author
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Boice, Ashley G., Poklis, Justin L., Guo, Chunqing, Wang, Xiang-Yang, Zhang, Shijun, and Halquist, Matt S.
- Published
- 2021
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14. Methodology for controlled administration of smoked synthetic cannabinoids JWH-018 and JWH-073.
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Cooper, Ziva D., Poklis, Justin L., and Liu, Fei
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SYNTHETIC marijuana , *PUBLIC health , *DESIGNER drugs , *PHYSIOLOGICAL effects of tobacco , *METABOLITES - Abstract
Synthetic cannabinoids (SCs) are a significant public health concern given their widespread use and severe effects associated with intoxication. However, there is a paucity of controlled human studies investigating the behavioral and physiological effects and pharmacokinetics of these compounds. Designing a reliable method to administer consistent, concentration-dependent synthetic cannabinoids is an integral component of controlled study of these compounds. Further, optimizing methods to assess the parent compounds and metabolites in plasma is critical in order to be able to establish their pharmacokinetics after administration. To develop a reliable method to administer smokable, concentration-dependent SCs, cigarettes were prepared with plant matter adulterated with increasing concentrations of the first generation cannabinoids found in SC products, JWH-018 and JWH-073. Cigarettes were assessed 1–6 months after preparation using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to determine compound stability over time and concentration consistency throughout the cigarettes. Optimal conditions to detect metabolites in human plasma as a function of storage temperature (−4 °C to −80 °C) and time (24 h - 1 month) were also determined. Analyses verified that the method utilized to develop SC cigarettes yielded consistent, concentration-dependent products within 25% of the expected concentrations. JWH-018, JWH-073 and metabolites in spiked plasma were stable under the time and temperature conditions; concentrations were within ±20% of target values. These studies provide techniques and methods to conduct controlled investigations of the dose-dependent effects of first generation SCs to begin understanding risks associated with use. This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’ [ABSTRACT FROM AUTHOR]
- Published
- 2018
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15. Postmortem detection of 25I-NBOMe [2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine] in fluids and tissues determined by high performance liquid chromatography with tandem mass spectrometry from a traumatic death.
- Author
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Poklis, Justin L., Devers, Kelly G., Arbefeville, Elise F., Pearson, Julia M., Houston, Eric, and Poklis, Alphonse
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METHICILLIN , *HIGH performance liquid chromatography , *TANDEM mass spectrometry , *DESIGNER drugs - Abstract
We present a traumatic fatality of a 19-year-old man who had ingested blotter paper containing 25INBOMe [2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine]. Postmortem specimens were analyzed by high performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS). Toxicology findings for fluids based upon blood or urine calibrators were as follows: peripheral blood, 405 pg/mL; heart blood, 410 pg/mL; urine, 2.86 ng/mL; and vitreous humor, 99 pg/mL. While findings based upon the method of standard additions were: gastric contents, 7.1 μg total; bile, 10.9 ng/g; brain, 2.54 ng/g and liver, 7.2 ng/g. To our knowledge the presented case is the first postmortem case of 25I-NBOMe intoxication documented by toxicological analysis of tissues and body fluids. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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16. Inhalation exposure to smoke from synthetic "marijuana" produces potent cannabimimetic effects in mice.
- Author
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Wiebelhaus JM, Poklis JL, Poklis A, Vann RE, Lichtman AH, Wise LE, Wiebelhaus, Jason M, Poklis, Justin L, Poklis, Alphonse, Vann, Robert E, Lichtman, Aron H, and Wise, Laura E
- Abstract
Background: Use of synthetic "marijuana" has increased in recent years, produced adverse effects and prompted the temporary DEA ban of five specific cannabinoid analogs, including JWH-018. The objectives of the current study include determining the chemical content of the herbal product, Buzz, assessing its behavioral effects upon inhalation exposure to mice, determining whether CB(1) receptors mediate its pharmacological activity, and ascertaining its biodisposition in blood and various organs.Methods: Using a nose-only exposure system, mice were exposed to smoke produced from combustion of an herbal incense product, Buzz, which contained 5.4% JWH-018. Cannabimimetic effects following smoke exposure were evaluated using the tetrad procedure, consisting of the following indices: hypomotility, antinociception, catalepsy, and hypothermia. Additionally, blood and tissues were collected for JWH-018 quantification.Results: Inhalation exposure to Buzz produced dose-related tetrad effects similar to marijuana as well as dose-related increased levels of JWH-018 in the blood, brain, heart, kidney, liver, lung, and spleen. The behavioral effects were blocked by rimonabant, a CB(1) receptor antagonist. Effects produced by Buzz were similar in magnitude and time-course to those produced by marijuana, though equipotent doses of Buzz and marijuana yielded considerably lower brain levels of JWH-018 than THC for the respective materials.Conclusions: Inhalation exposure to a product containing JWH-018 penetrates into the brain and other organs and produces CB(1) receptor-mediated behavioral pharmacological effects in mice. The increased potency of JWH-018 compared to THC, the variable amount of drug added to various herbal products, and unknown toxicity, undoubtedly contribute to public health risks of synthetic cannabinoids. [ABSTRACT FROM AUTHOR]- Published
- 2012
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17. Detection and disposition of JWH-018 and JWH-073 in mice after exposure to "Magic Gold" smoke.
- Author
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Poklis, Justin L, Amira, Dorra, Wise, Laura E, Wiebelhaus, Jason M, Haggerty, Brenda J, and Poklis, Alphonse
- Abstract
The disposition in mice of the cannabimimetics JWH-018 and JWH-073 in blood and brain following inhalation of the smoke from the herbal incense product (HIP) "Magic Gold" containing 3.6% JWH-018, 5.7% JWH-073 and less than 0.1% JWH-398 (w/w) is presented. Specimens were analyzed by HPLC/MS/MS. The validation of the method is also presented. Five C57BL6 mice were sacrificed 20 min after exposure to the smoke of 200 mg of "Magic Gold" and a second set of five exposed mice were sacrificed after 20 h. Twenty minutes after exposure to "Magic Gold" smoke, blood concentrations of JWH-018 ranged from 42 to 160 ng/mL (mean: 88 ng/mL ± 42) and those of JWH-073 ranged from 67 to 244 ng/mL (mean: 134 ng/mL ± 62). Brain concentrations 20 min after exposure to "Magic Gold" smoke for JWH-018 ranged from 225 to 453 ng/g (mean: 317 ng/g ± 81) and those of JWH-073 ranged from 412 to 873 ng/g (mean: 584 ng/g ± 163). Twenty hours after exposure to "Magic Gold" smoke, JWH-018 was detected and quantified in only two of the five blood samples. Blood concentrations of JWH-018 were 3.4 ng/mL and 9.4 ng/mL. JWH-073 was detected in only one blood specimen 20 h after exposure at 4.3 ng/mL. Brain concentrations 20 h post exposure for JWH-018 ranged from 7 to 32 ng/g (mean: 19 ng/g ± 9). JWH-073 was not detected in 20 h post exposure brain specimens. JWH-398 was not detected in any of the blood or brain samples. The disposition data presented with the limited data available from human experience provide reasonable expectations for forensic toxicologists in JWH-018 or JWH-073 cases. As with THC after smoking marijuana, blood and brain concentrations of JWH-018 and JWH-073 after HIP smoking can be expected to rise initially to readily detected values, and then drop dramatically over the next few hours to several ng/mL or ng/g, and finally to be at extremely low or undetectable concentrations by 24h apparently due to extensive biotransformation, and redistribution to body fat. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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- View/download PDF
18. The unexpected identification of the cannabimimetic, 5F-ADB, and dextromethorphan in commercially available cannabidiol e-liquids.
- Author
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Poklis, Justin L, Mulder, Haley A, and Peace, Michelle R
- Abstract
Electronic cigarettes (e-cigarettes) were developed as an alternative method for nicotine delivery and had a significant surge in popularity. E-liquids are formulations used in e-cigarettes, and consist of a ratio of propylene glycol (PG) and vegetable glycerin (VG), a pharmaceutical and/or herbal remedy and, usually, a flavoring agent. Presented is the evaluation of nine cannabidiol (CBD) e-liquids from a single manufacturer for cannabinoids and other psychoactive compounds by Direct Analysis in Real Time Mass Spectrometry (DART-MS) and Gas Chromatography Mass Spectrometry (GC/MS). The analysis of these products resulted in the detection of CBD in all nine produces and the unexpected detections of 5-fluoro MDMB-PINACA (5F-ADB) in four of the products and dextromethorphan (DXM) in one of the products. The analysis of these products illustrates the potential quality control issues that can occur in an unregulated industry. CBD products are believed by many users to offer heath benefits, but the detection of a dangerous cannabimimetic, 5F-ADB, and DXM in these products illustrates the need for oversight. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
19. Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS.
- Author
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Hermes, Douglas J., Xu, Changqing, Poklis, Justin L., Niphakis, Micah J., Cravatt, Benjamin F., Mackie, Ken, Lichtman, Aron H., Ignatowska-Jankowska, Bogna M., and Fitting, Sylvia
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NEUROPROTECTIVE agents , *FATTY acids , *ENZYME inhibitors , *NEUROTOXIC agents , *METHYL aspartate - Abstract
Abstract The HIV-1 transactivator of transcription (Tat) is a neurotoxin involved in the pathogenesis of HIV-1 associated neurocognitive disorders (HAND). The neurotoxic effects of Tat are mediated directly via AMPA/NMDA receptor activity and indirectly through neuroinflammatory signaling in glia. Emerging strategies in the development of neuroprotective agents involve the modulation of the endocannabinoid system. A major endocannabinoid, anandamide (N -arachidonoylethanolamine, AEA), is metabolized by fatty acid amide hydrolase (FAAH). Here we demonstrate using a murine prefrontal cortex primary culture model that the inhibition of FAAH, using PF3845, attenuates Tat-mediated increases in intracellular calcium, neuronal death, and dendritic degeneration via cannabinoid receptors (CB 1 R and CB 2 R). Live cell imaging was used to assess Tat-mediated increases in [Ca2+] i , which was significantly reduced by PF3845. A time-lapse assay revealed that Tat potentiates cell death while PF3845 blocks this effect. Additionally PF3845 blocked the Tat-mediated increase in activated caspase-3 (apoptotic marker) positive neurons. Dendritic degeneration was characterized by analyzing stained dendritic processes using Imaris and Tat was found to significantly decrease the size of processes while PF3845 inhibited this effect. Incubation with CB 1 R and CB 2 R antagonists (SR141716A and AM630) revealed that PF3845-mediated calcium effects were dependent on CB 1 R, while reduced neuronal death and degeneration was CB 2 R-mediated. PF3845 application led to increased levels of AEA, suggesting the observed effects are likely a result of increased endocannabinoid signaling at CB 1 R/CB 2 R. Our findings suggest that modulation of the endogenous cannabinoid system through inhibition of FAAH may be beneficial in treatment of HAND. Highlights • Neuronal injury is a major component of HAND pathology. • Endocannabinoid drugs show promise as a treatment for neurodegenerative disease. • Assessment of cannabinoid based interventions in neuroAIDS is limited. • FAAH inhibition blocks Tat induced neuronal dysfunction via cannabinoid receptors. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
20. Pharmacological evaluation of the natural constituent of Cannabis sativa, cannabichromene and its modulation by Δ(9)-tetrahydrocannabinol.
- Author
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Delong GT, Wolf CE, Poklis A, Lichtman AH, DeLong, Gerald T, Wolf, Carl E, Poklis, Alphonse, and Lichtman, Aron H
- Abstract
In contrast to the numerous reports on the pharmacological effects of Δ(9)-tetrahydrocannabinol (THC), the pharmacological activity of another substituent of Cannabis sativa, cannabichromene (CBC) remains comparatively unknown. In the present study, we investigated whether CBC elicits cannabinoid activity in the tetrad assay, which consists of the following four endpoints: hypomotility, antinociception, catalepsy, and hypothermia. Because cannabinoids are well documented to possess anti-inflammatory properties, we examined CBC, THC, and combination of both phytocannabinoids in the lipopolysaccharide (LPS) paw edema assay. CBC elicited activity in the tetrad that was not blocked by the CB(1) receptor antagonist, rimonabant. Moreover, a behaviorally inactive dose of THC augmented the effects of CBC in the tetrad that was associated with an increase in THC brain concentrations. Both CBC and THC elicited dose-dependent anti-inflammatory effects in the LPS-induced paw edema model. The CB(2) receptor, SR144528 blocked the anti-edematous actions of THC, but not those produced by CBC. Isobolographic analysis revealed that the anti-edematous effects of these cannabinoids in combination were additive. Although CBC produced pharmacological effects, unlike THC, its underlying mechanism of action did not involve CB(1) or CB(2) receptors. In addition, there was evidence of a possible pharmacokinetic component in which CBC dose-dependently increased THC brain levels following an i.v. injection of 0.3mg/kg THC. In conclusion, CBC produced a subset of behavioral activity in the tetrad assay and reduced LPS-induced paw edema through a noncannabinoid receptor mechanism of action. These effects were augmented when CBC and THC were co-administered. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
21. Preclinical investigation of the abused synthetic cannabinoid CP47,497.
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Samano, Kimberly L., Poklis, A., and Lichtman, A.H.
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- 2014
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22. Determination of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine enantiomers in whole blood
- Author
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Fitzgerald, R.L., Blanke, R.V., Glennon, R.A., Yousif, M.Y., Rosecrans, J.A., and Poklis, A.
- Published
- 1989
- Full Text
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23. Determination of pentazocine and tripelennamine in blood of T's and blues addicts by gas—liquid chromatography with a nitrogen detector
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Mackell, Mary Ann and Poklis, Alphonse
- Published
- 1982
- Full Text
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24. ABH Gel Is Not Absorbed From the Skin of Normal Volunteers.
- Author
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Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, and Parker G
- Abstract
BACKGROUND: Lorazepam (Ativan((R))), diphenhydramine (Benadryl((R))), haloperidol (Haldol((R))) (ABH) topical gel is currently widely used for nausea in hospice because of perceived efficacy and low cost and has been suggested for cancer chemotherapy. However, there are no studies of absorption, a prerequisite for effectiveness. We completed this study to establish whether ABH gel drugs are absorbed, as a prerequisite to effectiveness. INTERVENTION: Ten healthy volunteers, aged 25 to 58 years (mean 37 years), two African Americans and eight Caucasian Americans, applied the standard 1.0mL dose (2mg of lorazepam, 25mg of diphenhydramine, and 2mg of haloperidol in a pluronic lecithin organogel), rubbed on the volar surface of the wrists by the subject. MEASURES: Blood samples were obtained at 0, 30, 60, 90, 120, 180, and 240 minutes. Plasma concentrations were analyzed by liquid chromatography-tandem mass spectrometry using deuterated internal standards for each drug. OUTCOMES: No lorazepam or haloperidol was detected in any sample from any of the 10 volunteers down to a level of 0.05ng/mL. Diphenhydramine was found in multiple plasma samples at concentrations >0.05ng/mL in three patients, with the highest concentration of 0.30ng/mL in one person at 240 minutes. Overall, five of 10 patients exhibited detectable diphenhydramine in one or more samples, supporting limited absorption. No subject noted any side effects. CONCLUSIONS/LESSONS LEARNED: As commonly used, none of the lorazepam, haloperidol, or diphenhydramine in ABH gel is absorbed in sufficient quantities to be effective in the treatment of nausea and vomiting. Diphenhydramine is erratically absorbed at subtherapeutic levels. The efficacy of ABH gel should be confirmed in randomized trials before its use is recommended. [ABSTRACT FROM AUTHOR]
- Published
- 2012
25. Pharmacological evaluation of the natural constituent of Cannabis sativa, cannabichromene and its modulation by Δ9-tetrahydrocannabinol
- Author
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DeLong, Gerald T., Wolf, Carl E., Poklis, Alphonse, and Lichtman, Aron H.
- Subjects
- *
TETRAHYDROCANNABINOL , *HEMP , *PHARMACOKINETICS , *BIOLOGICAL assay , *BIOCHEMICAL mechanism of action , *CELL receptors , *DRUG administration , *HYPOTHERMIA - Abstract
Abstract: In contrast to the numerous reports on the pharmacological effects of Δ9-tetrahydrocannabinol (THC), the pharmacological activity of another substituent of Cannabis sativa, cannabichromene (CBC) remains comparatively unknown. In the present study, we investigated whether CBC elicits cannabinoid activity in the tetrad assay, which consists of the following four endpoints: hypomotility, antinociception, catalepsy, and hypothermia. Because cannabinoids are well documented to possess anti-inflammatory properties, we examined CBC, THC, and combination of both phytocannabinoids in the lipopolysaccharide (LPS) paw edema assay. CBC elicited activity in the tetrad that was not blocked by the CB1 receptor antagonist, rimonabant. Moreover, a behaviorally inactive dose of THC augmented the effects of CBC in the tetrad that was associated with an increase in THC brain concentrations. Both CBC and THC elicited dose-dependent anti-inflammatory effects in the LPS-induced paw edema model. The CB2 receptor, SR144528 blocked the anti-edematous actions of THC, but not those produced by CBC. Isobolographic analysis revealed that the anti-edematous effects of these cannabinoids in combination were additive. Although CBC produced pharmacological effects, unlike THC, its underlying mechanism of action did not involve CB1 or CB2 receptors. In addition, there was evidence of a possible pharmacokinetic component in which CBC dose-dependently increased THC brain levels following an i.v. injection of 0.3mg/kg THC. In conclusion, CBC produced a subset of behavioral activity in the tetrad assay and reduced LPS-induced paw edema through a noncannabinoid receptor mechanism of action. These effects were augmented when CBC and THC were co-administered. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
26. Chronic constriction injury reduces cannabinoid receptor 1 activity in the rostral anterior cingulate cortex of mice
- Author
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Hoot, Michelle R., Sim-Selley, Laura J., Poklis, Justin L., Abdullah, Rehab A., Scoggins, Krista L., Selley, Dana E., and Dewey, William L.
- Subjects
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NERVOUS system injuries , *CANNABINOIDS , *DRUG receptors , *CEREBRAL cortex , *DESENSITIZATION (Psychotherapy) , *PAIN , *LABORATORY mice , *NEUROPATHY - Abstract
Abstract: The present studies examined the effect of chronic neuropathic pain on cannabinoid receptor density and receptor-mediated G-protein activity within supraspinal brain areas involved in pain processing and modulation in mice. Chronic constriction injury (CCI) produced a significant decrease in WIN 55,212-2-stimulated [35S]GTPγS binding in membranes prepared from the rostral anterior cingulate cortex (rACC) of CCI mice when compared to sham-operated controls. Saturation binding with [3H]SR 141716A in membranes of the rACC showed no significant differences in binding between CCI and sham mice. Analysis of levels of the endocannabinoids anandamide (AEA) or 2-arachidonoylglycerol (2-AG) in the rACC following CCI showed no significant differences between CCI and sham mice. These data suggest that CCI produced desensitization of the cannabinoid 1 receptor in the rACC in the absence of an overall decrease in cannabinoid 1 receptor density or change in levels of AEA or 2-AG. These data are the first to show alterations in cannabinoid receptor function in the rostral anterior cingulate cortex in response to a model of neuropathic pain. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
27. Drinking water exposure to cadmium, an environmental contaminant, results in the exacerbation of autoimmune disease in the murine model
- Author
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Leffel, Elizabeth K., Wolf, Carl, Poklis, Alphonse, and White Jr, Kimber L.
- Subjects
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CADMIUM , *AUTOIMMUNITY , *ANTINUCLEAR factors - Abstract
Cadmium is a pervasive environmental contaminant. The primary route of exposure to the general population occurs via contaminated drinking water or food supplies. Our hypothesis was that cadmium could be a trigger for inducing autoimmune disease (AD) in genetically predisposed populations. Therefore, New Zealand Black/White F1 (NZBW) mice were exposed to cadmium via drinking water. Mice were exposed to: 0, 3, 30, 3000 or 10 000 parts per billion (ppb) of cadmium in tap water for 2, 4, 28, or 31 weeks. After 4 weeks of exposure, in the group of mice exposed to 10 000 ppb cadmium, there was an increased incidence of antinuclear antibodies (ANA). There was also deposition of immune complexes in all groups after 4 weeks of exposure. After 31 weeks, there were increases in IgG2a in mice exposed to low doses of cadmium. In an attempt to establish the progression from an autoimmune reaction to the development of AD, the biological marker for AD, proteinuria, was assessed. Onset of proteinuria was exacerbated by 11 weeks in mice exposed to cadmium. This data suggests that short-term exposure may result in a type of autoimmune reaction since the mice are beginning to produce ANA after only 4 weeks of exposure and there is immune-complex deposition in the kidney. Long-term exposure to cadmium appears to result in the exacerbation of AD as indicated by the development of proteinuria and continued presence of immune complexes in the kidney. The mechanism may involve the increased production of IgG2a, which is capable of forming immune complexes and causing autoimmune glomerulonephritis. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
28. Thermal antinociceptive responses to alcohol in DBA/2J and C57BL/6J inbred male and female mouse strains.
- Author
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White, Alyssa, Caillaud, Martial, Carper, Moriah, Poklis, Justin, Miles, Michael F., and Damaj, M. Imad
- Subjects
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ALCOHOLISM , *BLOOD alcohol , *LABORATORY mice , *OPIOID receptors , *ALCOHOL - Abstract
The phenomenon of alcohol analgesia and tolerance can facilitate misuse and lead to the development of alcohol use disorder (AUD). Numerous alcohol-induced behaviors are genetically influenced; however, it is unknown if alcohol analgesia has a genetic contribution. Rodent studies have shown that alcohol responses differ vastly between two widely studied inbred strains of mice, C57BL/6 J (B6) and DBA/2 J (D2). Here, we used B6 and D2 mice as an initial behavioral genetic analysis of acute alcohol-induced antinociception. The antinociceptive effect of orally-administered alcohol was characterized using the hot plate test in B6 and D2 mice of both sexes. Using the opioid receptor antagonist naloxone, the involvement of the opioid system was assessed. Locomotor activity and blood alcohol concentrations were also measured. Ovariectomized mice were used to evaluate the influence of ovarian sex hormones on alcohol-induced antinociception. Alcohol induced an antinociceptive effect in B6 and D2 male mice in a time- and dose-dependent manner. In addition, D2 male mice were more sensitive to the antinociceptive effect of alcohol than B6 male mice. However, locomotion is not impeded by the tested doses of alcohol in B6 mice. Female D2 and B6 mice failed to show significant antinociceptive effects in alcohol dose-response studies. In addition, alcohol-induced antinociception was still not evident in ovariectomized female mice. Male mice of both strains developed tolerance to this effect after repeated administration of alcohol. Strain differences were found in blood alcohol concentration. Finally, no difference was found in the blockade of alcohol antinociception by 2 mg/kg naloxone. Our results indicate that the antinociceptive effects of alcohol in the hot plate test are influenced by strain and sex. These findings support further genetic analysis of alcohol-induced antinociception to identify operative mechanisms and better assess the contribution of this phenotype to AUD. • Alcohol induces an antinociceptive effect in DBA/2J and C57BL/6J male mice in a time- and dose-dependent manner. • DBA/2J male mice are more sensitive to the antinociceptive effect of alcohol compared to C57BL/6J male mice. • Female DBA/2J and C57BL/6J mice are less sensitive to the antinociceptive effect of alcohol compared to male mice. • Male DBA/2J and C57BL/6 mice develop tolerance to alcohol-induced antinociception after repeated administration. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
29. Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex.
- Author
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Sticht, Martin A., Limebeer, Cheryl L., Rafla, Benjamin R., Abdullah, Rehab A., Poklis, Justin L., Ho, Winnie, Niphakis, Micah J., Cravatt, Benjamin F., Sharkey, Keith A., Lichtman, Aron H., and Parker, Linda A.
- Subjects
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CANNABINOIDS , *NAUSEA , *GASTROINTESTINAL diseases , *CEREBRAL cortex , *LITHIUM chloride - Abstract
Cannabinoid (CB) agonists suppress nausea in humans and animal models; yet, their underlying neural substrates remain largely unknown. Evidence suggests that the visceral insular cortex (VIC) plays a critical role in nausea. Given the expression of CB 1 receptors and the presence of endocannabinoids in this brain region, we hypothesized that the VIC endocannabinoid system regulates nausea. In the present study, we assessed whether inhibiting the primary endocannabinoid hydrolytic enzymes in the VIC reduces acute lithium chloride (LiCl)-induced conditioned gaping, a rat model of nausea. We also quantified endocannabinoid levels during an episode of nausea, and assessed VIC neuronal activation using the marker, c-Fos. Local inhibition of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of 2-arachidonylglycerol (2-AG), reduced acute nausea through a CB 1 receptor mechanism, whereas inhibition of fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of anandamide (AEA), was without effect. Levels of 2-AG were also selectively elevated in the VIC during an episode of nausea. Inhibition of MAGL robustly increased 2-AG in the VIC, while FAAH inhibition had no effect on AEA. Finally, we demonstrated that inhibition of MAGL reduced VIC Fos immunoreactivity in response to LiCl treatment. Taken together, these findings provide compelling evidence that acute nausea selectively increases 2-AG in the VIC, and suggests that 2-AG signaling within the VIC regulates nausea by reducing neuronal activity in this forebrain region. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
30. Relationship between discriminative stimulus effects and plasma methamphetamine and amphetamine levels of intramuscular methamphetamine in male rhesus monkeys.
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Banks, Matthew L., Smith, Douglas A., Kisor, David F., and Poklis, Justin L.
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METHAMPHETAMINE , *STIMULUS & response (Psychology) , *INTRAMUSCULAR injections , *DRUG abuse , *DRUG metabolism , *BLOOD plasma - Abstract
Methamphetamine is a globally abused drug that is metabolized to amphetamine, which also produces abuse-related behavioral effects. However, the contributing role of methamphetamine metabolism to amphetamine in methamphetamine's abuse-related subjective effects is unknown. This preclinical study was designed to determine 1) the relationship between plasma methamphetamine levels and methamphetamine discriminative stimulus effects and 2) the contribution of the methamphetamine metabolite amphetamine in the discriminative stimulus effects of methamphetamine in rhesus monkeys. Adult male rhesus monkeys (n = 3) were trained to discriminate 0.18 mg/kg intramuscular (+)-methamphetamine from saline in a two-key food-reinforced discrimination procedure. Time course of saline, (+)-methamphetamine (0.032–0.32 mg/kg), and (+)-amphetamine (0.032–0.32 mg/kg) discriminative stimulus effects were determined. Parallel pharmacokinetic studies were conducted in the same monkeys to determine plasma methamphetamine and amphetamine levels after methamphetamine administration and amphetamine levels after amphetamine administration for correlation with behavior in the discrimination procedure. Both methamphetamine and amphetamine produced full, ≥ 90%, methamphetamine-like discriminative stimulus effects. Amphetamine displayed a slightly, but significantly, longer duration of action than methamphetamine in the discrimination procedure. Both methamphetamine and amphetamine behavioral effects were related to methamphetamine and amphetamine plasma levels by a clockwise hysteresis loop indicating acute tolerance had developed to the discriminative stimulus effects. Furthermore, amphetamine levels after methamphetamine administration were absent when methamphetamine stimulus effects were greatest and peaked when methamphetamine discriminative stimulus effects returned to saline-like levels. Overall, these results demonstrate the methamphetamine metabolite amphetamine does not contribute to methamphetamine's abuse-related subjective effects. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
31. Differences across sexes on head-twitch behavior and 5-HT2A receptor signaling in C57BL/6J mice.
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Jaster, Alaina M., Younkin, Jason, Cuddy, Travis, de la Fuente Revenga, Mario, Poklis, Justin L., Dozmorov, Mikhail G., and González-Maeso, Javier
- Subjects
- *
LABORATORY mice , *LSD (Drug) , *SEX (Biology) , *SEROTONIN receptors , *PSILOCYBIN - Abstract
• Head twitch response (HTR) provides a functional readout of psychedelic activity in rodent models. • Differences across sexes in HTR has not been explicitly studied. • The psychedelic DOI elicited more HTR in female as compared to male C57BL/6J mice. • This sex-dependent effect was not observed in 129S6/SvEv mice. • Pharmacokinetic properties of DOI differed among sexes in C57BL/6J mice. Psychedelics, also known as classical hallucinogens, affect processes related to perception, cognition and sensory processing mostly via the serotonin 5-HT 2A receptor (5-HT 2A R). This class of psychoactive substances, which includes lysergic acid diethylamide (LSD), psilocybin, mescaline and the substituted amphetamine 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), is receiving renewed attention for their potential therapeutic properties as it relates to psychiatric conditions such as depression and substance use disorders. Current studies focused on the potentially clinical effects of psychedelics on human subjects tend to exclude sex as a biological variable. Much of the understanding of psychedelic pharmacology is derived from rodent models, but most of this preclinical research has only focused on male mice. Here we tested the effects of DOI on head-twitch behavior (HTR) – a mouse behavioral proxy of human psychedelic potential – in male and female mice. DOI elicited more HTR in female as compared to male C57BL/6J mice, a sex-specific exacerbated behavior that was not observed in 129S6/SvEv animals. Volinanserin (or M100907) – a 5-HT 2A R antagonist – fully prevente DOI induced HTR in male and female C57BL/6J mice. Accumulation of inositol monophosphate (IP 1) in the frontal cortex upon DOI administration showed no sex-related effect in C57BL/6J mice. However, the pharmacokinetic properties of DOI differed among sexes – brain and plasma concentrations of DOI were lower 30 and 60 min after drug administration in female as compared to male C57BL/6J mice. Together, these results suggest strain-dependent and sex-related differences in the behavioral and pharmacokinetic profiles of the 5-HT 2A R agonist DOI in C57BL/6J mice, and support the importance of studying sex as a biological variable in preclinical psychedelic research. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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32. Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice.
- Author
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Sierra, Salvador, Muchhala, Karan H., Jessup, Donald K., Contreras, Katherine M., Shah, Urjita H., Stevens, David L., Jimenez, Jennifer, Cuno Lavilla, Xiomara K., de la Fuente Revenga, Mario, Lippold, Kumiko M., Shen, Shanwei, Poklis, Justin L., Qiao, Liya Y., Dewey, William L., Akbarali, Hamid I., Damaj, M. Imad, and González-Maeso, Javier
- Subjects
- *
SEROTONIN , *SEROTONIN receptors , *OPIOID receptors , *DORSAL root ganglia , *MICE , *G protein coupled receptors , *PAIN management - Abstract
Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT 2A receptor (5-HT 2A R) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT 2A R knockout (5-HT 2A R −/− ) male, but not female mice; an effect that was reversed by Cre-loxP -mediated selective expression of 5-HT 2A R in dorsal root ganglion (DRG) neurons of 5-HT 2A R −/− littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT 2A R −/− animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT 2A R expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant. [Display omitted] • Adjunctive volinanserin augments oxycodone-induced antinociception in male but not female mice. • Adjunctive volinanserin does not affect oxycodone-induced conditioned place preference in male or female mice. • Adjunctive volinanserin reduces oxycodone-induced locomotor sensitization in male and female mice. • 5-HT 2A receptor in dorsal root ganglion neurons is necessary for the adjunctive antinociceptive effect of volinanserin. • Volinanserin may serve as a new approach to augment opioid-induced analgesia. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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33. Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents.
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Wiley, Jenny L., Walentiny, D. Matthew, Wright, M. Jerry, Beardsley, Patrick M., Burston, James J., Poklis, Justin L., Lichtman, Aron H., and Vann, Robert E.
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- *
CANNABINOIDS , *TETRAHYDROCANNABINOL , *LABORATORY mice , *MARIJUANA , *PSYCHIATRIC drugs , *ANANDAMIDE , *PHARMACOLOGY , *THERAPEUTICS - Abstract
Abstract: The mechanism through which marijuana produces its psychoactive effects is Δ9-tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical “first step” in determination of the role of these endocannabinoids in THC׳s psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC׳s discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
34. Visfatin-induced lipid raft redox signaling platforms and dysfunction in glomerular endothelial cells
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Boini, Krishna M., Zhang, Chun, Xia, Min, Han, Wei-Qing, Brimson, Christopher, Poklis, Justin L., and Li, Pin-Lan
- Subjects
- *
GLOMERULAR filtration rate , *ELECTRON paramagnetic resonance , *LIPOTROPIN , *BILAYER lipid membranes , *SPHINGOLIPIDS , *FREE radical reactions , *OXIDATIVE stress - Abstract
Abstract: Adipokines have been reported to contribute to glomerular injury during obesity or diabetes mellitus. However, the mechanisms mediating the actions of various adipokines on the kidney remained elusive. The present study was performed to determine whether acid sphingomyelinase (ASM)-ceramide associated lipid raft (LR) clustering is involved in local oxidative stress in glomerular endothelial cells (GECs) induced by adipokines such as visfatin and adiponectin. Using confocal microscopy, visfatin but not adiponectin was found to increase LRs clustering in the membrane of GECs in a dose and time dependent manner. Upon visfatin stimulation ASMase activity was increased, and an aggregation of ASMase product, ceramide and NADPH oxidase subunits, gp91 phox and p47 phox was observed in the LR clusters, forming a LR redox signaling platform. The formation of this signaling platform was blocked by prior treatment with LR disruptor filipin, ASMase inhibitor amitriptyline, ASMase siRNA, gp91 phox siRNA and adiponectin. Corresponding to LR clustering and aggregation of NADPH subunits, superoxide (O2 −) production was significantly increased (2.7 folds) upon visfatin stimulation, as measured by electron spin resonance (ESR) spectrometry. Functionally, visfatin significantly increased the permeability of GEC layer in culture and disrupted microtubular networks, which were blocked by inhibition of LR redox signaling platform formation. In conclusion, the injurious effect of visfatin, but not adiponectin on the glomerular endothelium is associated with the formation of LR redox signaling platforms via LR clustering, which produces local oxidative stress resulting in the disruption of microtubular networks in GECs and increases the glomerular permeability. [Copyright &y& Elsevier]
- Published
- 2010
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- View/download PDF
35. Methylnaltrexone crosses the blood-brain barrier and attenuates centrally-mediated behavioral effects of morphine and oxycodone in mice.
- Author
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Walentiny, D. Matthew, Komla, Essie, Moisa, Léa T., Mustafa, Mohammed A., Poklis, Justin L., Akbarali, Hamid I., and Beardsley, Patrick M.
- Subjects
- *
OPIOID analgesics , *ANALGESICS , *BLOOD-brain barrier , *OXYCODONE , *LIQUID chromatography-mass spectrometry , *OPIOID receptors , *MORPHINE - Abstract
Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic tolerance based on experiments conducted in mice. However, reports indicate that MNTX is demethylated to naltrexone (NTX) in mice, and NTX may subsequently cross the blood-brain barrier to antagonize centrally-mediated opioid effects. The goal of this study was to determine whether MNTX alters centrally-mediated behaviors elicited by the opioid analgesics, morphine and oxycodone, and to quantify concentrations of MNTX and NTX in blood and brain following their administration in mice. Combinations of MNTX and morphine were tested under acute and chronic conditions in thermal nociceptive assays. Effects of MNTX and NTX pretreatment were assessed in an oxycodone discrimination operant procedure. Blood and brain concentrations of these antagonists were quantified after their administration using liquid chromatography-mass spectrometry. MNTX dose-dependently attenuated acute and chronic morphine antinociception. MNTX and NTX dose-dependently antagonized the discriminative stimulus effects of oxycodone. MNTX and NTX were detected in both blood and brain after administration of MNTX, confirming its demethylation and demonstrating that MNTX itself can cross the blood-brain barrier. These results provide converging behavioral and analytical evidence that MNTX administration in mice attenuates centrally-mediated effects produced by opioid analgesics and results in functional concentrations of MNTX and NTX in blood and brain. Collectively, these findings indicate that MNTX cannot be administered systemically in mice for making inferences that its effects are peripherally restricted. • Methylnaltrexone is a peripherally restricted opioid receptor antagonist. • In mice, methylnaltrexone antagonized centrally-mediated morphine antinociception. • Methylnaltrexone reversed the discriminative stimulus effects of oxycodone. • Methylnaltrexone was detected in mouse brain after its administration. • Methylnaltrexone is not suitable to study peripherally-mediated processes in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
36. Abnormal podocyte TRPML1 channel activity and exosome release in mice with podocyte-specific Asah1 gene deletion.
- Author
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Li, Guangbi, Huang, Dandan, Bhat, Owais M., Poklis, Justin L., Zhang, Aolin, Zou, Yao, Kidd, Jason, Gehr, Todd W.B., and Li, Pin-Lan
- Subjects
- *
DELETION mutation , *CALCIUM channels , *SPHINGOSINE kinase , *GENE knockout , *LYSOSOMES , *MICE , *KNOCKOUT mice - Abstract
Podocytopathy and associated nephrotic syndrome (NS) have been reported in a knockout mouse strain (Asah1fl/fl/PodoCre) with a podocyte-specific deletion of α subunit (the main catalytic subunit) of acid ceramidase (Ac). However, the pathogenesis of podocytopathy of these mice remains unknown. The present study tested whether exosome release from podocytes is enhanced due to Asah1 gene knockout, which may serve as a pathogenic mechanism switching on podocytopathy and associated NS in Asah1fl/fl/PodoCre mice. We first demonstrated the remarkable elevation of urinary exosome excretion in Asah1fl/fl/PodoCre mice compared with WT/WT mice, which was accompanied by significant Annexin-II (an exosome marker) accumulation in glomeruli of Asah1fl/fl/PodoCre mice, as detected by immunohistochemistry. In cell studies, we also confirmed that Asah1 gene knockout enhanced exosome release in the primary cultures of podocyte isolated from Asah1fl/fl/PodoCre mice compared to WT/WT mice. In the podocytes from Asah1fl/fl/PodoCre mice, the interactions of lysosome and multivesicular body (MVB) were demonstrated to be decreased in comparison with those from their control littermates, suggesting reduced MVB degradation that may lead to increase in exosome release. Given the critical role of transient receptor potential mucolipin 1 (TRPML1) channel in Ca2+-dependent lysosome trafficking and consequent lysosome-MVB interaction, we tested whether lysosomal Ca2+ release through TRPML1 channels is inhibited in the podocytes of Asah1fl/fl/PodoCre mice. By GCaMP3 Ca2+ imaging, it was found that lysosomal Ca2+ release through TRPML1 channels was substantially suppressed in podocytes with Asah1 gene deletion. As an Ac product, sphingosine was found to rescue TRPML1 channel activity and thereby recover lysosome-MVB interaction and reduce exosome release of podocytes from Asah1fl/fl/PodoCre mice. Combination of N , N -dimethylsphingosine (DMS), a potent sphingosine kinase inhibitor, and sphingosine significantly inhibited urinary exosome excretion of Asah1fl/fl/PodoCre mice. Moreover, rescue of Aash1 gene expression in podocytes of Asah1fl/fl/PodoCre mice showed normal ceramide metabolism and exosome secretion. Based on these results, we conclude that the normal expression of Ac importantly contributes to the control of TRPML1 channel activity, lysosome-MVB interaction, and consequent exosome release from podocytes. Asah1 gene defect inhibits TRPML1 channel activity and thereby enhances exosome release, which may contribute to the development of podocytopathy and associated NS. • Podocyte-specific Asah1 gene knockout elevates urinary exosome excretion. • Asah1 gene knockout inhibits lysosome-MVB interaction and thereby enhances exosome release from podocytes. • TRPML1 channel activity is inhibited by Asah1 gene knockout. • Enhancement of TRPML1 channel activity attenuates exosome secretion from podocytes with Asah1 gene knockout. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
37. Adjunctive effect of the serotonin 5-HT2C receptor agonist lorcaserin on opioid-induced antinociception in mice.
- Author
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Sierra, Salvador, Lippold, Kumiko M., Stevens, David L., Poklis, Justin L., Dewey, William L., and González-Maeso, Javier
- Subjects
- *
OPIOID analgesics , *SEROTONIN agonists , *SEROTONIN , *SEROTONIN receptors , *OPIOID receptors , *DRUG side effects , *G protein coupled receptors - Abstract
Opioid-sparing adjuncts are treatments that aim to reduce the overall dose of opioids needed to achieve analgesia, hence decreasing the burden of side effects through alternative mechanisms of action. Lorcaserin is a serotonin 5-HT 2C receptor (5-HT 2C R) agonist that has recently been reported to reduce abuse-related effects of the opioid analgesic oxycodone. The goal of our studies was to evaluate the effects of adjunctive lorcaserin on opioid-induced analgesic-like behavior using the tail-flick reflex (TFR) test as a mouse model of acute thermal nociception. We show that whereas subcutaneous (s.c.) administration of lorcaserin alone was inactive on the TFR test, adjunctive lorcaserin (s.c.) significantly increased the potency of oxycodone as an antinociceptive drug. This effect was prevented by the 5-HT 2C R antagonist SB242084. A similar lorcaserin (s.c.)-induced adjunctive phenotype was observed upon administration of the opioid analgesics morphine and fentanyl. Remarkably, we also show that, opposite to the effects observed via s.c. administration, intrathecal (i.t.) administration of lorcaserin alone induced antinociceptive TFR behavior, an effect that was not prevented by the opioid receptor antagonist naloxone. This route of administration (i.t.) also led to a significant augmentation of oxycodone-induced antinociception. Lorcaserin (s.c.) did not alter the brain or blood concentrations of oxycodone, which suggests that its adjunctive effects on opioid-induced antinociception do not depend upon changes in opioid metabolism. Together, these data indicate that lorcaserin-mediated activation of the 5-HT 2C R may represent a new pharmacological approach to augment opioid-induced antinociception. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'. • Intrathecal administration of lorcaserin induces antinociception whereas subcutaneous injection lacks antinociceptive effect. • Adjunctive subcutaneous administration of lorcaserin augments opioid-induced antinociception. • These included oxycodone, morphine and fentanyl. • Adjunctive antinociceptive effect of lorcaserin is prevented by a 5-HT 2C receptor antagonist. • Lorcaserin may serve as a new approach to augment opioid-induced analgesia. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
38. In vivo evaluation of the CB1 allosteric modulator LDK1258 reveals CB1-receptor independent behavioral effects.
- Author
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Mustafa, Mohammed, Donvito, Giulia, Moncayo, Lauren, Swafford, Amelia, Poklis, Justin, Grauer, Ralph, Olszewska, Teresa, Ignatowska-Jankowska, Bogna, Kendall, Debra A., Lu, Dai, and Lichtman, Aron H.
- Subjects
- *
NOCICEPTIVE pain , *SCIATIC nerve injuries , *ALLOSTERIC regulation , *FOOD consumption , *ANANDAMIDE , *BIOCHEMICAL mechanism of action - Abstract
In the present study, we examined whether LDK1258, which produces strong CB 1 receptor allosteric effects in in vitro assays, would elicit in vivo effects consistent with allosteric activity. In initial studies, LDK1258 reduced food consumption and elicited delayed antinociceptive effects in the chronic constrictive injury of the sciatic nerve (CCI) model of neuropathic pain, which unexpectedly emerged 4 h post-injection. UPLC-MS/MS analysis quantified significant levels of LDK1258 in both blood and brain tissue at 30 min post-administration that remained stable up to 4 h. The observation that LDK1258 also produced respective antinociceptive and anorectic effects in rimonabant-treated wild type mice and CB 1 (−/−) mice suggests an off-target mechanism of action. Likewise, LDK1258 produced a partial array of common cannabimimetic effects in the tetrad assay, which were not CB 1 receptor mediated. Additionally, LDK1258 did not substitute for the CB 1 receptor orthosteric agonists CP55,940 or anandamide in the drug discrimination paradigm. In other in vivo assays sensitive to CB 1 receptor allosteric modulators, LDK1258 failed to shift the dose-response curves of either CP55,940 or anandamide in producing thermal antinociception, catalepsy, or hypothermia, and did not alter the generalization curve of either drug in the drug discrimination assay. Thus, this battery of tests yielded results demonstrating that LDK1258 produces antinociceptive effects in the CCI model of neuropathic pain, anorectic effects, and other in vivo pharmacological effects in a manner inconsistent with CB 1 receptor allosterism. More generally, this study offers a straightforward screening assay to determine whether newly synthesized CB 1 receptor allosteric modulators translate to the whole animal. • The CB 1 receptor allosteric modulator LDK1258 produces antinociception in a mouse neuropathic pain model. • LDK1258 produces in vivo pharmacological effects through a CB 1 receptor independent mechanism of action. • This in vivo screening assay tests whether CB1 receptor allosteric modulators translate to the whole animal. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
39. Vaccine blunts fentanyl potency in male rhesus monkeys.
- Author
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Tenney, Rebekah D., Blake, Steven, Bremer, Paul T., Zhou, Bin, Hwang, Candy S., Poklis, Justin L., Janda, Kim D., and Banks, Matthew L.
- Subjects
- *
RHESUS monkeys , *VACCINES , *BINDING site assay , *NOCICEPTIVE pain , *FENTANYL , *ANTIBODY formation - Abstract
One proposed factor contributing to the increased frequency of opioid overdose deaths is the emergence of novel synthetic opioids, including illicit fentanyl and fentanyl analogues. A treatment strategy currently under development to address the ongoing opioid crisis is immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness and selectivity of a fentanyl-tetanus toxoid conjugate vaccine to alter the behavioral effects of fentanyl and a structurally dissimilar mu-opioid agonist oxycodone in male rhesus monkeys (n = 3–4). Fentanyl and oxycodone produced dose-dependent suppression of behavior in an assay of schedule-controlled responding and antinociception in an assay of thermal nociception (50 °C). Acute naltrexone (0.032 mg/kg) produced an approximate 10-fold potency shift for fentanyl to decrease operant responding. The fentanyl vaccine was administered at weeks 0, 2, 4, 9, 19, and 44 and fentanyl or oxycodone potencies in both behavioral assays were redetermined over the course of 49 weeks. The vaccine significantly and selectively shifted fentanyl potency at least 10-fold in both assays at several time points over the entire experimental period. Mid-point titer levels correlated with fentanyl antinociceptive potency shifts. Antibody affinity for fentanyl as measured by a competitive binding assay improved over time to approximately 3–4 nM. The fentanyl vaccine also increased fentanyl plasma levels approximately 6-fold consistent with the hypothesis that the vaccine sequesters fentanyl in the blood. Overall, these results support the continued development and evaluation of this fentanyl vaccine in humans to address the ongoing opioid crisis. • Vaccine blunted fentanyl rate-suppression potency ~ 10-fold. • Vaccine blunted fentanyl antinociceptive potency ~25-fold. • Fentanyl vaccine was as effective as acute 0.032 mg/kg naltrexone. • Vaccine was selective for fentanyl versus oxycodone. • Antibody immune response ~ 3 nM affinity for fentanyl. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
40. Assessing nicotine dependence using an oral nicotine free-choice paradigm in mice.
- Author
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Bagdas, Deniz, Diester, Clare M., Riley, Jason, Carper, Moriah, Alkhlaif, Yasmin, AlOmari, Dana, Alayoubi, Hala, Poklis, Justin L., and Damaj, M. Imad
- Subjects
- *
NICOTINE addiction , *NICOTINE , *NICOTINIC acetylcholine receptors , *TYROSINE hydroxylase , *NUCLEUS accumbens , *CYCLOSERINE - Abstract
Models to assess the addictive-like properties of nicotine in mice are limited. Therefore, we aimed to characterize and validate an addiction index by using an oral nicotine free-choice paradigm in mice. Adult C57BL/6J, DBA/2J, or genetically modified mice carrying deletions for nicotinic acetylcholine receptor (nAChR) subunits, (n = 8–10/sex/group) were given a choice of water or nicotine (10–960 μg/ml) solution using a two-bottle free-choice (2BC) paradigm. In general, oral nicotine intake and preference were higher in female mice compared to males. Absence of nicotine led to withdrawal, and intermittent access resulted in an escalation in consumption and greater nicotine withdrawal than continuous exposure. Additionally, oral nicotine consumption increased nucleus accumbens tyrosine hydroxylase levels. While β2 and α6 KO mice showed a significant decrease in nicotine intake, deletion of α5 nAChRs increased nicotine consumption at high concentrations. Deletion of the α7 subunit altered the observed sex difference in nicotine consumption, with females consuming less than males. The α4β2 partial agonist varenicline decreased oral nicotine consumption. Although addition of quinine to the nicotine solution lowered nicotine intake, mice primed with nicotine did not lower their intake after quinine addition. Nicotine deprivation followed by re-exposure showed increased nicotine consumption, and DBA/2J mice consumed less nicotine compared to C57BL/6J. We validated the mouse 2BC paradigm to study nicotine's addictive-like properties including nicotine intake, preference, withdrawal, and escalation of nicotine consumption during binge drinking or after reinstatement of a deprivation period. • Oral nicotine consumption is sex-, strain- and concentration-dependent. • β2, α5 and α6 nAChR subunits play a key role in nicotine consumption. • Intermittency of nicotine solution leads to an escalation of nicotine consumption. • Absence of nicotine results in somatic and affective withdrawal signs. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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