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Article: Druggable Targets in Endocannabinoid Signaling.

Gregus, Ann M / Buczynski, Matthew W

Advances in experimental medicine and biology

2020 Volume 1274, Page(s) 177–201

Abstract: Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide. Since the discovery of ... ...

Abstract	Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide. Since the discovery of Δ
MeSH term(s)	Cannabinoids/antagonists & inhibitors ; Cannabinoids/metabolism ; Cannabis/chemistry ; Dronabinol/antagonists & inhibitors ; Dronabinol/metabolism ; Endocannabinoids/antagonists & inhibitors ; Endocannabinoids/metabolism ; Humans ; Molecular Targeted Therapy ; Signal Transduction/drug effects
Chemical Substances	Cannabinoids ; Endocannabinoids ; Dronabinol (7J8897W37S)
Language	English
Publishing date	2020-09-07
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-50621-6_8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: NAPE-PLD regulates specific baseline affective behaviors but is dispensable for inflammatory hyperalgesia.

Chen, Irene / Murdaugh, Laura B / Miliano, Cristina / Dong, Yuyang / Gregus, Ann M / Buczynski, Matthew W

Neurobiology of pain (Cambridge, Mass.)

2023 Volume 14, Page(s) 100135

Abstract: ... ...

Abstract	N
Language	English
Publishing date	2023-06-14
Publishing country	United States
Document type	Journal Article
ISSN	2452-073X
ISSN (online)	2452-073X
DOI	10.1016/j.ynpai.2023.100135
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Article: Effect of chronic vapor nicotine exposure on affective and cognitive behavior in male mice.

Murdaugh, Laura B / Miliano, Cristina / Chen, Irene / Faunce, Christine L / Natividad, Luis A / Gregus, Ann M / Buczynski, Matthew W

Research square

2024

Abstract: Nicotine use is a leading cause of preventable deaths worldwide, and most of those who attempt to quit will relapse. While electronic cigarettes and other electronic nicotine delivery systems (ENDS) were presented as a safer alternative to traditional ... ...

Abstract	Nicotine use is a leading cause of preventable deaths worldwide, and most of those who attempt to quit will relapse. While electronic cigarettes and other electronic nicotine delivery systems (ENDS) were presented as a safer alternative to traditional cigarettes and promoted as devices to help traditional tobacco smokers reduce or quit smoking, they have instead contributed to increasing nicotine use among youths. Despite this, ENDS also represent a useful tool to create novel preclinical animal models of nicotine exposure that more accurately represent human nicotine use. In this study, we validated a chronic, intermittent, ENDS-based passive vapor exposure model in mice, and then measured changes in multiple behaviors related to nicotine abstinence. First, we performed a behavioral dose curve to investigate the effects of different nicotine inter-vape intervals on various measures including body weight, locomotor activity, and pain hypersensitivity. Next, we performed a pharmacokinetic study to measure plasma levels of nicotine and cotinine following chronic exposure for each inter-vape interval. Finally, we utilized a behavior test battery at a single dosing regimen that produces blood levels equivalent to human smokers in order to characterize the effects of chronic nicotine, vehicle, or passive airflow and identified nicotine-induced impairments in cognitive behavior.
Language	English
Publishing date	2024-02-02
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3892315/v1
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Article ; Online: Effect of chronic vapor nicotine exposure on affective and cognitive behavior in male mice.

Murdaugh, Laura B / Miliano, Cristina / Chen, Irene / Faunce, Christine L / Natividad, Luis A / Gregus, Ann M / Buczynski, Matthew W

Scientific reports

2024 Volume 14, Issue 1, Page(s) 6646

Abstract	Nicotine use is a leading cause of preventable deaths worldwide, and most of those who attempt to quit will relapse. While electronic cigarettes and other electronic nicotine delivery systems (ENDS) were presented as a safer alternative to traditional cigarettes and promoted as devices to help traditional tobacco smokers reduce or quit smoking, they have instead contributed to increasing nicotine use among youths. Despite this, ENDS also represent a useful tool to create novel preclinical animal models of nicotine exposure that more accurately represent human nicotine use. In this study, we validated a chronic, intermittent, ENDS-based passive vapor exposure model in mice, and then measured changes in multiple behaviors related to nicotine abstinence. First, we performed a behavioral dose curve to investigate the effects of different nicotine inter-vape intervals on various measures including body weight, locomotor activity, and pain hypersensitivity. Next, we performed a pharmacokinetic study to measure plasma levels of nicotine and cotinine following chronic exposure for each inter-vape interval. Finally, we utilized a behavior test battery at a single dosing regimen that produces blood levels equivalent to human smokers in order to characterize the effects of chronic nicotine, vehicle, or passive airflow and identified nicotine-induced impairments in cognitive behavior.
MeSH term(s)	Adolescent ; Male ; Humans ; Mice ; Animals ; Nicotine ; Electronic Nicotine Delivery Systems ; Smoking ; Cotinine ; Gases ; Cognition
Chemical Substances	Nicotine (6M3C89ZY6R) ; Cotinine (K5161X06LL) ; Gases
Language	English
Publishing date	2024-03-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-56766-z
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Article ; Online: Differential roles of diacylglycerol lipase (DAGL) enzymes in nicotine withdrawal.

Buzzi, Belle / Koseli, Eda / Alkhlaif, Yasmin / Parker, Abigail / Mustafa, Mohammed A / Lichtman, Aron H / Buczynski, Matthew W / Damaj, M Imad

Brain research

2023 Volume 1817, Page(s) 148483

Abstract: Nicotine and tobacco-related deaths remains a leading cause of preventable death and disease in the United States. Several studies indicate that modulation of the endocannabinoid system, primarily of the endocannabinoid 2-Arachidonoylglycerol (2-AG), ... ...

Abstract	Nicotine and tobacco-related deaths remains a leading cause of preventable death and disease in the United States. Several studies indicate that modulation of the endocannabinoid system, primarily of the endocannabinoid 2-Arachidonoylglycerol (2-AG), alters nicotinic dependence behaviors in rodents. This study, using transgenic knock-out (KO) mice, evaluated the role of the two 2-AG biosynthesis enzymes, (Diacylglycerol lipase-α) DAGL-α and DAGL-β in spontaneous nicotine withdrawal. DAGL-α deletion prevents somatic and affective signs of nicotine withdrawal, while DAGL-β deletion plays a role in hyperalgesia due to nicotine withdrawal. These results suggest a differential role of these enzymes in the various signs of nicotine withdrawal. Our behavioral findings relate to the distribution of these enzymes with DAGL-β being highly expressed in macrophages and DAGL-α in neurons. This study offers new potential targets for smoking cessation therapies.
MeSH term(s)	Mice ; Animals ; Nicotine ; Lipoprotein Lipase ; Endocannabinoids ; Substance Withdrawal Syndrome ; Tobacco Use Disorder ; Mice, Knockout
Chemical Substances	Nicotine (6M3C89ZY6R) ; Lipoprotein Lipase (EC 3.1.1.34) ; Endocannabinoids
Language	English
Publishing date	2023-07-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2023.148483
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Article ; Online: Sex differences in neuroimmune and glial mechanisms of pain.

Gregus, Ann M / Levine, Ian S / Eddinger, Kelly A / Yaksh, Tony L / Buczynski, Matthew W

Pain

2021 Volume 162, Issue 8, Page(s) 2186–2200

Abstract: Abstract: Pain is the primary motivation for seeking medical care. Although pain may subside as inflammation resolves or an injury heals, it is increasingly evident that persistency of the pain state can occur with significant regularity. Chronic pain ... ...

Abstract	Abstract: Pain is the primary motivation for seeking medical care. Although pain may subside as inflammation resolves or an injury heals, it is increasingly evident that persistency of the pain state can occur with significant regularity. Chronic pain requires aggressive management to minimize its physiological consequences and diminish its impact on quality of life. Although opioids commonly are prescribed for intractable pain, concerns regarding reduced efficacy, as well as risks of tolerance and dependence, misuse, diversion, and overdose mortality rates limit their utility. Advances in development of nonopioid interventions hinge on our appreciation of underlying mechanisms of pain hypersensitivity. For instance, the contributory role of immunity and the associated presence of autoimmune syndromes has become of particular interest. Males and females exhibit fundamental differences in innate and adaptive immune responses, some of which are present throughout life, whereas others manifest with reproductive maturation. In general, the incidence of chronic pain conditions, particularly those with likely autoimmune covariates, is significantly higher in women. Accordingly, evidence is now accruing in support of neuroimmune interactions driving sex differences in the development and maintenance of pain hypersensitivity and chronicity. This review highlights known sexual dimorphisms of neuroimmune signaling in pain states modeled in rodents, which may yield potential high-value sex-specific targets to inform future analgesic drug discovery efforts.
MeSH term(s)	Analgesics, Opioid ; Chronic Pain ; Female ; Humans ; Male ; Neuroglia ; Quality of Life ; Sex Characteristics
Chemical Substances	Analgesics, Opioid
Language	English
Publishing date	2021-07-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	193153-2
ISSN	1872-6623 ; 0304-3959
ISSN (online)	1872-6623
ISSN	0304-3959
DOI	10.1097/j.pain.0000000000002215
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Article: Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception.

Bustin, Katelyn A / Shishikura, Kyosuke / Chen, Irene / Lin, Zongtao / McKnight, Nate / Chang, Yuxuan / Wang, Xie / Li, Jing Jing / Arellano, Eric / Pei, Liming / Morton, Paul D / Gregus, Ann M / Buczynski, Matthew W / Matthews, Megan L

bioRxiv : the preprint server for biology

2023

Abstract: Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery ... ...

Abstract	Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors)
Language	English
Publishing date	2023-02-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.02.526866
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Article ; Online: Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception.

Molecular and cellular neurosciences

2023 Volume 125, Page(s) 103842

Abstract	Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil®). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.
MeSH term(s)	Animals ; Mice ; Male ; Phenelzine/pharmacology ; Nociception ; Proteome ; Nerve Tissue Proteins
Chemical Substances	Phenelzine (O408N561GF) ; Proteome ; secernin 1 protein, mouse ; Nerve Tissue Proteins
Language	English
Publishing date	2023-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1046640-x
ISSN	1095-9327 ; 1044-7431
ISSN (online)	1095-9327
ISSN	1044-7431
DOI	10.1016/j.mcn.2023.103842
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Zs.A 3035: Show issues

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Article ; Online: Loren Parsons' contribution to addiction neurobiology.

De Luca, Maria A / Buczynski, Matthew W / Di Chiara, Gaetano

Addiction biology

2018 Volume 23, Issue 6, Page(s) 1207–1222

Abstract: Loren (Larry) H. Parsons passed away at the age of 51. In spite of his premature departure, Larry much contributed to the drug abuse field. Since his graduate studies for the Ph.D. in Chemistry in J.B. Justice lab, microdialysis is the tread that links ... ...

Abstract	Loren (Larry) H. Parsons passed away at the age of 51. In spite of his premature departure, Larry much contributed to the drug abuse field. Since his graduate studies for the Ph.D. in Chemistry in J.B. Justice lab, microdialysis is the tread that links Larry's research topics, namely, the role of dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamate and endocannabinoids (eCBs) in drug reinforcement and dependence. Larry was the first to show that abstinence from chronic cocaine reduces extracellular DA in the NAc, consistent with the so called 'dopamine depletion hypothesis' of cocaine addiction. Another Larry's major contributions are the studies on 5-HT and 5-HT receptors' role in cocaine stimulant actions, which resulted in the identification of 5-HT1B receptors as a critical substrate of cocaine reinforcement. By applying mass spectrometry to eCBs analysis in brain dialysates, Larry's lab showed that ethanol, heroin, nicotine and cocaine differentially affect anandamide and 2-arachidonoylglicerol overflow in the NAc shell, a critical site of drugs of abuse DA stimulant actions. Larry also applied microdialysis to study GABA and glutamate's role in ethanol dependence and heroin reinforcement, providing in vivo evidence for a sensitization of corticotropin-releasing factor-dependent release of GABA in the central amygdala in withdrawal from chronic ethanol and for a reduction of GABA transmission in the ventral pallidum in heroin but not cocaine intravenous self-administration. Larry showed the wide possibilities of microdialysis as a general purpose methodology for monitoring neurotransmitters and neuromodulators in the brain extracellular compartment. From this viewpoint, he stands as the best advocate for microdialysis.
Language	English
Publishing date	2018-06-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1324314-7
ISSN	1369-1600 ; 1355-6215
ISSN (online)	1369-1600
ISSN	1355-6215
DOI	10.1111/adb.12642
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Zs.A 4586: Show issues

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Article: From Synapse to Function: A Perspective on the Role of Neuroproteomics in Elucidating Mechanisms of Drug Addiction.

Natividad, Luis A / Buczynski, Matthew W / McClatchy, Daniel B / Yates, John R

Proteomes

2018 Volume 6, Issue 4

Abstract: 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, ...

Abstract	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.
Language	English
Publishing date	2018-12-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720995-7
ISSN	2227-7382
ISSN	2227-7382
DOI	10.3390/proteomes6040050
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