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Article ; Online: An economon model of drug addiction.

Negus, S Stevens

2024 Volume 241, Issue 3, Page(s) 417–425

Abstract: The term "economon" (i:'ka.nə.muhn; plural: economa) is introduced here to describe an economic unit composed of two participants engaged in mutually reinforcing operant behavior. Economa are basic building blocks of transactional behavior that aggregate ...

Abstract	The term "economon" (i:'ka.nə.muhn; plural: economa) is introduced here to describe an economic unit composed of two participants engaged in mutually reinforcing operant behavior. Economa are basic building blocks of transactional behavior that aggregate in social networks called economies. In a drug-addiction economon, operant behavior by one participant (the "supplier") provides an addictive drug as a reinforcer to the second participant (a "Person with Substance Use Disorder; PwSUD"). Reciprocal operant behavior by the PwSUD usually provides money as a reinforcer to the supplier. After defining the features of the drug-addiction economon, this article discusses its implications for (1) prevalence and virulence of drug addiction, (2) opportunities for drug-addiction research in general, (3) the "brain-disease model of addiction" in particular, and (4) factors that mitigate harm or promote risk of drug addiction. The economon model is intended to provide a novel perspective on the uniquely human disorder of drug addiction.
MeSH term(s)	Humans ; Conditioning, Operant ; Substance-Related Disorders ; Behavior, Addictive ; Brain
Language	English
Publishing date	2024-01-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-024-06535-7
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Article ; Online: Core Outcome Measures in Preclinical Assessment of Candidate Analgesics.

Negus, S Stevens

Pharmacological reviews

2019 Volume 71, Issue 2, Page(s) 225–266

Abstract: All preclinical procedures for analgesic drug discovery involve two components: 1) a "pain stimulus" (the principal independent variable), which is delivered to an experimental subject with the intention of producing a pain state; and 2) a "pain behavior" ...

Abstract	All preclinical procedures for analgesic drug discovery involve two components: 1) a "pain stimulus" (the principal independent variable), which is delivered to an experimental subject with the intention of producing a pain state; and 2) a "pain behavior" (the principal dependent variable), which is measured as evidence of that pain state. Candidate analgesics are then evaluated for their effectiveness to reduce the pain behavior, and results are used to prioritize drugs for advancement to clinical testing. This review describes a taxonomy of preclinical procedures organized into an "antinociception matrix" by reference to their types of pain stimulus (noxious, inflammatory, neuropathic, disease related) and pain behavior (unconditioned, classically conditioned, operant conditioned). Particular emphasis is devoted to pain behaviors and the behavioral principals that govern their expression, pharmacological modulation, and preclinical-to-clinical translation. Strengths and weaknesses are compared and contrasted for procedures using each type of behavioral outcome measure, and the following four recommendations are offered to promote strategic use of these procedures for preclinical-to-clinical analgesic drug testing. First, attend to the degree of homology between preclinical and clinical outcome measures, and use preclinical procedures with behavioral outcome measures homologous to clinically relevant outcomes in humans. Second, use combinations of preclinical procedures with complementary strengths and weaknesses to optimize both sensitivity and selectivity of preclinical testing. Third, take advantage of failed clinical translation to identify drugs that can be back-translated preclinically as active negative controls. Finally, increase precision of procedure labels by indicating both the pain stimulus and the pain behavior in naming preclinical procedures.
MeSH term(s)	Analgesics/pharmacology ; Animals ; Behavior, Animal/drug effects ; Conditioning, Operant/drug effects ; Disease Models, Animal ; Drug Discovery/methods ; Drug Evaluation, Preclinical/methods ; Humans ; Outcome Assessment (Health Care) ; Pain/drug therapy
Chemical Substances	Analgesics
Language	English
Publishing date	2019-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	209898-2
ISSN	1521-0081 ; 0031-6997
ISSN (online)	1521-0081
ISSN	0031-6997
DOI	10.1124/pr.118.017210
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Article ; Online: Addressing the Opioid Crisis: The Importance of Choosing Translational Endpoints in Analgesic Drug Discovery.

Negus, S Stevens

Trends in pharmacological sciences

2018 Volume 39, Issue 4, Page(s) 327–330

Abstract: The opioid crisis has stimulated renewed interest in analgesic drug development. This effort will involve preclinical-to-clinical translational research and will benefit from a focus on endpoints that are both clinically relevant and shared across ... ...

Abstract	The opioid crisis has stimulated renewed interest in analgesic drug development. This effort will involve preclinical-to-clinical translational research and will benefit from a focus on endpoints that are both clinically relevant and shared across laboratory animals and humans. Measures of pain-related functional impairment and behavioral depression could serve this purpose.
MeSH term(s)	Analgesics/adverse effects ; Analgesics/therapeutic use ; Analgesics, Opioid/adverse effects ; Analgesics, Opioid/therapeutic use ; Animals ; Drug Discovery/methods ; Humans ; Opioid-Related Disorders/etiology ; Opioid-Related Disorders/prevention & control ; Pain/drug therapy ; Translational Medical Research/methods
Chemical Substances	Analgesics ; Analgesics, Opioid
Language	English
Publishing date	2018-02-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2018.02.002
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Article ; Online: Temporal parameters of enhanced opioid reward after initial opioid exposure in rats.

Moerke, Megan J / Negus, S Stevens

Psychopharmacology

2021 Volume 238, Issue 3, Page(s) 725–734

Abstract: Rationale: Mu opioid receptor agonists are indispensable for the treatment of pain, but clinical use carries the inherent risk of transition from effective treatment to abuse. Abuse potential appears to increase rapidly during periods of initial opioid ... ...

Abstract	Rationale: Mu opioid receptor agonists are indispensable for the treatment of pain, but clinical use carries the inherent risk of transition from effective treatment to abuse. Abuse potential appears to increase rapidly during periods of initial opioid exposure in humans, and this increase in opioid reward during initial opioid exposure can be modeled in rats using an intracranial self-stimulation (ICSS) procedure. Objectives: The goal of the present study was to examine temporal parameters of this phenomenon. Methods: Adult male Sprague-Dawley rats responded for electrical brain stimulation using a frequency-rate ICSS procedure. In the first experiment, rats received daily morphine injections for 6 days, and morphine effects on ICSS were re-determined 1 day, 1 week, or 1 month after the repeated morphine treatment regimen to evaluate the persistence of enhanced opioid reward. In the second experiment, rats received six repeated morphine injections with different interdose intervals (two per day, one per day, every other day, every fourth day), and morphine effects were re-determined 1 day after the last dose to determine dosing frequencies sufficient to produce enhanced opioid reward. Results: Results of the first experiment indicated that enhanced opioid reward was greatest 1 day after the morphine treatment regimen and completely dissipated after 4 weeks. The second experiment indicated that all dosing frequencies tested were sufficient to produce enhanced reward. Conclusions: Taken together, these results suggest that enhancement of opioid reward after initial opioid exposure is relatively transient but can be produced by a range of different dosing frequencies.
MeSH term(s)	Analgesics, Opioid/administration & dosage ; Analgesics, Opioid/pharmacology ; Animals ; Brain/drug effects ; Brain/metabolism ; Electric Stimulation ; Male ; Morphine/administration & dosage ; Morphine/pharmacology ; Pain/drug therapy ; Pain/metabolism ; Pain/psychology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu/agonists ; Reward ; Self Stimulation/drug effects ; Time Factors
Chemical Substances	Analgesics, Opioid ; Receptors, Opioid, mu ; Morphine (76I7G6D29C)
Language	English
Publishing date	2021-01-07
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-020-05725-3
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Article ; Online: Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain.

Santos, Edna J / Giddings, Arianna N / Kandil, Farah A / Negus, S Stevens

Frontiers in pain research (Lausanne, Switzerland)

2023 Volume 4, Page(s) 1150236

Abstract: This study evaluated climbing in mice as a tool to assess the expression and treatment of pain-related behavioral depression in male and female ICR mice. Mice were videotaped during 10-min sessions in a vertical plexiglass cylinder with wire mesh walls, ... ...

Abstract	This study evaluated climbing in mice as a tool to assess the expression and treatment of pain-related behavioral depression in male and female ICR mice. Mice were videotaped during 10-min sessions in a vertical plexiglass cylinder with wire mesh walls, and "Time Climbing" was scored by observers blind to treatments. Initial validation studies demonstrated that baseline climbing was stable across repeated days of testing and depressed by intraperitoneal injection of dilute lactic acid (IP acid) as an acute pain stimulus. Additionally, IP acid-induced depression of climbing was blocked by the positive-control non-steroidal anti-inflammatory drug (NSAID) ketoprofen but not by the negative control kappa opioid receptor agonist U69593. Subsequent studies examined effects of single-molecule opioids (fentanyl, buprenorphine, naltrexone) and of fixed-proportion fentanyl/naltrexone mixtures (10:1, 3.2:1, and 1:1) that vary in their efficacy at the mu opioid receptor (MOR). Opioids administered alone produced a dose- and efficacy-dependent decrease in climbing, and fentanyl/naltrexone-mixture data indicated that climbing in mice is especially sensitive to disruption by even low-efficacy MOR activation. Opioids administered as a pretreatment to IP acid failed to block IP acid-induced depression of climbing. Taken together, these findings support the utility of climbing in mice as an endpoint to evaluate candidate-analgesic effectiveness both to (a) produce undesirable behavioral disruption when the test drug is administered alone, and (b) produce a therapeutic blockade of pain-related behavioral depression. The failure of MOR agonists to block IP acid-induced depression of climbing likely reflects the high sensitivity of climbing to disruption by MOR agonists.
Language	English
Publishing date	2023-04-17
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-561X
ISSN (online)	2673-561X
DOI	10.3389/fpain.2023.1150236
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Article ; Online: Effects of naltrexone on amphetamine choice in rhesus monkeys and rats.

Robinson, Hannah L / Moerke, Megan Jo / Banks, Matthew L / Negus, S Stevens

Experimental and clinical psychopharmacology

2023 Volume 31, Issue 6, Page(s) 1080–1091

Abstract: Clinical amphetamine use is constrained by high abuse potential, and amphetamine use disorder is a persistent clinical problem with no approved medications for its treatment. The opioid antagonist naltrexone has been reported to reduce some abuse-related ...

Abstract	Clinical amphetamine use is constrained by high abuse potential, and amphetamine use disorder is a persistent clinical problem with no approved medications for its treatment. The opioid antagonist naltrexone has been reported to reduce some abuse-related effects of amphetamine. This study used an amphetamine-versus-food choice procedure in rhesus monkeys and rats to test the hypothesis that naltrexone might serve as either (a) a maintenance medication for amphetamine use disorder treatment or (b) an "abuse-deterrent" adjunct to clinical amphetamine formulations. Male rhesus monkeys and male and female rats were trained to choose between increasing unit doses of intravenous amphetamine and an alternative food reinforcer during daily behavioral sessions. Experiment 1 evaluated effectiveness of continuous naltrexone maintenance to reduce amphetamine-versus-food choice in both monkeys and rats. Experiment 2 combined naltrexone with amphetamine in fixed-proportion amphetamine + naltrexone mixtures to evaluate the effectiveness of naltrexone in both species to reduce mixture choice relative to amphetamine-alone choice. Amphetamine maintained a dose-dependent increase in amphetamine choice in both monkeys and rats. Naltrexone maintenance did not significantly decrease amphetamine choice in either species. Addition of naltrexone to amphetamine reduced amphetamine choices per session in monkeys, but behavior was not reallocated to food choice, and in rats, the addition of naltrexone only decreased food choice without significantly affecting amphetamine choice. These results argue against the use of naltrexone as either (a) a maintenance medication for treatment of amphetamine use disorder or (b) an "abuse-deterrent" adjunct to amphetamine for clinical applications. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
MeSH term(s)	Male ; Female ; Rats ; Animals ; Amphetamine/pharmacology ; Naltrexone/pharmacology ; Naltrexone/therapeutic use ; Macaca mulatta ; Cocaine ; Narcotic Antagonists/pharmacology ; Narcotic Antagonists/therapeutic use ; Substance-Related Disorders/drug therapy ; Choice Behavior ; Dose-Response Relationship, Drug ; Self Administration
Chemical Substances	Amphetamine (CK833KGX7E) ; Naltrexone (5S6W795CQM) ; Cocaine (I5Y540LHVR) ; Narcotic Antagonists
Language	English
Publishing date	2023-05-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1209960-0
ISSN	1936-2293 ; 1064-1297
ISSN (online)	1936-2293
ISSN	1064-1297
DOI	10.1037/pha0000655
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Article ; Online: Editorial: Preclinical Animal Models and Measures of Pain: Improving Predictive Validity for Analgesic Drug Development.

Tappe-Theodor, Anke / Negus, S Stevens / Martin, Thomas J

Frontiers in pain research (Lausanne, Switzerland)

2022 Volume 3, Page(s) 867786

Language	English
Publishing date	2022-03-23
Publishing country	Switzerland
Document type	Editorial
ISSN	2673-561X
ISSN (online)	2673-561X
DOI	10.3389/fpain.2022.867786
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Article ; Online: Role of Efficacy as a Determinant of Locomotor Activation by Mu Opioid Receptor Ligands in Female and Male Mice.

Santos, Edna J / Banks, Matthew L / Negus, S Stevens

The Journal of pharmacology and experimental therapeutics

2022 Volume 382, Issue 1, Page(s) 44–53

Abstract: Mu opioid receptor (MOR) agonists produce locomotor hyperactivity in mice as one sign of opioid-induced motor disruption. The goal of this study was to evaluate the degree of MOR efficacy required to produce this hyperactivity. Full dose-effect curves ... ...

Abstract	Mu opioid receptor (MOR) agonists produce locomotor hyperactivity in mice as one sign of opioid-induced motor disruption. The goal of this study was to evaluate the degree of MOR efficacy required to produce this hyperactivity. Full dose-effect curves were determined for locomotor activation produced in male and female Institute of Cancer Research (ICR) mice by (1) eight different single-molecule opioids with high to low MOR efficacy and (2) a series of fixed-proportion fentanyl/naltrexone mixtures with high to low fentanyl proportions. Data from the mixtures were used to quantify the efficacy requirement for MOR agonist-induced hyperactivity relative to efficacy requirements determined previously for other MOR agonist effects. Specifically, efficacy requirement was quantified as the EP50 value, which is the "Effective Proportion" of fentanyl in a fentanyl/naltrexone mixture that produces a maximal effect equal to 50% of the maximal effect of fentanyl alone. Maximal hyperactivity produced by each drug and mixture in the present study correlated with previously published data for maximal stimulation of GTPɣS binding in MOR-expressing Chinese hamster ovary cells as an in vitro measure of relative efficacy. Additionally, the EP
MeSH term(s)	Analgesics, Opioid/pharmacology ; Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Drug ; Female ; Fentanyl/pharmacology ; Ligands ; Male ; Mice ; Naltrexone/pharmacology ; Rats ; Receptors, Opioid, mu/metabolism
Chemical Substances	Analgesics, Opioid ; Ligands ; Receptors, Opioid, mu ; Naltrexone (5S6W795CQM) ; Fentanyl (UF599785JZ)
Language	English
Publishing date	2022-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.121.001045
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Article ; Online: Contextual extinction of drug-associated discriminative stimuli fails to attenuate drug-vs-food choice in rhesus monkeys.

Banks, Matthew L / Hutsell, Blake A / Negus, S Stevens

Journal of the experimental analysis of behavior

2022 Volume 117, Issue 3, Page(s) 505–517

Abstract: Relapse within the context of a substance use disorder can be triggered by cues that function as discriminative stimuli to signal contingencies of drug availability and promote drug-taking behavior. Extinction procedures can weaken this association ... ...

Abstract	Relapse within the context of a substance use disorder can be triggered by cues that function as discriminative stimuli to signal contingencies of drug availability and promote drug-taking behavior. Extinction procedures can weaken this association between drug-associated cues and drug-taking behavior and may reduce the probability of relapse. This study evaluated a regimen of extinction training on cocaine and heroin self-administration in rhesus monkeys under a drug-vs-food choice procedure. Behavior was initially maintained under a concurrent schedule of food (1-g food pellets; fixed-ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection; fixed-ratio 10) (n = 4 males) or heroin injections (0-0.01 mg/kg/injection; fixed-ratio 10) (n = 3 females and 1 male) during daily 2-hr choice sessions. Subsequently, choice sessions were supplemented by daily 20-hr saline self-administration sessions for 14 consecutive days. During saline self-administration sessions, only drug-associated discriminative stimuli were presented and responding produced saline injections. Drug continued to be available during choice sessions. Prior to extinction training, both cocaine and heroin maintained dose-dependent increases in drug-vs-food choice. Exposure to 14 saline self-administration sessions failed to significantly decrease drug choice and increase food choice. These preclinical results do not support the effectiveness of extinguishing drug-associated discriminative stimuli as a nonpharmacological treatment strategy for reducing drug choice.
MeSH term(s)	Animals ; Cocaine/pharmacology ; Dose-Response Relationship, Drug ; Female ; Heroin/pharmacology ; Macaca mulatta ; Male ; Pharmaceutical Preparations ; Recurrence
Chemical Substances	Pharmaceutical Preparations ; Heroin (70D95007SX) ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2022-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	219405-3
ISSN	1938-3711 ; 0022-5002
ISSN (online)	1938-3711
ISSN	0022-5002
DOI	10.1002/jeab.734
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Article ; Online: Effects of environmental manipulations on cocaine-vs-social choice in male and female rats.

Marcus, Madison M / Negus, S Stevens / Banks, Matthew L

Pharmacology, biochemistry, and behavior

2022 Volume 220, Page(s) 173462

Abstract: Cocaine use disorder occurs in an environment where cocaine and other nondrug commodities are concurrently available. Preclinical drug-vs-nondrug choice procedures are one simplified method of modeling this complex clinical environment. The present study ...

Abstract	Cocaine use disorder occurs in an environment where cocaine and other nondrug commodities are concurrently available. Preclinical drug-vs-nondrug choice procedures are one simplified method of modeling this complex clinical environment. The present study established a discrete-trial cocaine-vs-social interaction choice procedure in male and female rats and determined sensitivity of choice behavior to manipulations of reinforcer magnitude and non-contingent "sample" reinforcer presentation. Rats could make up to nine discrete choices between an intravenous cocaine infusion (0.1-1.0 mg/kg/inf) and social interaction with a same-sex social "Partner" rat. Cocaine infusions were available under a progressive-ratio (PR) schedule of reinforcement, and social interaction was available under a fixed-ratio (FR) 3 schedule. Social interaction was chosen over no or small cocaine doses (saline, 0.01 mg/kg/inf) and behavior was reallocated away from social and towards cocaine at larger cocaine doses (1.0 mg/kg/inf). Manipulating social interaction time as one method to alter social reinforcer magnitude did not significantly alter cocaine-vs-social choice. Removing the non-contingent reinforcer presentations before the discrete choice trials also failed to affect cocaine-vs-social choice, suggesting the time interval was sufficient to minimize any potential influence of the non-contingent cocaine infusions on subsequent choice behavior. Overall, the present results were consistent with previous drug-vs-social choice studies and extend our knowledge of environmental factors impacting drug-vs-social choice. Future studies determining the pharmacological sensitivity of cocaine-vs-social choice will be important in expanding the preclinical utility of these procedures for candidate medication drug development.
MeSH term(s)	Animals ; Choice Behavior ; Cocaine/pharmacology ; Conditioning, Operant ; Dose-Response Relationship, Drug ; Female ; Male ; Rats ; Reinforcement Schedule ; Self Administration
Chemical Substances	Cocaine (I5Y540LHVR)
Language	English
Publishing date	2022-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	191042-5
ISSN	1873-5177 ; 0091-3057
ISSN (online)	1873-5177
ISSN	0091-3057
DOI	10.1016/j.pbb.2022.173462
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