Search

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light–dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects.

The kappa agonist structure-activity relationship around the novel, pyrrolidinyl substituted pyranopiperazine scaffold was developed. More specifically, the dichloroPhenylAcetamide-Pyrrolidinyl-PyranoPiperazine (PAPPP) core A was the focus of our work. The modulation of kappa receptor potency/G-protein activation and arrestin recruitment with respect to changes of the piperazine R group in A was demonstrated. Reduced β

Persons with dual severe opioid and cocaine use disorders are at risk of considerable morbidity, and the bidirectional relationship of escalation of mu-opioid agonists and cocaine use is not well understood. The aim of this study was to examine the bidirectional relationship between escalation of heroin and cocaine use in volunteers dually diagnosed with opioid and cocaine dependence (OD + CD). Volunteers from New York with OD + CD (total n = 295; male = 182, female = 113; age ≥ 18 years) were interviewed with the Structured Clinical Interview for the DSM-IV Axis I Disorders and Kreek-McHugh-Schluger-Kellogg scales for dimensional measures of drug exposure, which also collect ages of 1st use and onset of heaviest use. Time of escalation was defined as age of onset of heaviest use minus age of 1st use in whole years. Times of escalation of heroin and cocaine were positively correlated in both men (Spearman r = .34, 95% confidence interval [CI: .17, .48], p < .0001) and women (Spearman r = .51, [.27, .50], p < .0001) volunteers. After we adjusted for demographic variables, a Cox regression showed that time of cocaine escalation was a predictor of time of heroin escalation (hazard ratio [HR] = 0.97, 95% CI [0.95, 0.99], p = .003). Another Cox regression showed that this relationship is bidirectional, because time of heroin escalation was also a predictor of time of cocaine escalation (HR = 0.98, [0.96-0.99], p = .016). In these adjusted models, gender was not a significant predictor of time of escalation of either heroin or cocaine. Therefore, escalation did not differ robustly by gender when adjusting for demographics and other major variables. Overall, rapid escalation of cocaine use was a predictor of rapid escalation of heroin use, and vice versa, in persons with dual severe opioid and cocaine use disorders. These findings suggest a shared vulnerability to rapid escalation of these 2 drugs in persons with dual severe opioid and cocaine use disorders. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

ImportanceDrug overdoses from opioids like fentanyl and heroin and stimulant drugs such as methamphetamine and cocaine are a major cause of mortality in the United States, with potential sex differences across the lifespan.ObjectiveTo determine overdose mortality for specific drug categories across the lifespan of males and females, using a nationally representative state-level sample.DesignState-level analyses of nationally representative epidemiological data on overdose mortality for specific drug categories, across 10-year age bins (age range: 15-74).SettingPopulation-based study of Multiple Cause of Death 2020-2021 data from the Centers of Disease Control and Prevention (CDC WONDER platform).ParticipantsDecedents in the United States in 2020-2021Main outcome measuresThe main outcome measure was sex-specific rates of overdose death (per 100,000) for: synthetic opioids excluding methadone (ICD-10 code: T40.4; predominantly fentanyl), heroin (T40.1), psychostimulants with potential for misuse, excluding cocaine (T43.6, predominantly methamphetamine; labeled “psychostimulants” hereafter), and cocaine (T40.5). Multiple regression analyses were used to control for ethnic-cultural background, household net worth, and sex-specific rate of misuse of the relevant substances (from the National Survey on Drug Use and Health, 2018-2019).ResultsFor each of the drug categories assessed, males had greater overall overdose mortality than females, after controlling for rates of drug misuse. The mean male/female sex ratio of mortality rate for the separate drug categories was relatively stable across jurisdictions: synthetic opioids (2.5 [95%CI, 2.4-2.7]), heroin, (2.9 [95%CI, 2.7-3.1], psychostimulants (2.4 [95%CI, 2.3-2.5]), and cocaine (2.8 [95%CI, 2.6-2.9]). With data stratified in 10-year age bins, the sex difference generally survived adjustment for state-level ethnic-cultural and economic variables, and for sex-specific misuse of each drug type (especially for bins in the 25-64 age range). For synthetic opioids, the sex difference survived adjustment across the lifespan (i.e., 10-year age bins ranging from 15-74), including adolescence, adulthood and late adulthood.Conclusions and RelevanceThe robustly greater overdose mortality in males versus females for synthetic opioids (predominantly fentanyl), heroin, and stimulant drugs including methamphetamine and cocaine indicate that males who misuse these drugs are significantly more vulnerable to overdose deaths. These results call for research into diverse biological, behavioral, and social factors that underlie sex differences in human vulnerability to drug overdose.Key PointsQuestionWhat are the current national trends in overdose mortality from opioids (synthetic opioids such as fentanyl, and heroin) and stimulant drugs (psychostimulants such as methamphetamine and cocaine) for males and females, over the lifespan (overall range 15-74 years)?FindingsState-level analyses of data from CDC for 2020-2021 indicate that after controlling for rates of drug misuse, males had significantly greater (2-3 fold) overdose mortality rates than females for synthetic opioids, heroin, psychostimulants and cocaine. These findings were generally consistent across the lifespan, studied as 10-year age bins (especially in the 25-64 age range).MeaningThese data indicate that males who misuse opioids and stimulant drugs are considerably more vulnerable to overdose mortality, compared to females. This finding calls for research on the underlying biological, behavioral, and social factors.

Vadim Yuferov,1,* Eduardo R Butelman,1,* Matthew Randesi,1 Wim van den Brink,2 Peter Blanken,3 Jan M van Ree,4 Mary Jeanne Kreek1 1Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, 10065, USA; 2Amsterdam University Medical Centers, Location Academic Medical Center, Department of Psychiatry, University of Amsterdam, Amsterdam, The Netherlands; 3Parnassia Addiction Research Centre, The Hague, The Netherlands; 4Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands*These authors contributed equally to this workCorrespondence: Eduardo R ButelmanLaboratory on the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USATel +1 212 327-8490Fax +1 212 327-8574Email butelme@rockefeller.eduIntroduction: A functional tandem repeat polymorphism in the promoter of the serotonin transporter (SERT) gene (SLC6A4) has been studied for association to neuropsychiatric conditions, including substance use disorders. Short (S) forms of this repeat result in reduced transcription, and presumably greater synaptic levels of serotonin, which are involved in opioid and cocaine-induced reward. Dual exposure to heroin and cocaine is a common pattern of poly-drug use and is associated with considerable morbidity. We hypothesize that SLC6A4 variants are associated with cocaine exposure in subjects with an opioid dependence diagnosis (OD), and also in non-dependent opioid users (NOD). Other single nucleotide polymorphisms (SNPs) of SLC6A4 may also be likewise associated.Materials and Methods: This study determined whether variants of the SLC6A4 promoter repeats and two intronic SNPs, rs16965628 and rs2066713, are associated with categorical diagnoses of opioid dependence (DSM-IV criteria) and with dimensional aspects of cocaine use, in a Caucasian cohort (n=591). Three groups of subjects were examined: (1) 276 subjects with opioid dependence diagnosis (OD); (2) 163 subjects who had used opioids for non-medical reasons but never had an opioid dependence diagnosis (NOD); (3) 152 healthy controls (HC).Results: Aside from high exposure to heroin in the OD group, relatively high exposure to cocaine was detected in both OD and NOD groups. The SERT repeat genotype (classified as “long-long” [LL] versus ”short-long” plus “short-short” [SL+SS]) was not associated with categorical opioid dependence diagnoses. A nominally significant association was identified with the [SL+SS] genotype of SLC6A4 and cocaine KMSK scores ≥“cutpoint” for a cocaine dependence diagnosis (p=0.026). The [SL+SS] genotype was associated with more rapid cocaine escalation than the LL genotype. No significant associations of rs16965628 and rs2066713 SNPs were found overall.Conclusion: The functional SERT promoter tandem repeat genotype may be associated to heavy cocaine exposure and more rapid escalation of cocaine use, in persons with and without opioid dependence diagnosis.Keywords: cocaine, serotonin transporter, SLC6A4, KMSK scale, escalation

The kappa-opioid receptor (KOR) / dynorphin system is implicated with behavioral and neurobiological effects of stress exposure (including heavy exposure to drugs of abuse) in translational animal models. Thus some KOR-antagonists can decrease the aversive, depressant-like and anxiety-like effects caused by stress exposure. The first generation of selective KOR-antagonists have slow onsets (hours) and extremely long durations of action (days-weeks), in vivo. A new generation of KOR antagonists with rapid onset and shorter duration of action can potentially decrease the effects of stress exposure in translational models, and may be of interest for medication development. This study examined the rapid onset anti-stress effects of one of the shorter acting novel KOR-antagonists (LY2795050, (3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)) in a single-session open space swim (OSS) stress paradigm (15 min duration), in adult male and female C57BL/6 J mice. LY2795050 (0.32 mg/kg, i.p.) had rapid onset (within 15 min) and short duration (

Rationale The dynorphin/ kappa-opioid receptor (KOR) system (encoded by PDYN and OPRK1 genes respectively) is highly regulated by repeated exposure to drugs of abuse, including mu-opioid agonists and cocaine. These changes in the dynorphin/KOR system can then influence the rewarding effects of these drugs of abuse. Activation of the dynorphin/KOR system is also thought to have a role in the pro-addictive effects of stress. Recent in vitro assays showed that the OPRK1 intron 2 may function as a genomic enhancer in the regulation KOR expression and contains a glucocorticiod-responsive sequence site. We hypothesize that SNPs in intron 2 of OPRK1 are associated with categorical opioid or cocaine dependence diagnoses, as well as with dimensional aspects of drug use (i.e., magnitude of drug exposure). Methods This study includes 577 subjects ≥18 years old, with African ancestry (AA) from the USA. They were divided into three groups: 152 control subjects, 142 persons with lifetime opioid dependence diagnosis (OD), and 283 subjects with lifetime cocaine dependence diagnosis (CD). Five SNPs (rs16918909, rs7016778, rs997917, rs6473797, rs10111937) that span 10 Kb nucleotides in intron 2 of the OPRK1 were used for the association analyses. Genotyping was performed with the Smokescreen® array or sequencing of PCR amplified DNA fragments. Association analyses for OD and CD diagnoses and the OPRK1 intron 2 alleles were carried out with Fisher’s exact test. The Kreek-McHugh-Schluger-Kellogg (KMSK) scales were used for dimensional measure of maximum exposure to specific drugs, using Mann-Whitney tests. Results Two SNPs, rs997917 and rs10111937 showed point-wise significant allelic association (p 0.05). However, significant associations of several genotype patterns (diplotypes) were found with cocaine dependence, but none for opioid dependence. The most significant genotype pattern with cocaine dependence diagnosis occurred for rs6473797 and rs10111937 (pcorr =0.036, odds ratio=1.92, FDR Conclusions This study provides additional support of potential importance of regulatory regions of intron 2 OPRK1 in development of cocaine and opioid dependence diagnoses, in a population with African-American ancestry.

Background One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. Methods A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. Results A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01–0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. Conclusions Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

Background: Novel short-acting κ(kappa)-opioid receptor selective antagonists are translational tools to examine the impact of the κ-receptor/dynorphin system in assays related to central nervous system dysfunction (e.g., substance use disorders, anhedonia and depression). The effects of such compounds have been compared in males and females under very limited conditions. Aims: The goal of this study was to examine potential sex differences in the effects of a κ-agonist and a short-acting κ-antagonist in an ethologically relevant test of anhedonia, the “splash test” of self-grooming, and also in the forced swim test and in locomotor activity. Methods: We examined the dose-dependence of grooming deficits caused by the κ-agonist U50,488 (0.1–3.2 mg/kg intraperitoneal (i.p.)) in gonadally intact adult male and female C57BL/6J mice. We then compared the effects of the short-acting κ-antagonist LY2795050 ((3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)); 0.032–0.1 mg/kg i.p.) in blocking grooming deficits caused by U50,488 (3.2 mg/kg). The effects of LY2795050 were also studied in the forced swim test (FST). The effects of LY2795050 in blocking the locomotor depressant effects of U50,488 (10 mg/kg) were also studied. Results: U50,488 produced dose-dependent grooming deficits in male and female mice, and LY2795050 prevented these effects. In contrast, LY2795050 decreased immobility in the FST in males at a dose of 0.1 mg/kg, but not in females, up to a dose of 0.32 mg/kg. Also, LY2795050 (0.32 mg/kg) prevented and also reversed the locomotor-depressant effects of U50,488 (10 mg/kg), in males and females. Conclusions: This study further implicates the κ-receptor system in ethologically relevant aspects of anhedonia, and confirms sexual dimorphism in some behavioral effects of novel κ-antagonists.

The kappa opioid receptor (KOR) and its primary cognate ligands, the dynorphin peptides, are involved in diverse physiological processes. Disruptions to the KOR/dynorphin system have been found to likely play a role in multiple neuropsychological disorders, and hence KOR has emerged as a potential therapeutic target. Targeting KOR is complicated by close homology to the mu and delta opioid receptors (MOR and DOR), and many KOR ligands have at least moderate affinity to MOR and/or DOR. Animal models utilizing primarily very long-lasting selective KOR antagonists (3 weeks following a single dose) have demonstrated that KOR antagonism attenuates certain anxiety-like and depression-like behaviors and blocks stress- and cue-induced reinstatement to drug seeking. Recently, relatively selective KOR antagonists with medication-like pharmacokinetic and pharmacodynamic properties and durations of action have been developed. One of these, JNJ-67953964 (also referred to as CERC-501, LY2456302, OpraKappa or Aticaprant) has been studied in humans, and shown to be safe, relatively KOR selective, and able to substantially attenuate binding of a KOR PET tracer to CNS localized KOR for greater than 24 h. While animal studies have indicated that compounds of this structural class are capable of normalizing withdrawal signs in animal models of cocaine and alcohol dependence and reducing cocaine and alcohol intake/seeking, additional studies are needed to determine the value of these second generation KOR antagonists in treating mood disorders and substance use disorders in humans.

Background Persons with severe opioid or cocaine use disorders are particularly vulnerable to morbidity and mortality. Heaviest use of mu-opioid receptor agonists and cocaine typically commences in early adulthood and is preceded by substantial adolescent exposure to cannabis and/or alcohol. Little information exists on the age trajectories of exposure to cannabis or alcohol in persons diagnosed with severe opioid or cocaine use disorders, compared to persons diagnosed with other substance use disorders (unrelated to opioids or cocaine). Method This observational study had n = 854 volunteers (male = 581, female = 273; ≥18 years of age at the time of interview) and examined the ages of onset of heaviest use of cannabis and alcohol in persons diagnosed by DSM-IV criteria with opioid dependence (OD), both opioid and cocaine dependence (OD + CD) and cocaine dependence (CD). These age trajectory measures were compared to persons with other substance use disorders (primarily cannabis and alcohol use disorders, termed “Any Other Diagnoses”). Results Unadjusted survival analyses showed persons diagnosed with either OD + CD or CD had earlier onset of heaviest use of cannabis (mean ages of 16.2 and 17.8, respectively) compared to the “Any Other Diagnoses” reference group (mean age = 19.5). A multivariate logistic regression showed that later onset of heaviest use of cannabis was associated with lower odds of being in the OD + CD or CD groups, when compared to the reference group. Conclusions Persons diagnosed with severe cocaine use disorders or dual opioid and cocaine use disorders exhibit a pattern of heavy and especially early adolescent exposure to cannabis, compared to persons with other substance use disorders.

The widely abused prescription opioid oxycodone is a mu-opioid receptor (MOP-r) agonist and addiction to such opioids is a relapsing disorder. The human MOP-r gene (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G, which affects risk of severe opioid use disorders. A112G (G/G) knock-in mice are models of human A118G carriers. We examined oxycodone self-administration (SA) in male and female G/G versus wild type (A/A) mice in SA sessions and in relapse-like behavior. Adult male and female G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, FR1) for 10 consecutive days. Following 10-day home cage drug free withdrawal, the mice were re-exposed to oxycodone SA for a further 10 days. MOP-r receptor mRNA in various brain regions were examined immediately after the last re-exposure session. We found that G/G mice had greater oxycodone SA than A/A mice in the initial and in re-exposure sessions. Mice of both genotypes had greater oxycodone intake during the re-exposure period than during the initial exposure. We also detected differences in MOP-r gene expression due to genotype, sex and oxycodone SA history in the dorsal striatum, hippocampus, and prefrontal cortex. These studies may improve our understanding of MOP-r-agonist self-exposure and relapse in human carriers of the A118G SNP.

The kappa opioid receptor (KOR) and its primary cognate ligands, the dynorphin peptides, are involved in diverse physiological processes. Disruptions to the KOR/dynorphin system have been found to likely play a role in multiple neuropsychological disorders, and hence KOR has emerged as a potential therapeutic target. Targeting KOR is complicated by close homology to the mu and delta opioid receptors (MOR and DOR), and many KOR ligands have at least moderate affinity to MOR and/or DOR. Animal models utilizing primarily very long-lasting selective KOR antagonists (>3 weeks following a single dose) have demonstrated that KOR antagonism attenuates certain anxiety-like and depression-like behaviors and blocks stress- and cue-induced reinstatement to drug seeking. Recently, relatively selective KOR antagonists with medication-like pharmacokinetic and pharmacodynamic properties and durations of action have been developed. One of these, JNJ-67953964 (also referred to as CERC-501, LY2456302, OpraKappa or Aticaprant) has been studied in humans, and shown to be safe, relatively KOR selective, and able to substantially attenuate binding of a KOR PET tracer to CNS localized KOR for greater than 24 h. While animal studies have indicated that compounds of this structural class are capable of normalizing withdrawal signs in animal models of cocaine and alcohol dependence and reducing cocaine and alcohol intake/seeking, additional studies are needed to determine the value of these second generation KOR antagonists in treating mood disorders and substance use disorders in humans.

Background Persons dually diagnosed with opioid and cocaine dependence (OD + CD) present a clinical challenge and are at risk of morbidity and mortality. The time of escalation of heroin and cocaine exposure in persons with OD + CD remain understudied, and the influence of gender and other variables have not been examined. This observational study focused on the time of escalation of heroin and cocaine in volunteers with OD + CD, examining gender and exposure to other drugs (e.g., cannabis or alcohol) as predictors. Ages of first use and of onset of heaviest use of each drug were collected (in whole years). Time of escalation was defined as the interval between age of first use and onset of heaviest use. Volunteers sequentially ascertained adult volunteers recruited from the New York Metropolitan area, of which n = 297 were diagnosed with OD + CD. Methods Instruments administered were the SCID-I diagnostic interview (DSM-IV criteria), BIS-11 impulsiveness scale, and KMSK scales, dimensional measures of maximal exposure to specific drugs. Results In volunteers with OD + CD, ages of onset of heaviest use of cannabis (median age = 15) and alcohol (median age = 19) were in adolescence or emerging adulthood and preceded those for heroin and cocaine (median ages = 26 and 25, respectively). Maximal levels of cannabis and alcohol exposure were high, in volunteers with OD + CD. In adjusted Cox regressions, gender was not a significant predictor of time of heroin or cocaine escalation. However, more rapid time of alcohol escalation was a predictor of more rapid time of escalation of both heroin and cocaine, in volunteers with OD + CD.

BACKGROUND AND OBJECTIVES Addictions to heroin or to cocaine are associated with substantial psychiatric comorbidity, including depression. Poly-drug self-exposure (eg, to heroin, cocaine, cannabis, or alcohol) is also common, and may further affect depression comorbidity. METHODS This case-control study examined the relationship of exposure to the above drugs and depression comorbidity. Participants were recruited from methadone maintenance clinics, and from the community. Adult male and female participants (n = 1,201) were ascertained consecutively by experienced licensed clinicians. The instruments used were the SCID-I, and Kreek-McHugh-Schluger-Kellogg (KMSK) scales, which provide a rapid dimensional measure of maximal lifetime self-exposure to each of the above drugs. This measure ranges from no exposure to high unit dose, high frequency, and long duration of exposure. RESULTS A multiple logistic regression with stepwise variable selection revealed that increasing exposure to heroin or to cocaine was associated greater odds of depression, with all cases and controls combined. In cases with an opioid dependence diagnosis, increasing cocaine exposure was associated with a further increase in odds of depression. However, in cases with a cocaine dependence diagnosis, increasing exposure to either cannabis or alcohol, as well as heroin, was associated with a further increase in odds of depression. DISCUSSION AND CONCLUSIONS This dimensional analysis of exposure to specific drugs provides insights on depression comorbidity with addictive diseases, and the impact of poly-drug exposure. SCIENTIFIC SIGNIFICANCE A rapid analysis of exposure to drugs of abuse reveals how specific patterns of drug and poly-drug exposure are associated with increasing odds of depression. This approach detected quantitatively how different patterns of poly-drug exposure can result in increased odds of depression comorbidity, in cases diagnosed with opioid versus cocaine dependence. (Am J Addict 2017;26:632-639).

Since the discovery and verification of the components of the endogenous opioid system in the 1970s, consisting of the mu, kappa, and delta-opioid receptors, and the cognate ligands β-endorphin, the enkephalins, and the dynorphins, a role for the endogenous opioid system in addiction to opiates has been established. Further, studies demonstrated that long term opiate addiction results in a relative endogenous endorphin deficiency which contributes to the chronic relapsing nature of the disease. Subsequent studies, utilizing pharmacological approaches, gene expression and receptor binding techniques in animal models of addiction, as well as transgenic mouse knockout studies, have revealed the endogenous opioid system to be important in the effects of other addictive substances, and this has been verified in human genetics studies demonstrating associations of variants in genes encoding the components of the opioid system with addiction to opiates, cocaine, and alcohol.

Cocaine use disorders (CUD) cause major morbidity and optimized prevention efforts are critical. It is unclear if trait impulsivity and exposure to cannabis or alcohol are associated with age trajectory of cocaine use (e.g., age of onset of heaviest use, or time of escalation), or with vulnerability to develop a CUD. This is an observational study with volunteers (≥ 18 years old), from a metropolitan area. The sample (n = 1,010) included: n = 360 normal volunteers, n = 438 with cocaine dependence (CD) diagnoses, and n = 212 with other addictive diseases. Trait impulsivity was examined with BIS-11 scores. Maximal self-exposure to cannabis, alcohol, and cocaine were characterized dimensionally with Kreek-McHugh-Schluger-Kellogg (KMSK) scales. Time of escalation was defined as the interval between age of first use and age of onset of heaviest use. Onset of maximal use of cannabis (median age = 17) and alcohol (median age = 21) preceded that of cocaine (median age = 27), in volunteers with CD. Multivariate Cox regressions in volunteers with CD show that increasing self-exposure to cannabis was a predictor of earlier onset of heaviest use of cocaine. Also, more rapid time of escalation of alcohol was a predictor of more rapid time of escalation of cocaine. A multiple logistic regression shows that increasing self-exposure to cannabis or alcohol was a positive predictor of odds of CD diagnosis. Trait impulsivity and gender were not significant predictors in these multivariate analyses. This study shows that aspects of adolescent exposure to nonmedical cannabis and alcohol are predictors of early onset of CUD, and may be potentially targeted for prevention efforts. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective Naltrexone and nalmefene are approved for the treatment of alcohol use disorders, in different countries. Naltrexone is also approved for the treatment for opioid use disorders, most recently in a depot formulation. These compounds target primarily μ(mu)- and κ(kappa)-opioid receptor systems, which are involved in the downstream neurobiological effects of alcohol and in the modulation of neuroendocrine stress systems. The study objective was to compare the neuroendocrine effects of naltrexone and nalmefene on adrenocorticotropic hormone (ACTH), cortisol, and prolactin, in normal volunteers. Method Adult normal volunteers (n = 11 male and n = 9 female) were studied in a stress-minimized inpatient setting on three consecutive days, after intravenous saline, naltrexone HCl (10 mg), or nalmefene HCl (10 mg), in fixed order. ACTH, cortisol, and prolactin were analyzed pre-injection and up to 180 min post-injection. Results Naltrexone and nalmefene caused elevations in ACTH and cortisol compared with saline. Nalmefene had a greater effect on ACTH and cortisol, compared with naltrexone. Both compounds also caused elevations in prolactin in males (females were not examined, due to the influence of menstrual cycle on prolactin). Conclusions This study suggests that both nalmefene and naltrexone have effects potentially due to κ-partial agonism in humans, as well as antagonist effects at μ-receptors.

The kappa (κ) opioid receptor/dynorphin system modulates depression-like states and anhedonia, as well adaptations to stress and exposure to drugs of abuse. Several relatively short-acting small molecule κ-receptor antagonists have been synthesized, and their behavioral profile has been examined under some conditions. The hypothesis of this study is that pharmacological manipulations of the κ-receptor system will result in changes in ethologically relevant anhedonic-like behaviors in mice. Adult male C57BL/6j mice (n = 6-8) were examined for self-grooming behavior in the splash test (in which robust self-grooming is elicited by spraying the dorsum of the mouse with a sucrose solution). The κ-agonist salvinorin A (0.56-1.8 mg/kg) produced dose-dependent decreases in self-grooming, a marker of anhedonia. The selectivity, potency, and duration of action of two relatively short-acting κ-antagonists, LY2444296 [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl) pyrrolidin-1-yl)methyl)phenoxy)benzamide] and LY2795050 [3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide], were studied for their effectiveness in preventing grooming deficits caused by salvinorin A (1.8 mg/kg). κ-selective doses of both LY2444296 (0.032-1 mg/kg) and LY2795050 (0.032-0.32 mg/kg) dose- and time-dependently prevented the grooming deficits caused by salvinorin A (1.8 m/kg). We also found that a κ-selective dose of each of these antagonists decreased immobility in the forced swim test, a common test of anti-anhedonia effects. This study shows that the κ-receptor system is involved in an ethologically relevant measure of anhedonia, and that κ-selective doses of these antagonists can produce effects consistent with rapid anti-anhedonia. SIGNIFICANCE STATEMENT: Activation of the κ-opioid receptor system results in grooming deficits in mice, an ethologically relevant marker of anhedonia. Shorter acting κ-antagonists are able to cause effects consistent with rapid antianhedonia.

Two effective treatments for opioid addiction, methadone and buprenorphine-naloxone maintenance, should be widely implemented., Opioid use disorders (OUDs) are diseases of the brain with behavioral, psychological, neurobiological, and medical manifestations. Vulnerability to OUDs can be affected by factors such as genetic background, environment, stress, and prolonged exposure to μ-opioid agonists for analgesia. Two standard-of-care maintenance medications, methadone and buprenorphine-naloxone, have a long-term positive influence on health of persons with opioid addiction. Buprenorphine and another medication, naltrexone, have also been approved for administration as monthly depot injections. However, neither medication is used as widely as needed, due largely to stigma, insufficient medical education or training, inadequate resources, and inadequate access to treatment. Ongoing directions in the field include (i) personalized approaches leveraging genetic factors for prediction of OUD vulnerability and prognosis, or for targeted pharmacotherapy, and (ii) development of novel analgesic medicines with new neurobiological targets with reduced abuse potential, reduced toxicity, and improved effectiveness, especially for chronic pain states other than cancer pain.

The dynorphin/kappa opioid receptor (Dyn/KOR) system is involved in reward processing and dysphoria/anhedonia. Exposure to mu-opioid receptor agonists such as heroin increases expression of the prodynorphin gene (PDYN) in the brain. In this study in a Caucasian cohort, we examined the association of the functional PDYN 68-bp repeat polymorphism with opioid use disorders. In this case-control study, 554 subjects with Caucasian ancestry (142 healthy controls, 153 opioid-exposed, but never opioid dependent, NOD, and 259 with an opioid dependence diagnosis, OD) were examined for association of the PDYN 68-bp repeats with the diagnosis of opioid dependence (DSM-IV criteria), with a dimensional measure of heroin exposure (KMSK scale), and age trajectory parameters of heroin use (age of heroin first use, and age of onset of heaviest use). The PDYN 68-bp repeat genotype (classified as: “short-short” [SS], “long-long” [LL], and “short-long” [SL], based on the number of repeats) was not associated with categorical opioid dependence diagnoses. However, the LL genotype was associated with later age of first heroin use than the SS + SL genotype (19 versus 18 years; p < 0.01). This was also confirmed by a significant positive correlation between the number of repeats and the age of first use of heroin, in volunteers with OD (Spearman r = 0.16; p = 0.01). This suggests that the functional PDYN 68-bp repeat genotype is associated with the age of first use of heroin in Caucasians diagnosed with opioid dependence.

Cocaine addiction is a chronic brain disease characterized by compulsive drug intake and dysregulation of brain reward systems. Few preclinical studies have modeled the natural longitudinal course of cocaine addiction. Extended access self-administration protocols are powerful tools for modeling the advanced stages of addiction; however, few studies have duration of drug access longer than 12 h/session, potentially limiting their construct validity. Identification of changes in cocaine intake patterns during the development of addictive-like states may allow better treatments for vulnerable subjects. The kappa opioid receptor (KOPr) system has been implicated in the neurobiological regulation of addictive states as well as mood and stress disorders, with selective KOPr antagonists proposed as possible pharmacotherapeutic agents. Chronic cocaine exposure increases the expression of KOPr and its endogenous agonists, the dynorphins, in several brain areas in rodents. To examine the behavioral pattern of intake during chronic (14 days) 18 h intravenous cocaine self-administration (0.5 mg/kg/infusion) and the effect of a novel short-acting KOPr antagonist LY2444296 HCl (3 mg/kg) administered during sessions 8 to 14 of chronic 18 h/day cocaine self-administration and prior to a single re-exposure session after 2 cocaine-free withdrawal days. Both daily and hourly cocaine intake patterns changed over 14 days of 18 h self-administration. LY pretreatment affected the pattern of self-administration across the second week of extended access cocaine self-administration and prevented the increase in cocaine intake during re-exposure. Overall, the KOPr antagonist attenuated escalated cocaine consumption in a rat model of extended access cocaine self-administration.

The aim of the present study was to investigate alterations in gene expression of opioid system components induced by extended access (18 h) cocaine self-administration and to determine the impact of genetic background in the vulnerability to escalate cocaine intake. Comparing two inbred rat strains, we previously reported that Lewis rats progressively escalated cocaine consumption compared to Fischer rats, in a new translational model of intravenous cocaine self-administration, which included 14 sessions of 18-h operant sessions in which rats were allowed to select the cocaine unit dose to self-administer. We compare here Fischer and Lewis rats in the gene expression of endogenous opioid peptides (Pomc, Penk, Pdyn) and cognate receptors (Oprm, Oprk and Oprd) in reward-related brain regions, after exposure to either cocaine self-administration or yoked-saline, in the aforementioned translational paradigm. We performed a correlation analysis between the mRNA level, found in the Dorsal Striatum (DS), Nucleus accumbens (NAcc) shell and core respectively, and individual cocaine intake. Our findings show that the gene expression of all the aforementioned opioid genes exhibit strain-dependent differences in the DS, in absence of cocaine exposure. Also, different strain-specific cocaine-induced mRNA expression of Oprm and Oprk was found in DS. Only few differences were found in the ventral parts of the striatum. Moreover, gene expression level of Pdyn, Penk, Oprk, and Oprm in the DS was significantly correlated with cocaine intake only in Fischer rats. Overall, these data shed light on potential genetic differences which may predispose of subjects to initiate and escalate cocaine consumption.

Background: The impact of increasing non-medical cannabis use on vulnerability to develop opioid use disorders has received considerable attention, with contrasting findings. A dimensional analysis of self-exposure to cannabis and other drugs, in individuals with and without opioid dependence (OD) diagnoses, may clarify this issue. Objective: To examine the age of onset of maximal self-exposure to cannabis, alcohol, cocaine, and heroin, in volunteers diagnosed with OD, using a rapidly administered instrument (the KMSK scales). To then determine whether maximal self-exposure to cannabis, alcohol, and cocaine is a dimensional predictor of odds of OD diagnoses. Methods: This outpatient observational study examined maximal self-exposure to these drugs, in volunteers diagnosed with DSM-IV OD or other drug diagnoses, and normal volunteers. In order to focus more directly on opioid dependence diagnosis as the outcome, volunteers who had cocaine dependence diagnoses were excluded. Male and female adults of diverse ethnicity were consecutively ascertained from the community, and from local drug treatment programs, in 2002–2013 (n = 574, of whom n = 94 had OD diagnoses). The age of onset of maximal self-exposure of these drugs was examined. After propensity score matching for age at ascertainment, gender, and ethnicity, a multiple logistic regression examined how increasing self-exposure to non-medical cannabis, alcohol and cocaine affected odds of OD diagnoses. Results: Volunteers with OD diagnoses had the onset of heaviest use of cannabis in the approximate transition between adolescence and adulthood (mean age = 18.9 years), and onset of heaviest use of alcohol soon thereafter (mean age = 20.1 years). Onset of heaviest use of heroin and cocaine was detected later in the lifespan (mean ages = 24.7 and 25.3 years, respectively). After propensity score matching for demographic variables, we found that the maximal self-exposure to cannabis and cocaine, but not to alcohol, was greater in volunteers with OD diagnoses, than in those without this diagnosis. Also, a multiple logistic regression detected that increasing self-exposure to cannabis and cocaine, but not alcohol, was a positive predictor of OD diagnosis. Conclusions/Importance: Increasing self-exposure to non-medical cannabis, as measured with a rapid dimensional instrument, was a predictor of greater odds of opioid dependence diagnosis, in propensity score-matched samples.

Background Cannabis use disorders (CUDs) cause substantial neuropsychiatric morbidity and comorbidity. There is evidence for gender-based differences in CUDs, for instance, a greater prevalence in males than in females. The main active component of cannabis is delta 9-tetrahydrocannabinol (delta 9-THC), a partial agonist of the cannabinoid type 1 receptor. Preclinical studies show that genetic or pharmacological manipulation of the kappa opioid receptor/dynorphin system modulates the effects of delta 9-THC. Methods In this case-control study of adult African Americans (n=476; 206 females, 270 males), we examined the association of the functional prodynorphin 68 bp (PDYN 68 bp) promoter repeats with categorical diagnoses of cannabis dependence (Diagnostic and Statistical Manual of Mental Disorders-IV criteria), as well as with a rapid dimensional measure of maximum lifetime cannabis exposure (the Kreek–McHugh–Schluger–Kellogg cannabis scale). Results The PDYN 68 bp genotype (examined as short–short [SS], short–long [SL], or long–long [LL], based on the number of repeats) was not significantly associated with categorical cannabis-dependence diagnoses, either in males or in females. However, in males, the PDYN 68 bp SS+SL genotype was associated with both greater odds of any use of cannabis (p

Background The Kreek-McHugh-Schluger-Kellogg (KMSK) scales provide a rapid assessment of maximal self-exposure to specific drugs and can be used as a dimensional instrument. This study provides a re-evaluation of the KMSK scales for cannabis, alcohol, cocaine, and heroin in a relatively large multi-ethnic cohort, and also the first systematic comparison of gender-specific profiles of drug exposure with this scale. Methods This was an observational study of n = 1,133 consecutively ascertained adult volunteers. The main instruments used were the SCID-I interview (DSM-IV criteria) and KMSK scales for cannabis, alcohol, cocaine, and heroin. Results Participants were 852 volunteers (297 female) with specific DSM-IV abuse or dependence diagnoses, and 281 volunteers without any drug diagnoses (154 female). Receiver operating characteristic (ROC) curves were calculated for concurrent validity of KMSK scores with the respective DSM-IV dependence diagnoses. The areas under the ROC curves for men and women combined were 99.5% for heroin, 97% for cocaine, 93% for alcohol, and 85% for cannabis. Newly determined optimal KMSK “cutpoint” scores were identical for men and women for cocaine and heroin dependence diagnoses, but were higher in men than in women, for cannabis and alcohol dependence diagnoses. Conclusions This study confirms the scales’ effectiveness in performing rapid dimensional analyses for cannabis, alcohol, cocaine, and heroin exposure, in a cohort larger than previously reported, with “cutpoints” changed from initial determinations, based on this larger sample. The KMSK scales also detected gender differences in self-exposure to alcohol and cannabis that are associated with the respective dependence diagnoses.

The κ-opioid receptor (KOP-r) system and its endogenous ligands, the dynorphins, are involved in the neurobiological regulation of addictive states, and of mood. There are limited data on the impact of selective KOP-r antagonism in humans on basic biobehavioral functions, or on addictive diseases and mood disorders. Previously studied selective KOP-r antagonists have unusual pharmacodynamic and pharmacokinetic properties (slow development of KOP-r selectivity, extremely long duration of action) that limit translation to human studies. A recently developed selective KOP-r-antagonist, Opra Kappa (LY2456302; CERC-501), has medication-like duration of action, oral bioavailability, and target engagement. The current study is the first investigation of the effects of a KOP-r-antagonist in cocaine-dependent persons in comparison with normal volunteers. In a stress-minimized inpatient setting, we determined the neuroendocrine and neurobehavioral effects of repeated administration of an active dose of Opra Kappa (10 mg p.o. daily, four consecutive days in comparison with an initial baseline day). Healthy volunteers (n=40), persons diagnosed with cocaine dependence in early abstinence (

Substance use disorders are a group of chronic relapsing disorders of the brain, which have massive public health and societal impact. In some disorders (e.g., heroin/prescription opioid addictions) approved medications have a major long-term benefit. For other substances (e.g., cocaine, amphetamines and cannabis) there are no approved medications, and for alcohol there are approved treatments, which are not in wide usage. Approved treatments for tobacco use disorders are available, and novel medications are also under study. Areas covered: Medication-based approaches which are in advanced preclinical stages, or which have reached proof-of concept clinical laboratory studies, as well as clinical trials. Expert opinion: Current challenges involve optimizing translation between preclinical and clinical development, and between clinical laboratory studies to therapeutic clinical trials. Comorbidities including depression or anxiety are challenges for study design and analysis. Improved pharmacogenomics, biomarker and phenotyping approaches are areas of interest. Pharmacological mechanisms currently under investigation include modulation of glutamatergic, GABA, vasopressin and κ-receptor function, as well as inhibition of monoamine re-uptake. Other factors that affect potential market size for emerging medications include stigma, availability of treatment settings, adoption by clinicians, and the prevalence of persons with SUD who are not actively treatment-seeking.

The recruitment of the stress circuitry contributes to a shift from positive to negative reinforcement mechanisms sustaining long-term cocaine addiction. The kappa opioid receptor (KOPr) signaling is upregulated by stress and chronic cocaine exposure. While KOPr agonists induce anhedonia and dysphoria, KOPr antagonists display antidepressant and anxiolytic properties. Most of the knowledge on KOPr antagonism is based on drugs with unusual pharmacokinetic and pharmacodynamic properties, complicating interpretation of results. Here we characterized in vivo behavioral and neuroendocrine effects of the novel relatively short-acting KOPr antagonist LY2444296. To date, no study has investigated whether systemic KOPr blockade reduced anxiety-like and depressive-like behaviors in animals previously exposed to chronic extended access cocaine self-administration. We tested the effect of LY2444296 in blocking KOPr-mediated aversive and neuroendocrine effects. Then, we tested acute systemic LY2444296 in reducing anxiety- and depression-like behaviors, as well as releasing the stress hormone corticosterone (CORT), observed after chronic extended access (18 h/day for 14 days) cocaine self-administration. LY2444296 blocked U69,593-induced place aversion and -reduced motor activity as well as U69,593-induced release of serum CORT, confirming its major site of action, without exerting an effect per se. Acute systemic administration of LY2444296 reduced anxiety-like and depressive-like behaviors, as well as CORT release, in rats tested after chronic extended access cocaine self-administration, but not in cocaine-naive rats. Results suggest that acute blockade of KOPr by a relatively short-acting antagonist produces therapeutic-like effects selectively in rats with a history of chronic extended access cocaine self-administration.

Illicit use of prescription opioid analgesics (e.g., oxycodone) in adolescence is a pressing public health issue. Our goal was to determine whether oxycodone self administration differentially affects striatal neurotransmitter receptor gene expression in the dorsal striatum of adolescent compared to adult C57BL/6J mice. Groups of adolescent mice (4 weeks old, n= 12) and of adult mice (11 weeks old, n= 11) underwent surgery during which a catheter was implanted into their jugular veins. After recovering from surgery, mice self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or served as yoked saline controls. Mice were sacrificed within 1 h after the last self-administration session and the dorsal striatum was isolated for mRNA analysis. Gene expression was analyzed with real time PCR using a commercially available neurotransmitter receptor PCR array containing 84 genes. We found that adolescent mice self administered less oxycodone than adult mice over the 14 days. Monoamine oxidase A (Maoa) and neuropeptide Y receptor 5 mRNA levels were lower in adolescent mice than in adult mice without oxycodone exposure. Oxycodone self administration increased Maoa mRNA levels compared to controls in both age groups. There was a positive correlation of the amount of oxycodone self administered in the last session or across 14 sessions with Maoa mRNA levels. Gastrin-releasing peptide receptor mRNA showed a significant Drug × Age interaction, with point-wise significance. More genes in the dorsal striatum of adolescents (19) changed in response to oxycodone self administration compared to controls than in adult (4) mice. Overall, this study demonstrates that repeated oxycodone self administration alters neurotransmitter receptors gene expression in the dorsal striatum of adolescent and adult mice.

Cocaine addiction is a chronic relapsing disease with periods of chronic escalating self-exposure, separated by periods of abstinence/withdrawal of varying duration. Few studies compare such cycles in preclinical models. This study models an “addiction-like cycle” in mice to determine neurochemical/molecular alterations that underlie the chronic, relapsing nature of this disease. Groups of male C57BL/6J mice received acute cocaine exposure (14-day saline/14-day withdrawal/13-day saline + 1-day cocaine), chronic cocaine exposure (14 day cocaine) or chronic re-exposure (14-day cocaine/14-day withdrawal/14-day cocaine). Escalating-dose binge cocaine (15–30 mg/kg/injection × 3/day, i.p. at hourly intervals) or saline (14-day saline) was administered, modeling initial exposure. In “re-exposure” groups, after a 14-day injection-free period (modeling abstinence/withdrawal), mice that had received cocaine were re-injected with 14-day escalating-dose binge cocaine, whereas controls received saline. Microdialysis was conducted on the 14th day of exposure or re-exposure to determine striatal dopamine content. Messenger RNA levels of preprodynorphin ( Pdyn ), dopamine D1 ( Drd1 ) and D2 ( Drd2 ) in the caudate putamen were determined by real-time PCR. Basal striatal dopamine levels were lower in mice after 14-day escalating exposure or re-exposure than in those in the acute cocaine group and controls. Pdyn mRNA levels were higher in the cocaine groups than in controls. Long-term adaptation was observed across the stages of this addiction-like cycle, in that the effects of cocaine on dopamine levels were increased after re-exposure compared to exposure. Changes in striatal dopaminergic responses across chronic escalating cocaine exposure and re-exposure are a central feature of the neurobiology of relapsing addictive states.

Addictive diseases, including addiction to heroin, prescription opioids, or cocaine, pose massive personal and public health costs. Addictions are chronic relapsing diseases of the brain caused by drug-induced direct effects and persisting neuroadaptations at the epigenetic, mRNA, neuropeptide, neurotransmitter, or protein levels. These neuroadaptations, which can be specific to drug type, and their resultant behaviors are modified by various internal and external environmental factors, including stress responsivity, addict mindset, and social setting. Specific gene variants, including variants encoding pharmacological target proteins or genes mediating neuroadaptations, also modify vulnerability at particular stages of addiction. Greater understanding of these interacting factors through laboratory-based and translational studies have the potential to optimize early interventions for the therapy of chronic addictive diseases and to reduce the burden of relapse. Here, we review the molecular neurobiology and genetics of opiate addiction, including heroin and prescription opioids, and cocaine addiction.

Addictions to cocaine or heroin/prescription opioids [short-acting mu-opioid receptor (MOPr) agonists] involve relapsing cycles, with experimentation/escalating use, withdrawal/abstinence, and relapse/re-escalation. Kappa-opioid receptors (KOPr; encoded by OPRK1), and their endogenous agonists, the dynorphins (encoded by PDYN) have counter-modulatory effects on reward caused by cocaine or MOPr agonist exposure, and exhibit plasticity in addictive-like states. KOPr/dynorphin activation is implicated in depression/anxiety, often co-morbid with addictions. In this Opinion article, we propose that particular stages of the addiction cycle are differentially affected by KOPr/dynorphin systems. Vulnerability and resilience can be due to pre-existing (e.g., genetic) factors, or epigenetic modifications of the OPRK1 or PDYN genes during the addiction cycle. Pharmacotherapeutic approaches limiting changes in KOPr/dynorphin tone, especially with KOPr partial agonists, may hold potential for the treatment of specific drug addictions and psychiatric co-morbidity.

Opioid receptors (MOP-r, KOP-r, DOP-r, as well as NOP-r) and their endogenous neuropeptide agonist systems are involved in diverse neurobiological and behavioral functions, in health and disease. These functions include pain and analgesia, addictions, and psychiatric diseases (e.g., depression-, anxiety-like, and stress-related disorders). Drug discrimination assays have been used to characterize the behavioral pharmacology of ligands with affinity at MOP-r, KOP-r, or DOP-r (and to a lesser extent NOP-r). Therefore, drug discrimination studies with opioid ligands have an important continuing role in translational investigations of diseases that are affected by these neurobiological targets and their pharmacotherapy.

Adolescent and young adult abuse of short-acting MOP-r agonists such as oxycodone is a pressing public health issue. Few preclinical studies have examined how adolescent exposure to oxycodone impacts its effects in the transition to adulthood. Objective To determine in mice how chronic adolescent oxycodone self-administration (SA) affects subsequent oxycodone-induced conditioned place preference (CPP), locomotor activity, and anti-nociception once mice reach early adulthood. Methods Adolescent C57BL/6J male mice (4 weeks old, n = 6–11) and adult mice (10 weeks old, n = 6–10) were surgically implanted with indwelling jugular catheters. Mice then acquired oxycodone self-administration (14 consecutive 2-hr daily sessions; 0.25 mg/kg/infusion) followed by a 14-day drug-free (withdrawal) period in home cage. After the 14-day drug-free period, mice underwent a 10-day oxycodone CPP procedure (0, 1, 3, 10 mg/kg i.p.) or were tested for acute oxycodone-induced antinociception in the hot plate assay (3.35, 5, 7.5 mg/kg i.p.). Results Mice that self-administered oxycodone during adolescence exhibited greater oxycodone-induced CPP (at the 3 mg/kg dose) than their yoked saline controls and mice that self-administered oxycodone during adulthood. Oxycodone dose-dependently increased locomotor activity, but sensitization developed only to the 3 mg/kg in the mice that underwent oxycodone self-administration as adolescents. Mice that self-administered oxycodone as adolescents decreased in the anti-nociceptive effects of oxycodone in one dose (5 mg/kg), whereas animals that self-administered oxycodone as adults did not show this effect. Conclusion Chronic adolescent oxycodone self-administration led to increased oxycodone-induced CPP (primarily 1 and 3 mg/kg, i.p.) and reduced antinociceptive effect of oxycodone (5 mg/kg, i.p.) in adulthood.

Opioid receptors (MOP-r, KOP-r, DOP-r, as well as NOP-r) and their endogenous neuropeptide agonist systems are involved in diverse neurobiological and behavioral functions, in health and disease. These functions include pain and analgesia, addictions, and psychiatric diseases (e.g., depression-, anxiety-like, and stress-related disorders). Drug discrimination assays have been used to characterize the behavioral pharmacology of ligands with affinity at MOP-r, KOP-r, or DOP-r (and to a lesser extent NOP-r). Therefore, drug discrimination studies with opioid ligands have an important continuing role in translational investigations of diseases that are affected by these neurobiological targets and their pharmacotherapy.

Salvia divinorum is a hallucinogenic plant originally used in traditional ethnomedical practice in certain cultures, but is now widely available in the industrialized world through a variety of sources. The main active component of Salvia divinorum is salvinorin A, a diterpene shown to be a selective high-efficacy κ-opioid receptor (KOP-r) agonist, without affinity for the site of action of classic hallucinogens (the 5-HT 2A receptor). Preparations containing salvinorin A cause robust but short-lasting visual and proprioceptive hallucinations, with commonly reported dissociative effects. These effects may be qualitatively similar to previously reported “psychotomimetic” effects observed in humans with synthetic KOP-r agonists. In preclinical animal models, salvinorin A produces behavioral and neurobiological effects qualitatively similar to those observed with synthetic KOP-r agonists. These effects include a decrease in dopaminergic activation. Activation of KOP-r receptors by synthetic and endogenous neuropeptide agonists (the dynorphins) are known to exert a negative modulatory function on dopaminergic systems. Other salvinorin A–induced effects (similar to those of KOP-r agonists) include aversion, anhedonia, and depressant-like and sedative like-effects. Furthermore, salvinorin A also produces robust prolactin release, a neuroendocrine biomarker measure previously used to study KOP-r agonist effects in humans.

Modification of the furan ring of salvinorin A ( 1 ), the main active component of Salvia divinorum , has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position ( 5 ) has allowed for the synthesis of analogues with new carbon–carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind–Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind–Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12- epi - 1 ( 3 ) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12 , 19 , 23 , 25 , and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 ( 31 ) has similar affinity to 1 . Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors.

Although morphine and other mu-opioid agonists are the main analgesics for severe pain, these compounds have potential for abuse and/or addiction. This has complicated the use of mu-agonists in the treatment of chronic pain. However, clinical studies show that when mu-agonist analgesics are appropriately used to control pain, actual abuse or addiction does not usually occur, although some risk factors that increase vulnerability need to be considered, including genetic variation. We review recent findings on molecular adaptations in sustained pain models, and propose how these adaptations (including sustained release of the endogenous mu-agonist beta-endorphin) can result in decreased abuse potential of mu-agonists in chronic pain states. We also review data on particular gene polymorphisms (e.g. in the mu-receptor gene) that could also influence the relative abuse potential of mu-agonists in clinical pain populations.