Nor-LAAM loaded PLGA microparticles for treating opioid use disorder.

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt%) and an average diameter (19 µm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

Nor-LAAM loaded PLGA Microparticles for Treating Opioid Use Disorder.

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt.%) and an average diameter (19 µm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

Risk and protective factors for self-harm thoughts and behaviours in transgender and gender diverse people: A systematic review.

Background: Self-harm (any self-injury or -poisoning regardless of intent) is highly prevalent in transgender and gender diverse (TGD) populations. It is strongly associated with various adverse health and wellbeing outcomes, including suicide. Despite increased risk, TGD individuals' unique self-harm pathways are not well understood. Following PRISMA guidelines we conducted the first systematic review of risk and protective factors for self-harm in TGD people to identify targets for prevention and intervention. Methods: We searched five electronic databases (PubMed, PsychInfo, Scopus, MEDLINE, and Web of Science) published from database inception to November 2023 for primary and secondary studies of risk and/or protective factors for self-harm thoughts and behaviours in TGD people. Data was extracted and study quality assessed using Newcastle-Ottawa Scales. Findings: Overall, 78 studies published between 2007 and 2023 from 16 countries (N = 322,144) were eligible for inclusion. Narrative analysis identified six key risk factors for self-harm in TGD people (aged 7-98years) were identified. These are younger age, being assigned female at birth, illicit drug and alcohol use, sexual and physical assault, gender minority stressors (especially discrimination and victimisation), and depression or depressive symptomology. Three important protective factors were identified: social support, connectedness, and school safety. Other possible unique TGD protective factors against self-harm included: chosen name use, gender-identity concordant documentation, and protective state policies. Some evidence of publication bias regarding sample size, non-responders, and confounding variables was identified. Interpretation: This systematic review indicates TGD people may experience a unique self-harm pathway. Importantly, the risk and protective factors we identified provide meaningful targets for intervention. TGD youth and those assigned female at birth are at increased risk. Encouraging TGD people to utilise and foster existing support networks, family/parent and peer support groups, and creating safe, supportive school environments may be critical for self-harm and suicide prevention strategies. Efforts to reduce drug and alcohol use and experiences of gender-based victimisation and discrimination are recommended to reduce self-harm in this high-risk group. Addressing depressive symptoms may reduce gender dysphoria and self-harm. The new evidence presented in this systematic review also indicates TGD people may experience unique pathways to self-harm related to the lack of social acceptance of their gender identity. However, robust longitudinal research which examines gender-specific factors is now necessary to establish this pathway.

Precision computerised cognitive behavioural therapy (cCBT) for adolescents with depression: a pilot and feasibility randomised controlled trial protocol for SPARX-UK.

BACKGROUND: A serious game called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts), originally developed in New Zealand and incorporating cognitive behavioural therapy (CBT) principles, has been shown to help reduce symptoms of depression and anxiety in adolescents with mild to moderate depression in studies undertaken in Australasia. However, SPARX has never been trialled in the United Kingdom (UK), and there have been issues relating to low engagement when it has been used in a real-world context. AIMS: To conduct the first pilot and feasibility randomised controlled trial (RCT) in England to explore the use of SPARX in different settings. The trial will explore whether SPARX supported by an e-coach (assistant psychologists) improves adherence and engagement compared with self-directed (i.e. self-help) use. The trial results will be used to inform the optimal mode of delivery (SPARX supported vs. SPARX self-directed), to calculate an appropriate sample size for a full RCT, and to decide which setting is most suitable. METHODS: Following consultation with young people to ensure study suitability/appropriateness, a total of 120 adolescents (11-19 years) will be recruited for this three-arm study. Adolescents recruited for the study across England will be randomised to receive either SPARX with human support (from an e-coach), self-directed SPARX, or a waitlist control group. Assessments will be conducted online at baseline, week 4, and 8-10-week post-randomisation. The assessments will include measures which capture demographic, depression (Patient Health Questionnaire modified for adolescents [PHQ-A]) and anxiety (Revised Child Anxiety and Depression Scale [RCADS]) symptomatology, and health-related quality-of-life data (EQ-5D-Y and proxy version). Analyses will be primarily descriptive. Qualitative interviews will be undertaken with a proportion of the participants and clinical staff as part of a process evaluation, and the qualitative data gathered will be thematically analysed. Finally, feasibility data will be collected on recruitment details, overall study uptake and engagement with SPARX, participant retention, and youth-reported acceptability of the intervention. DISCUSSION: The findings will inform the design of a future definitive RCT of SPARX in the UK. If the subsequent definitive RCT demonstrates that SPARX is effective, then an online serious game utilising CBT principles ultimately has the potential to improve the provision of care within the UK's health services if delivered en masse. TRIAL REGISTRATION: ISRCTN: ISRCTN15124804. Registered on 16 January 2023, https://www.isrctn.com/ISRCTN15124804 .

NCP, a dual kappa and mu opioid receptor agonist, is a potent analgesic against inflammatory pain without reinforcing or aversive properties.

While agonists of mu (MOR) and kappa (KOR) opioid receptors have analgesic effects, they produce euphoria and dysphoria, respectively. Other side effects include respiratory depression and addiction for MOR agonists and sedation for KOR agonists. We reported that 17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6ß-{[4'-(2'-cyanopyridyl)]carboxamido}cmorphinan (NCP) displayed potent KOR full agonist and MOR partial agonist activities (58%) with 6.5x KOR-over-MOR selectivity in vitro Herein, we characterized pharmacological effects of NCP in rodents. In mice, NCP exerted analgesic effects against inflammatory pain in both the formalin test and the acetic acid writhing test, with A50 values of 47.6 and 14.4 microg/kg (s.c.), respectively. The analgesic effects in the acetic acid writhing test were mediated by the KOR. NCP at doses much higher than those effective in reducing inflammatory pain did not produce antinociception in the hot plate and tail flick tests, inhibit compound 48/80-induced scratching, cause conditioned place aversion (CPA) or preference, impair rotarod performance, inhibit locomotor activity, cause respiratory depression, or precipitate morphine withdrawal. However, NCP (10~100 microg/kg) inhibited gastrointestinal transit with a maximum of ~40% inhibition. In MOR knockout mice, NCP caused CPA, demonstrating that its lack of CPA is due to combined actions on the MOR and KOR. Following s.c. injection, NCP penetrated into the mouse brain. In rats trained to self-administer heroin, NCP (1~320 microg/kg/infusion) did not function as a reinforcer. Thus, NCP produces potent analgesic effects via KOR without side effects except constipation. Therefore, dual full KOR/partial MOR agonists with moderate KOR-over-MOR selectivity may be promising as non-addictive analgesics for inflammatory pain. Significance Statement Developing non-addictive analgesics is crucial for reducing opioid overdose deaths, minimizing drug misuse, and promoting safer pain management practices. Herein, pharmacology of a potential non-addictive analgesic, NCP, is reported. NCP has full KOR agonist / partial MOR agonist activities with a 6.5 x selectivity for KOR over MOR. Unlike MOR agonists, analgesic doses of NCP do not lead to self-administration or respiratory depression. Furthermore, NCP does not produce aversion, hypolocomotion, or motor incoordination, side effects typically associated with KOR activation.

Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys.

RATIONALE: Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects. OBJECTIVE: The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A. METHODS: Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018 mg/kg/injection). Once trained, cocaine (0.018 mg/kg/injection) or oxycodone (0.0056 mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1-3.2 µg/kg/injection), nalfurafine (0.0032-0.1 µg/kg/injection), triazole 1.1 (3.2-100.0 µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components. RESULTS: Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed. CONCLUSIONS: These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse.

Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure-Activity Relationship Study on Nalfurafine Analogues.

Discovery of analgesics void of abuse liability is critical to battle the opioid crisis in the United States. Among many strategies to achieve this goal, targeting more than one opioid receptor seems promising to minimize this unwanted side effect while achieving a reasonable therapeutic profile. In the process of understanding the structure-activity relationship of nalfurafine, we identified a potential analgesic agent, NMF, as a dual kappa opioid receptor/delta opioid receptor agonist with minimum abuse liability. Further characterizations, including primary in vitro ADMET studies (hERG toxicity, plasma protein binding, permeability, and hepatic metabolism), and in vivo pharmacodynamic and toxicity profiling (time course, abuse liability, tolerance, withdrawal, respiratory depression, body weight, and locomotor activity) further confirmed NMF as a promising drug candidate for future development.

Sensitivity of a fentanyl-vs.-social interaction choice procedure to environmental and pharmacological manipulations.

Recent studies have shown that social interaction can serve as an alternative reinforcer to opioid self-administration under a choice context in rats. However, additional parametric studies are needed to evaluate the sensitivity of opioid-vs.-social interaction procedures relative to more established opioid-vs.-food procedures. The current study evaluated the sensitivity of a novel fentanyl-vs.-social interaction choice procedure to environmental and pharmacological manipulations previously shown to affect fentanyl-vs.-food choice. Male and female rats (responder rats; n = 6/sex) were trained to respond in a discrete-trial choice procedure for either 30-s access to a same-sex "partner" rat or an intravenous fentanyl infusion. Once trained, the effects of fentanyl unit dose (0, 0.32-10 µg/kg/inf), partner rat presence, opioid-dependence status, chronic naltrexone administration (0.032, 0.1 mg/kg/h), and response requirement for fentanyl self-administration (fixed ratio 1-320) were determined across weeks. The fentanyl-vs.-social interaction choice procedure was sensitive to the unit dose of fentanyl, chronic naltrexone treatment, and fentanyl response requirement. However, the magnitude of these effects on fentanyl choice was smaller than those reported in published fentanyl-vs.-food choice studies. Furthermore, fentanyl-vs.-social interaction choice was not sensitive to removal of the partner rat or opioid-dependence status. Minimal sex differences were detected. These results suggest that this fentanyl-vs.-social interaction choice procedure is less sensitive to environmental and pharmacological interventions than previously established opioid-vs.-food choice procedures. The observed discrepancy in sensitivity between the procedures suggests that social interaction may have qualitatively different reinforcing properties compared to more commonly assessed alternative reinforcers such as food (preclinical) or money (human laboratory).

Effect of TRV130 and methadone on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats.

The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However, methadone has undesirable effects that limit its clinical efficacy. Intermediate efficacy MOR agonists may treat OUD with fewer undesirable effects. We compared the effects of methadone with the intermediate efficacy MOR agonist TRV130 (oliceridine) on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats. Male rats (n = 20) were trained under a fentanyl-vs.-food choice procedure. Rats were then provided extended fentanyl (3.2 µg/kg/infusion) access (6 p.m.-6 a.m.) for 10 days to produce opioid dependence/withdrawal. Rats were treated with vehicle (n = 7), TRV130 (3.2 mg/kg; n = 8), or methadone (3.2 mg/kg; n = 5) three times per day after each extended-access session (8:30 a.m., 11 a.m., 1:30 p.m.). Withdrawal sign scoring (1:55 p.m.) and choice tests (2-4 p.m.) were conducted daily. Vehicle, TRV130, and methadone effects on fentanyl choice were redetermined in post-opioid-dependent rats. Vehicle-, TRV130-, and methadone-treated rats had similar fentanyl intakes during extended access. Vehicle-treated rats exhibited increased withdrawal signs and decreased bodyweights. Both methadone and TRV130 decreased these withdrawal signs. TRV130 was less effective than methadone to decrease fentanyl choice and increase food choice in opioid-dependent rats. Neither methadone nor TRV130 decreased fentanyl choice in post-opioid-dependent rats. Results suggest that higher MOR activation is required to reduce fentanyl choice than withdrawal signs in fentanyl-dependent rats. Additionally, given that TRV130 did not precipitate withdrawal in opioid-dependent rats, intermediate efficacy MOR agonists like TRV130 may facilitate the transition of patients with OUD from methadone to lower efficacy treatments like buprenorphine.

Acute pain-related depression of operant responding maintained by social interaction or food in male and female rats.

RATIONALE: Clinically relevant pain is often associated with functional impairment and behavioral depression, including depression of social behavior. Moreover, recovery of function is a major goal in pain treatment. We used a recently developed model of operant responding for social interaction in rats to evaluate the vulnerability of social behavior to an experimental pain manipulation and the sensitivity of pain-depressed social behavior to treatment with clinically effective analgesics. METHODS: Sprague-Dawley male and female rats were trained to lever press for social access to another rat, and responding was evaluated after treatment with (a) intraperitoneal injection of dilute lactic acid (IP acid; 0.18-5.6%) administered alone as a visceral noxious stimulus, (b) the mu-opioid receptor (MOR) agonist morphine (0.32-10 mg/kg) or nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (10 mg/kg) administered alone, or (c) morphine or ketoprofen administered before IP acid. For comparison, the same treatments were evaluated in separate rats trained to lever press for food delivery. RESULTS: Both IP acid alone and morphine alone more potently decreased responding maintained by social interaction than by food, whereas ketoprofen did not affect responding for either reinforcer. In general, analgesics were most effective to rescue operant responding when relatively low IP acid concentrations produced significant but submaximal behavioral depression; however, morphine was not effective to rescue responding for social interaction. CONCLUSIONS: Operant responding maintained by social interaction was more sensitive to pain-related disruption and less responsive to opioid analgesic rescue than food-maintained operant responding. Social behavior may be especially vulnerable to depression by pain states.

The development of a consensus statement for the prescription of powered wheelchair standing devices in Duchenne muscular dystrophy.

PURPOSE: To develop a consensus statement for the prescription of a Powered Wheelchair Standing Device (PWSD) in young people with Duchenne muscular dystrophy (DMD). MATERIALS AND METHODS: An international multidisciplinary panel comprising clinicians and users (young people with DMD) along with their parents was consulted. A literature review was undertaken and a Delphi method was utilised to generate consensus statements. To supplement limited literature, round one of the Delphi process comprised questions consistent with the International Classification of Functioning, Disability and Health model of disability to generate items based on expert opinion and was completed by 38 clinicians and nine users. Thirty-seven participants completed two further rounds rating the importance of each item with a five-point scale. Agreement of 70% or more participants for items indicated consensus. RESULTS: Consensus was reached for 47 of 80 items. Tolerance and comfort in supported standing for at least 10 min, ankle contracture less than 10 degrees and user goals reflecting motivation to use the standing function were agreed as necessary in guiding the decision to trial a PWSD. Evidence of family, therapist and servicing support were also considered critical in enabling continuity of PWSD use. CONCLUSIONS: PWSD is a mobility option that offers choice, control and opportunity for independence. This consensus statement can assist clinicians with decision-making around factors influencing successful implementation and optimisation of PWSD for young people with DMD.Implications for RehabilitationTolerance and comfort in supported standing for at least 10 minutes, ankle contracture limited to less than 10 degrees and the child's goals reflecting motivation to use the standing position were agreed to be necessary considerations in guiding the decision to trial a PWSD.Trialling a PWSD when the child is predicted to lose the ability to walk within a one to two year period was recommended although a PWSD could be suitable for a child who was unable to walk.Evidence of family, therapist and servicing support was considered critical in enabling continuity of PWSD use.

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance.

BACKGROUND AND PURPOSE: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the µ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse-related measures and heroin versus food choice. EXPERIMENTAL APPROACH: For relapse assessment, we trained male and female rats to self-administer heroin (6 h·day-1 , 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg-1 ·d-1 ). Effects of chronic BU08028 delivery were tested on (1) incubation of heroin-seeking in a non-drug Context B, (2) extinction responding reinforced by heroin-associated discrete cues in Context B, (3) reinstatement of heroin-seeking induced by re-exposure to Context A and (4) re-acquisition of heroin self-administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. KEY RESULTS: Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re-acquisition of heroin self-administration selectively in females. Chronic BU08028 had minimal effects on context-induced reinstatement and heroin versus food choice in both sexes. Finally, exploratory post hoc analyses suggest that BU08028 decreased extinction responding selectively in males. CONCLUSIONS AND IMPLICATIONS: Chronic BU08028 delivery had both beneficial and detrimental, sex-dependent, effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 would not be an effective opioid maintenance treatment in humans.

Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription.

BACKGROUND: Opioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown. METHODS: Male (n=13) and female (n=12) rats responded under a fentanyl-vs.-food "choice" procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h self-administration sessions. After two weeks of this self-administration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined. RESULTS: Prior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited similar increases in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with a greater number of differentially expressed genes in the NAc and VTA of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females. CONCLUSIONS: These results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.

A drug-vs-food "choice" self-administration procedure in rats to investigate pharmacological and environmental mechanisms of substance use disorders.

BACKGROUND: Preclinical drug self-administration procedures are commonly used to investigate expression, mechanisms, and treatment of substance use disorders. NEW METHOD: The aims were to back-translate an intravenous drug-vs-food choice procedure primarily utilized in monkeys to male and female rats and to develop a surgical method for sustained intravenous catheter patency suitable for long-term drug-choice studies. RESULTS: The surgical protocol resulted in a median intravenous jugular catheter patency in male and female rats of 126 days (range: 25-365 days). Drug-vs-food choice was established with opioids (fentanyl and heroin), psychostimulants (cocaine, methamphetamine, and amphetamine), and an opioid/psychostimulant mixture (fentanyl + methamphetamine). The average time from catheter implantation to stable choice behavior across all drugs was 27 sessions (range: 16-44 sessions). Choice behavior stabilized more quickly for cocaine and fentanyl than for other drugs. Manipulations of both environmental variables (e.g., response requirement or food reinforcer magnitude) and pharmacological variables (e.g., extended access drug self-administration or continuous buprenorphine treatment via osmotic pump) significantly shifted opioid-vs-food choice consistent with previous monkey studies. COMPARISON WITH EXISTING METHODS: Duration of intravenous catheter patency in rats was suitable for long-term, within-subject drug choice studies. Effects of environmental and pharmacological manipulations in rats confirmed and extended previous results from monkeys. CONCLUSIONS: The concordance of behavioral results between rats and monkeys using the present drug-vs-food choice procedure supports its utility to improve our basic understanding of the expression and mechanisms of substance use disorders towards to development of more effective therapeutics.

Lack of effect of different pain-related manipulations on opioid self-administration, reinstatement of opioid seeking, and opioid choice in rats.

RATIONALE AND OBJECTIVE: Pain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here, we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food. METHODS: In Experiment 1, rats self-administered fentanyl in the presence or absence of repeated intraplantar capsaicin injections in distinct contexts to model context-specific exposure to cutaneous nociception. After capsaicin-free extinction in both contexts, we tested if capsaicin would reinstate fentanyl seeking. In Experiment 2, rats self-administered heroin after intraperitoneal (i.p.) lactic acid injections to model acute visceral inflammatory pain. After lactic acid-free extinction, we tested if lactic acid would reinstate heroin seeking. In Experiment 3, we tested if repeated i.p. lactic acid or intraplantar Complete Freund's Adjuvant (CFA; to model sustained inflammatory pain) would increase fentanyl choice over food. RESULTS: In Experiments 1-2, neither capsaicin nor lactic acid reinstated opioid seeking after extinction, and lactic acid did not increase heroin-induced reinstatement. In Experiment 3, lactic acid and CFA decreased reinforcement rate without affecting fentanyl choice. CONCLUSIONS: Results extend the range of conditions across which pain-related manipulations fail to increase opioid seeking in rats and suggest that enhanced opioid-addiction risk in humans with chronic pain involves factors other than enhanced opioid reinforcement and relapse.

Effects of kappa opioid receptor agonists on fentanyl vs. food choice in male and female rats: contingent vs. non-contingent administration.

RATIONALE: Strategies are needed to decrease the abuse liability of mu opioid receptor (MOR) agonists. One strategy under consideration is to combine MOR agonists with kappa opioid receptor (KOR) agonists. OBJECTIVES: The effects of KOR agonists (U50488, nalfurafine) on fentanyl-vs.-food choice were compared under conditions where the KOR agonists were added to the intravenously self-administered fentanyl (contingent delivery) or administered as subcutaneous pretreatments (non-contingent delivery) in male and female rats. METHODS: Rats were trained to respond under a concurrent schedule of fentanyl (0, 0.32-10 µg/kg/infusion) and food reinforcement. In experiment 1, U50488 and nalfurafine were co-administered with fentanyl as fixed-proportion mixtures (contingent administration). In experiment 2, U50488 (1-10 mg/kg) and nalfurafine (3.2-32 µg/kg) were administered as acute pretreatments (non-contingent administration). The selective KOR antagonist, nor-BNI (32 mg/kg), was administered prior to contingent and non-contingent KOR-agonist treatment in experiment 3. RESULTS: Both U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. However, evidence for punishment corresponded with an elimination of operant responding in the majority of rats. Non-contingent U50488 and nalfurafine administration only decreased the number of choices made during the behavioral session without altering fentanyl choice. Contingent and non-contingent KOR-agonist effects on fentanyl choice were both attenuated by nor-BNI. CONCLUSIONS: These results illustrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.

Medications Development for Treatment of Opioid Use Disorder.

This review describes methods for preclinical evaluation of candidate medications to treat opioid use disorder (OUD). The review is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effectiveness, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and effects of candidate medications. Effects of opioid medications and vaccines on opioid choice in nondependent and opioid-dependent subjects are reviewed. Various nonopioid medications have also been examined, but none yet have been identified that safely and reliably reduce opioid choice. Future research will focus on (1) strategies for increasing safety and/or effectiveness of opioid medications (e.g., G-protein-biased µ-opioid agonists), and (2) continued development of nonopioid medications (e.g., clonidine) that might serve as adjunctive agents to current opioid medications.

A synthetic opioid vaccine attenuates fentanyl-vs-food choice in male and female rhesus monkeys.

AIM: Opioid-targeted vaccines are under consideration as candidate Opioid Use Disorder medications. We recently reported that a fentanyl-targeted vaccine produced a robust and long-lasting attenuation of fentanyl-vs-food choice in rats. In the current study, we evaluated an optimized fentanyl-targeted vaccine in rhesus monkeys to determine whether vaccine effectiveness to attenuate fentanyl choice translated to a species with greater phylogenetic similarity to humans. METHODS: Adult male (2) and female (3) rhesus monkeys were trained to respond under a concurrent schedule of food (1 g pellets) and intravenous fentanyl (0, 0.032-1 µg/kg/injection) reinforcement during daily 2 h sessions. Fentanyl choice dose-effect functions were determined daily and 7-day buprenorphine treatments (0.0032-0.032 mg/kg/h IV; n = 4-5) were determined for comparison to vaccine effects. Subsequently, a fentanyl-CRM197 conjugate vaccine was administered at week 0, 3, 8, 15 over a 29-week experimental period during which fentanyl choice dose-effect functions continued to be determined daily. RESULTS: Buprenorphine significantly decreased fentanyl choice and reciprocally increased food choice. Vaccination eliminated fentanyl choice and increased food choice in four-of-the-five monkeys. A transient and less robust vaccine effect was observed in the fifth monkey. Fentanyl-specific antibody concentrations peaked after the third vaccination to approximately 50 µg/mL while anti-fentanyl antibody affinity increased to a sustained low nanomolar level. CONCLUSION: These results translate fentanyl vaccine effectiveness from rats to rhesus monkeys to decrease fentanyl-vs-food choice, albeit with greater individual differences observed in monkeys. These results support the potential and further clinical evaluation of this fentanyl-targeted vaccine as a candidate Opioid Use Disorder medication.

Evaluation of a Dual Fentanyl/Heroin Vaccine on the Antinociceptive and Reinforcing Effects of a Fentanyl/Heroin Mixture in Male and Female Rats.

Opioid-targeted vaccines represent an emerging treatment strategy for opioid use disorder. To determine whether concurrent vaccination against two commonly abused opioids (fentanyl and heroin) would confer broader spectrum opioid coverage, the current study evaluated dual fentanyl/heroin conjugate vaccine effectiveness using a warm water tail-withdrawal and a fentanyl/heroin-vs-food choice procedure in male and female rats across a 105-day observation period. Vaccine administration generated titers of high-affinity antibodies to both fentanyl and heroin sufficient to decrease the antinociceptive potency of fentanyl (25-fold), heroin (4.6-fold), and a 1:27 fentanyl/heroin mixture (7.5-fold). Vaccination did not alter the antinociceptive potency of the structurally dissimilar opioid agonist methadone. For comparison, continuous treatment with a naltrexone dose (0.032 mg/kg/h) shown previously to produce clinically relevant plasma-naltrexone levels decreased the antinociceptive potency of fentanyl, heroin, and the 1:27 fentanyl/heroin mixture by approximately 20-fold. Naltrexone treatment also shifted the potency of 1:27 fentanyl/heroin mixture in a drug-vs-food choice self-administration procedure 4.3-fold. In contrast, vaccination did not attenuate 1:27 fentanyl/heroin mixture self-administration in the drug-vs-food choice procedure. These data demonstrate that a vaccine can simultaneously attenuate the thermal antinociceptive effects of two structurally dissimilar opioids. However, the vaccine did not attenuate fentanyl/heroin mixture self-administration, suggesting a greater magnitude of vaccine responsiveness is required to decrease opioid reinforcement relative to antinociception.