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Effects of chronic 5-day treatment with buprenorphine (0.01-0.1 mg/kg/day) on choice between heroin and food. Other details as in Fig. 1.
Source publication
Several medications are approved for treatment of opiate abuse, but determinants of their clinical effectiveness are not completely understood. States of opiate dependence or withdrawal may constitute one important set of determinants. To test this hypothesis, the effects of naloxone, buprenorphine, and methadone were assessed on choice between her...
Context in source publication
Context 1
... the same dose of naloxone increased intake of 0.1 mg/kg/injection heroin from a mean of 3.1 injections (mean intake 0.31 mg/kg) to 8.3 injections (mean intake 0.83 mg/kg). Figure 2 and Table 1 show the effects of buprenorphine treatment. As with naloxone, buprenorphine produced dose- dependent rightward shifts in the heroin choice dose-effect curve, increased the heroin choice ED 50 value, and increased response rates during availability of the highest dose of 0.1 mg/kg/injection heroin. ...
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Introduction:
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Citations
... The novel nor-LAAM MP through the HIP method exhibited promising attributes of high drug loading and sustained drug release suitable for parenteral administration. We tested the efficacy of lead nor-LAAM MP following a single SQ injection in fentanyl-dependent rats using a self-drug administration method, which is a widely studied preclinical approach to induce fentanyl dependence and evaluate withdrawal symptoms [23,24]. We believe that a sustained-release nor-LAAM-MP formulation is advantageous as it can enhance drug bioavailability, minimize adverse effects, reduce dosing frequency, and improve patient adherence [25]. ...
... To assess the therapeutic potential of nor-LAAM as a novel OUD pharmacotherapy, we employed a preclinical approach involving fentanyl self-administration to induce opioid dependence and somatic withdrawal in SD rats. Drug self-administration is a well-established methodology that has previously demonstrated sensitivity to clinically used OUD medications such as methadone and buprenorphine on opioid choice in both opioid-dependent rats and rhesus monkeys [23,24]. Given the absence of prior data regarding the effectiveness of nor-LAAM, our initial investigation sought to examine the influence of orally administered nor-LAAM solution in attenuating fentanyl choice among fentanyl-dependent rats. ...
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.
... Work in rhesus monkeys has further demonstrated that heroin (vs. food) choice increases following cessation of 21-h heroin access (Negus, 2006;Negus and Rice 2009). A number of pharmacological manipulations that reduce signs of opioid withdrawal reduce self-administration behaviors, including reinstatement, in rats, and these manipulations can include a wide range of pharmacological targets including α1 adrenergic receptors (Greenwell et al. 2009), CRF (Park et al. 2015), PPAR-γ, (de Guglielmo et al. 2017), dopamine D3 receptors (de Guglielmo et al. 2019), and 5α-Reductase (Bosse et al. 2021). ...
Withdrawal from opioids involves a negative affective state that promotes maintenance of drug-seeking behavior and relapse. As such, understanding the neurobiological mechanisms underlying withdrawal from opioid drugs is critical as scientists and clinicians seek to develop new treatments and therapies. In this review, we focus on the neural systems known to mediate the affective and somatic signs and symptoms of opioid withdrawal, including the mesolimbic dopaminergic system, basolateral amygdala, extended amygdala, and brain and hormonal stress systems. Evidence from preclinical studies suggests that these systems are altered following opioid exposure and that these changes mediate behavioral signs of negative affect such as aversion and anxiety during withdrawal. Adaptations in these systems also parallel the behavioral and psychological features of opioid use disorder (OUD), highlighting the important role of withdrawal in the development of addictive behavior. Implications for relapse and treatment are discussed as well as promising avenues for future research, with the hope of promoting continued progress toward characterizing neural contributors to opioid withdrawal and compulsive opioid use.
... 58,60 In particular, drug choice self-administration procedures have been useful in evaluating candidate medication effects that produce selective decreases in drug-maintained behaviors from medication effects that result in nonspecific decreases in behavior. 58,61,62 Because clinical treatment goals are not only to decrease addictive drug-maintained behavior but also promote behavioral reallocation to nondrug-reinforced behaviors, preclinical choice procedures provide a simplified assessment of this behavioral allocation between drug and nondrug reinforcers. 58,61−63 Under baseline conditions, liquid food was chosen over no or small (3.2 and 10 μg/kg/infusion) heroin doses (dashed lines; Figure 5A,B). ...
Mu opioid receptor (MOR) selective antagonists and partial agonists have clinical utility for the treatment of opioid use disorders (OUDs). However, the development of many has suffered due to their poor pharmacokinetic properties and/or rapid metabolism. Our recent efforts to identify MOR modulators have provided 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3-carboxamido)morphinan (NAQ), a low-efficacy partial agonist, that showed sub-nanomolar binding affinity to the MOR (K i 0.6 nM) with selectivity over the delta opioid receptor (δ/μ 241) and the kappa opioid receptor (κ/μ 48). Its potent inhibition of the analgesic effect of morphine (AD 50 0.46 mg/kg) and precipitation of significantly less withdrawal symptoms even at 100-fold greater dose than naloxone represents a promising molecule for further development as a novel OUD therapeutic agent. Therefore, further in vitro and in vivo characterization of its pharmacokinetics and pharmacodynamics properties was conducted to fully understand its pharmaceutical profile. NAQ showed favorable in vitro ADMET properties and no off-target binding to several classes of GPCRs, enzymes, and ion channels. Following intravenous administration, 1 mg/kg dose of NAQ showed a similar in vivo pharmacokinetic profile to naloxone; however, orally administered 10 mg/kg NAQ demonstrated significantly improved oral bioavailability over both naloxone and naltrexone. Abuse liability assessment of NAQ in rats demonstrated that NAQ functioned as a less potent reinforcer than heroin. Chronic 5 day NAQ pretreatment decreased heroin self-administration in a heroin-vs-food choice procedure similar to the clinically used MOR partial agonist buprenorphine. Taken together, these studies provide evidence supporting NAQ as a promising lead to develop novel OUD therapeutics.
... However, other studies have shown consistent dose-related effects. Negus (2006), for example, reported that chronic buprenorphine administration produced dose-dependent rightward shifts in the reinforcing effects of heroin, and Gerak and France (2021) reported that chronic administration of buprenorphine produced a dose-related decrease in heroin versus food choice. Overall, the magnitude and pattern of the decreases in fentanyl self-administration observed here following LYN-013 administration were similar the effects of acute or chronic buprenorphine on self-administration of other opioids by rhesus monkeys. ...
Background
Due to the poor oral bioavailability of buprenorphine, an oral formulation has not been thought possible. Lyndra Therapeutics is developing a once-weekly long-acting oral product containing buprenorphine. We evaluated the efficacy of this formulation in reducing intravenous (i.v.) fentanyl self-administration by three male and three female rhesus monkeys.
Methods
Buprenorphine HCl and naloxone HCl were co-formulated using an 11:1 ratio of buprenorphine:naloxone in a controlled-release gastric residence formulation administered in an oral capsule (LYN-013). Naloxone was included to determine the feasibility of combining naloxone with buprenorphine in the formulation as an abuse deterrent. Complete fentanyl dose-response functions were determined during each session. The efficacy of single doses of 56/5, 112/10 and 168/15 mg buprenorphine/naloxone in reducing fentanyl self-administration was examined over 13 days. Results: LYN-013 significantly decreased the rate of responding for fentanyl for 3 days and significantly reduced total intake of fentanyl for 8 days. Time to maximal buprenorphine levels (Tmax) ranged between 56 and 68 hr for all 3 doses. The maximal buprenorphine level (Cmax) following 168 mg was 2.3 ng/ml which was significantly greater that those observed for 56 mg (1.22 ng/ml) and 112 mg (1.35 ng/ml). Finally, the area-under-curves (AUCtau) were buprenorphine dose-dependently increased from 88 to 127 to 265 hr*ng/mL. There were no signs of non-specific changes in behavior.
Conclusions
A once-weekly oral buprenorphine/naloxone formulation produced sustained suppression of fentanyl self-administration in monkeys suggesting that oral delivery of buprenorphine with this formulation could provide a new opportunity to treat opioid use disorders (OUD).
... "choice" procedures [31,32]. For example, research using opioiddependent nonhuman primates has shown that MOR agonists decrease opioid choice and increase food choice in a MOR efficacy dependent manner (methadone ≥ morphine > buprenorphine) [33][34][35][36]. This literature illustrates the sensitivity of choice procedures to MOR efficacy and aligns with the clinical effectiveness of these MOUDs [2,[37][38][39]. ...
... Naltrexone and buprenorphine decrease opioid self-administration in both nonopioid-dependent monkeys [49,50] and rats [51,52], but when opioid dependence has been established, both treatments can precipitate withdrawal and increase opioid choice [53,54]. In contrast, methadone decreases opioid self-administration in opioiddependent nonhuman primates undergoing withdrawal [34,35] but in non-opioid-dependent or post-dependent nonhuman primates, methadone decreases opioid self-administration only at doses that markedly suppress many other behaviors [35,55]. The present methadone effects on fentanyl choice are consistent with the nonhuman primate literature and extend these findings to rats. ...
... Naltrexone and buprenorphine decrease opioid self-administration in both nonopioid-dependent monkeys [49,50] and rats [51,52], but when opioid dependence has been established, both treatments can precipitate withdrawal and increase opioid choice [53,54]. In contrast, methadone decreases opioid self-administration in opioiddependent nonhuman primates undergoing withdrawal [34,35] but in non-opioid-dependent or post-dependent nonhuman primates, methadone decreases opioid self-administration only at doses that markedly suppress many other behaviors [35,55]. The present methadone effects on fentanyl choice are consistent with the nonhuman primate literature and extend these findings to 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.
... This is consistent with several other pivotal studies that have established a "reward hierarchy" for other substances (Banks & Negus, 2017;Lenoir et al., 2007). However, the opposite has also been observed, where drug abuse can shift behavior away from nondrug rewards to drug reward (Negus, 2006). More work is needed to fully test this idea in our model. ...
Background
Negative emotional states are associated with the initiation and maintenance of alcohol use and drive relapse to drinking during withdrawal and protracted abstinence. Physical exercise is correlated with decreased negative affective symptoms, although a direct relationship between drinking patterns and exercise level has not been fully elucidated.
Methods
We incorporated intermittent running wheel access into a chronic continuous access, two‐bottle choice alcohol drinking model in female C57BL/6J mice. Wheel access was granted intermittently once mice established a preference for alcohol over water. After 6 weeks, alcohol was removed (forced abstinence) and mice were given continuous access to unlocked or locked wheels. Negative affect‐like behavior, home cage behavior, and metabolic activity were measured during protracted abstinence.
Results
Wheel access shifted drinking patterns in the mice, increasing drinking when the wheel was locked, and decreasing drinking when unlocked. Moreover, alcohol preference and consumption were strongly negatively correlated with the amount of running. An assessment of negative affect‐like behavior in abstinence via the novelty suppressed feeding and saccharin preference tests (SPT) showed that unlimited wheel access mitigated abstinence‐induced latency increases. Mice in abstinence also spent more time sleeping during the active dark cycle than control mice, providing additional evidence for abstinence‐induced anhedonia‐ and depression‐like behavior. Furthermore, running wheel access in abstinence decreased dark cycle sleep to comparable alcohol‐ and wheel‐naïve mice. Given the positive impact of exercise and the negative impact of alcohol on metabolic health, we compared metabolic phenotypes of alcohol‐abstinent mice with and without wheel access. Wheel access increased energy expenditure, carbon dioxide production, and oxygen consumption, providing a potential metabolic mechanism through which wheel access improves affective state.
Conclusions
This study suggests that including exercise in AUD treatment regimens has the potential to reduce drinking, improve affective state during abstinence and could serve as a non‐pharmacological approach to prevent the development of an AUD in high‐risk individuals.
... Indeed, the first drug self-administration study ever conducted in animals demonstrated a withdrawal-induced increase in opioid-vs.-food choice in morphine-dependent chimpanzees (Spragg, 1940), and this phenomenon has been replicated in opioiddependent baboons (Griffiths et al., 1975), rhesus monkeys (Negus, 2006;Negus and Rice, 2009), and rats (Townsend et al., 2021) (Fig. 1D). Overall, choice procedures can provide a framework to investigate both mechanisms of impaired sensitivity to non-drug reinforcers and strategies to normalize that sensitivity, increase non-drug reinforcer effectiveness to compete with drug reinforcers, and decrease overall drug choice. ...
... Buprenorphine, as an approved and widely used medication for the treatment of opioid use disorder, is a partial opioid agonist that is more clinically effective than methadone and naltrexone . However, when administered chronically, such as when it is used as a maintenance medication, buprenorphine has mild dependence liability (Negus, 2006). To reduce abuse liability, agonist/ antagonist formulations (e.g. ...
... For example, methadone is used clinically only in highly opioid-dependent patients, whereas naltrexone is used primarily in patients who are detoxified. Consistently, in preclinical research, methadone decreases opioid self-administration but not nondrug reinforcer self-administration in dependent subjects undergoing withdrawal but has abuse liability in originally non-dependent subjects, who have limited access to the abused opioid (Negus, 2006). However, naltrexone decreases opioid self-administration but not nondrug reinforcer self-administration in non-dependent subjects by blocking μ receptor-activated reinforcement but induces a withdrawal-associated increase in opioid choice in dependent subjects (Negus, 2009;Townsend et al., 2019). ...
Opioid use disorder is a worldwide societal problem and public health burden. Strategies for treating opioid use disorder can be divided into those that target the opioid receptor system and those that target non‐opioid receptor systems, including the dopamine and glutamate receptor systems. Currently, the clinical drugs used to treat opioid use disorder include the opioid receptor agonists methadone and buprenorphine, which are limited by their abuse liability, and the opioid receptor antagonist naltrexone, which is limited by poor compliance. Therefore, the development of effective medications with lower abuse liability and better potential for compliance is urgently needed. Based on recent advances in the understanding of the neurobiological mechanisms underlying opioid use disorder, potential treatment strategies and targets have emerged. This review focuses on the progress made in identifying potential targets and developing medications to treat opioid use disorder, including progress made by our laboratory, and provides insights for future medication development.
LINKED ARTICLES
This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc
... Sex-specific effects of opioid withdrawal methadone and other high efficacy MOR agonists block withdrawal-associated increases in opioid choice and promote behaviors maintained by alternative reinforcers (10)(11)(12)(13)(14)21). Overall, the sensitivity of preclinical opioid-vs.-food ...
... However, opioid withdrawal unmasked behavioral sex differences ( Figure 1H). In male rats, spontaneous opioid withdrawal coincided with a robust increase in choice of the smaller unit doses of fentanyl (Figure 2A), consistent with decades of preclinical studies using male opioid-withdrawn subjects (10)(11)(12)(13)(14)(15). Male rats also significantly increased choice for fentanyl over food in the first component, even when fentanyl was unavailable. ...
... Male rats also significantly increased choice for fentanyl over food in the first component, even when fentanyl was unavailable. This may reflect an increase in drug-seeking behavior or a loss of stimulus control, Moreover, this observation was consistent with previous findings in male monkeys using a similar opioid-choice procedure (13,14). Conversely, opioid withdrawal coincided with a significant decrease in choice of the largest unit dose of fentanyl in females ( Figure 2B). ...
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.
... Therefore, the aims of the present study were to 1) translate and 2) validate an IV drug-vs-food choice procedure originally developed for nonhuman primates to rats (Banks and Blough, 2015;Negus, 2006Negus, , 2003. The drug-vs-food choice procedure described in this manuscript varies from a published drug-vs-food choice procedure in rats that is also based on and originally developed for nonhuman primates (Thomsen et al., 2013(Thomsen et al., , 2008. ...
... A total of five drugs of abuse: fentanyl, heroin, cocaine, methamphetamine, and amphetamine were trained in the drug-vs-food choice procedure to determine the broad applicability of the procedure across two pharmacological classes. Once drug-vs-food choice was established, environmental variables (e.g., food reinforcer magnitude, response requirement) and pharmacological variables (continuous buprenorphine treatment) were manipulated to validate translation to rats of published results in nonhuman primates Woolverton, 1992, 1991;Negus, 2006Negus, , 2003. Furthermore, a final experiment determined behavioral interactions between fentanyl and methamphetamine reinforcement because of the rising clinical incidence of polysubstance opioid and psychostimulant abuse (Al-Tayyib et al., 2017;Karilsa et al., 2019;LaRue et al., 2019). ...
... Furthermore, a final experiment determined behavioral interactions between fentanyl and methamphetamine reinforcement because of the rising clinical incidence of polysubstance opioid and psychostimulant abuse (Al-Tayyib et al., 2017;Karilsa et al., 2019;LaRue et al., 2019). For this experiment, a multi-modal drug self-administration procedure was used that included a 2 h drug-vs-food choice session component (to assess behavioral allocation) and a 12 h extended access drug self-administration component (to allow for increased drug intake) to model aspects of a similar multi-modal drug self-administration procedure in rhesus monkeys (Banks and Negus, 2010;Negus, 2006) and in rats studies with fentanyl alone (Townsend et al., 2019a). ...
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.
