6-Monoacetylmorphine (6-MAM), Not Morphine, Is Responsible for the Rapid Neural Effects Induced by Intravenous Heroin

Perekopskiy, David; Kiyatkin, Eugene A.

doi:10.1021/acschemneuro.9b00305

Cited by 15 publications

(7 citation statements)

References 21 publications

(49 reference statements)

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“…Modelled brain concentrations of heroin, 6-monoacetylmorphine (6-MAM) and morphine (left axis) and cumulative intake (right axis) throughout the 10th heroin self-administration training session of representative rats (infusions: continuous access = 31; intermittent access = 39). Note the scales are adapted to the levels of each compoundGottas et al, 2013;Perekopskiy & Kiyatkin, 2019;Solis et al, 2017)…”

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confidence: 99%

Increased heroin intake and relapse vulnerability in intermittent relative to continuous self‐administration: Sex differences in rats

D’Ottavio

Reverte

Ragozzino

et al. 2022

British J Pharmacology

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Background and Purpose Studies using intermittent‐access drug self‐administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent‐ and continuous‐access self‐administration on heroin intake, patterns of self‐administration and cue‐induced heroin‐seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites. Experimental Approach Rats were trained to self‐administer a palatable solution and then heroin (0.075 mg·kg−1 per inf) either continuously (6 h·day−1; 10 days) or intermittently (6 h·day−1; 5‐min access every 30‐min; 10 days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin‐seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test. Key Results Intermittent access exacerbated heroin self‐administration and was characterized by a burst‐like intake, yielding higher brain peaks of heroin and 6‐monoacetylmorphine concentrations. Moreover, intermittent access increased cue‐induced heroin‐seeking during early, but not late abstinence. Heroin‐seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle. Conclusions and Implications Intermittent heroin access in rats resembles critical features of heroin use disorder: a self‐administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder. 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

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confidence: 99%

Increased heroin intake and relapse vulnerability in intermittent relative to continuous self‐administration: Sex differences in rats

D’Ottavio

Reverte

Ragozzino

et al. 2022

British J Pharmacology

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“…Interestingly, mAb 4G12 only showed significance in tail flick tests starting at 45 min postdrug exposure but was able to bring mice back to baseline faster than controls, similar to 11D12 (Figure b). These results further reinforce the simple antinociception data, vide supra , wherein an antibody targeting heroin is important for early intervention rather than 6-AM, which has been considered the main active metabolite of interest to inhibit for effective therapeutic effects. ,, …”

Section: Resultsmentioning

confidence: 99%

“…These results further reinforce the simple antinociception data, vide supra, wherein an antibody targeting heroin is important for early intervention rather than 6-AM, which has been considered the main active metabolite of interest to inhibit for effective therapeutic effects. 21,29,38 Pharmacokinetics. To observe how the selected mAbs alter heroin's metabolism in vivo, we conducted pharmacokinetic studies by injecting nai ̈ve mice IV with either drug, mAb, or drug and mAb.…”

Section: Monoclonal Antibody Development and Selectionmentioning

confidence: 99%

Development of an Effective Monoclonal Antibody against Heroin and Its Metabolites Reveals Therapies Have Mistargeted 6-Monoacetylmorphine and Morphine over Heroin

et al. 2022

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The opioid epidemic is a global public health crisis that has failed to abate with current pharmaceutical treatments. Moreover, these FDA-approved drugs possess numerous problems such as adverse side effects, short half-lives, abuse potential, and recidivism after discontinued use. An alternative treatment model for opioid use disorders is immunopharmacotherapy, where antibodies are produced to inhibit illicit substances by sequestering the drug in the periphery. Immunopharmacotherapeutics against heroin have engaged both active and passive vaccines targeting heroin’s metabolites, 6-monoacetylmorphine (6-AM) and morphine, since decades of research have stated that heroin’s psychoactive and lethal effects are mainly attributed to these compounds. However, concerted efforts to develop effective immunopharmacotherapies against heroin abuse have faced little clinical advancement, suggesting a need for reassessing drug target selection. To address this issue, four unique monoclonal antibodies were procured with distinct affinity to either heroin, 6-AM, or morphine. Examination of these antibodies through in vitro and in vivo tests revealed monoclonal antibody 11D12 as the optimal therapeutic and provided crucial insights into the key chemical species to target for blunting heroin’s psychoactive and lethal effects. These findings offer clarification into the problematic attempts of therapeutics targeting heroin’s metabolites and provide a path forward for future heroin immunopharmacotherapy development.

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“…Antidrug vaccines have been investigated for cocaine, nicotine, methamphetamine, , and opioids, and while created in many formats, their overall success still depends upon three components: carrier protein (T-cell epitope), adjuvant, and hapten . With the opioid crisis in full view, opioid vaccines have taken center stage − including heroin vaccines that have undergone extensive examination. Although success has been claimed with several heroin vaccines, our continued efforts to rationally design suitable heroin-hapten-drug candidates that are complementary to our pre-existing vaccine arsenal is equally important.…”

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confidence: 99%

“…Heroin is sequentially metabolized into 6-monoacetylmorphine (6AM) and then to morphine (Figure ), and it is often believed that morphine is responsible for the neural effects of heroin . However, recent assessments have shown that 6-AM is primarily responsible for the rapid effects of this drug, although heroin does possess μ-opioid binding and receptor activation. ,, Constructed upon these criteria, an improved vaccine would be one that could elicit antibodies capable of blocking heroin and its psychoactive metabolites from entering the brain, thereby preventing heroin-induced reinforcement, pharmacokinetics, and locomotor activity. Herein, we detail how hapten deuteration presents a viable tactic that meets these heroin vaccine requirements as observed by titer, specificity, affinity, drug blood–brain distribution, and antinociception evaluation.…”

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confidence: 99%

Enhancement of a Heroin Vaccine through Hapten Deuteration

et al. 2020

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The United States is in the midst of an unprecedented epidemic of opioid substance use disorder, and while pharmacotherapies including opioid agonists and antagonists have shown success, they can be inadequate and frequently result in high recidivism. With these challenges facing opioid use disorder treatments immunopharmacotherapy is being explored as an alternative therapy option and is based upon antibody−opioid sequestering to block brain entry. Development of a heroin vaccine has become a major research focal point; however, producing an efficient vaccine against heroin has been particularly challenging because of the need to generate not only a potent immune response but one against heroin and its multiple psychoactive molecules. In this study, we explored the consequence of regioselective deuteration of a heroin hapten and its impact upon the immune response against heroin and its psychoactive metabolites. Deuterium (H dAc ) and cognate protium heroin (H Ac ) haptens were compared head to head in an inclusive vaccine study. Strikingly the H dAc vaccine granted greater efficacy in blunting heroin analgesia in murine behavioral models compared to the H Ac vaccine. Binding studies confirmed that the H dAc vaccine elicited both greater quantities and equivalent or higher affinity antibodies toward heroin and 6-AM. Blood−brain biodistribution experiments corroborated these affinity tests. These findings suggest that regioselective hapten deuteration could be useful for the resurrection of previous drug of abuse vaccines that have met limited success in the past.

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6-Monoacetylmorphine (6-MAM), Not Morphine, Is Responsible for the Rapid Neural Effects Induced by Intravenous Heroin

Cited by 15 publications

References 21 publications

Increased heroin intake and relapse vulnerability in intermittent relative to continuous self‐administration: Sex differences in rats

Increased heroin intake and relapse vulnerability in intermittent relative to continuous self‐administration: Sex differences in rats

Development of an Effective Monoclonal Antibody against Heroin and Its Metabolites Reveals Therapies Have Mistargeted 6-Monoacetylmorphine and Morphine over Heroin

Enhancement of a Heroin Vaccine through Hapten Deuteration

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