You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Methocinnamox in Opioid Use Disorder Treatment: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Colleen Jordan.

Methocinnamox (MCAM) is a novel mu opioid receptor antagonist with an extended duration of action. MCAM has potential to reduce the burden of the opioid epidemic by being used as an overdose rescue treatment and a long-term treatment for opioid use disorder (OUD). The currently available treatments for OUD include naloxone, naltrexone, and methadone. These treatments have certain limitations, which include short duration of action, patient non-compliance, and diversion. MCAM could potentially be used as both a rescue and long-term treatment for opioid misuse. This is due to its pseudo-irreversible antagonism of the mu opioid receptor, abnormally long duration of action of nearly two weeks, and the possibility of using kappa or delta opioid receptor agonists for pain management during OUD treatment. MCAM’s novel pharmacokinetic and pharmacodynamic properties open a new avenue for treating opioid misuse.

  • methocinnamox
  • opioid use disorder
  • naloxone
  • naltrexone
  • methadone
  • buprenorphine
  • overdose
  • treatment
  • receptors
  • addiction

1. Introduction

Over one million Americans have died from overdoses during the opioid epidemic [1]. Opioid addiction and misuse remain a prevalent issue in the United States (US), leading to millions of deaths [2]. Opioids were originally discovered from poppy plants and were used to reduce pain sensation ranging from acute to severe, but in recent history, accessibility to opioids increased across the globe for illicit recreational use, despite increased restrictions for distribution in clinical pain relief therapy [3,4][3][4]. The intended use of opioids was for the reduction of pain sensation by agonizing the opioid receptors located in the central nervous system (CNS) [5]. There are three major opioid receptor types, mu (MOR), delta (DOR), and kappa (KOR), but the MOR is the main receptor for providing analgesic effects [5,6][5][6]. In the past, many people turned to opioids to relieve daily suffering from chronic pain, and these drugs readily became addictive and created dependence [2]. The ubiquitous use of opioids and the addiction to these drugs in the US has exacerbated the strain on resources in hospitals, emergency rooms, and on first responders as they try to save lives with the limited resources currently available [2]. Naloxone is the only drug available to treat opioid overdose to be approved by the US Food and Drug Administration (FDA) in the last 50 years, while current opioid users are younger and experimenting with synthetic opioids beyond pain relief [7,8][7][8]. Naloxone is a competitive MOR antagonist with a high affinity for the MOR receptor used to reverse respiratory and CNS depression in those experiencing an opioid overdose [9,10][9][10]. Naloxone does not help decrease future use of prescription or illicit opioids, and the use of synthetic opioids will require higher doses of naloxone, which could increase adverse effects such as tachycardia and hypertension [11,12][11][12]. Naloxone is also currently misused at “Narcan parties,” where attendees intentionally overdose knowing they can be rescued by naloxone [13]. Naltrexone has extended-release formulas intended to reduce relapse and promote adherence, yet patient noncompliance and retention continue to be limiting factors [14]. Methadone is commonly used to treat opioid addiction as a replacement for illicit opiates but is itself an addictive substance that can lead to withdrawal if dosage is not closely monitored by a licensed professional [15]. Buprenorphine is currently used to treat OUD, and while it reduces illicit drug use, it is equal to or even less effective than methadone for retaining patients in treatment [15]. Additionally, buprenorphine is sold on the black market on websites such as streetrx.com for those attempting to treat opioid dependency on their own, and it was involved in more drug arrests than methadone, as reported to the Maine Diversion Alert program [16,17][16][17]. Methadone and buprenorphine are substitution treatments that substantially reduce opioid deaths during treatment, but immediately following cessation of treatment, the mortality risk notably increases [18]. For these reasons [1[1][2],2], there is an urgent need for new opioid misuse interventions [19].
Methocinnamox (MCAM) is a novel drug candidate that is a pseudo-irreversible MOR antagonist, thereby preventing other opioid agonists from binding for a two-week period [19,20,21][19][20][21]. Due to the long-lasting effects of MCAM, it can be a safer and more effective alternative medication for OUD [22,23][22][23]. MCAM has the potential to change the course of opioid misuse and help prevent subsequent renarcotization after administration [24,25][24][25].

2. Methocinnamox in Opioid Use Disorder Treatment

Pain Receptors

2.1. Pain Receptors

MCAM is a long-lasting, pseudo-irreversible (non-covalent binding), potent, MOR antagonist that reversibly binds KOR and DOR and has no known interaction with other nociceptors. Thus, KOR and DOR agonists could be provided concomitantly for pain relief during treatment for OUD, although KOR agonists are known to cause dysphoria in humans and therefore may not be useful for pain relief therapy [20,22,23,24,49,50,51][20][22][23][24][26][27][28]. The unique pharmacodynamics of MCAM contribute to its long-lasting effects. The need for new MOR to induce the euphoric and depressive effects of opioid receptor agonists as receptor turnover is what limits the duration of action (DOA) [19,24][19][24]. This is crucial because MOR agonists can potentially not only induce the G protein-coupled receptor (GPCR) pathway, but can also induce β-arrestin activation, leading to adverse effects such as respiratory depression [52,53][29][30]. MOR, KOR and DOR belong to the largest membrane receptor family called the trimeric GPCR superfamily. Opioids activate the inhibitory (Gi) signaling pathway to initiate analgesic functions [54,55,56,57][31][32][33][34]. GPCRs are known for their trimeric subunits consisting of alpha (Gα), beta (Gβ), and gamma (Gγ) [58][35]. After an opioid agonist (endogenous or exogenous) binds, a signal stimulates Gα to migrate and suppress adenylate cyclase activity, thereby reducing cyclic AMP production [58][35]. The Gβγ acts as a modulator for the signaling pathway, resulting in reduced neurotransmitter release and membrane hyperpolarization [58][35].
Since GPCRs are widespread, these are the target for 50% of marketed pharmacological therapeutics, revolving around the common amino-terminal peptide sequence, Tyr-Gly-Gly-Phe, which is referred to as the “opioid motif”, as it directly interacts with the opioid receptor [59][36]. Examples of MOR agonists include oxycodone, fentanyl, heroin, morphine, and methadone. Buprenorphine is a partial MOR agonist but a KOR antagonist [60,61][37][38]. MOR antagonists include naloxone, naltrexone, and MCAM. Activation of the KOR hyperpolarizes neurons that are activated indirectly by MOR, thus creating synergistic antinociception [7,62][7][39]. Pain is multidimensional and dependent on subjective thresholds. Chronic pain, which may be concurrent with anxiety, may be associated with neuroplastic changes in the amygdala, which may heighten the emotional and affective consequences of pain [63,64][40][41]. Opioid analgesics are highly effective in most cases against acute pain, but the desired effects mediated by the opioid receptor family may lead to craving, addiction, or dependence as a result of neurological changes [65,66,67,68][42][43][44][45]. Repetitive opioid use will thus increase the threshold for analgesic effects secondary to compensatory upregulation of vesicular calcium content while developing opioid tolerance, and it may decrease one’s quality of life [55,69,70][32][46][47].

Methocinnamox

2.2. Methocinnamox

MCAM, shown in Figure 1, was first mentioned in a publication in 2000 by researchers from the University of Michigan Medical School and the University of Bristol, but was initially discarded because it was believed to be useful only for MOR research [8,108][8][48]. However, it is currently being studied for its promise in the opioid crisis as a long-term OUD treatment [109,110][49][50].
/media/item_content/202204/626b3f054ecfapharmacy-10-00048-g001.png
Figure 1. Methocinnamox’s chemical structure. Molecular Formula: C30H32N2O4, PubChem CID: 46877713, IUPAC name: (E)-N-(4R,4aS,7aR,12bR)-3-(cyclopropylmethyl)-9-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro3,2-eisoquinolin-4a-yl-3-(4-methylphenyl)prop-2-enamide (compound/methocinnamox) [112][51].
Naltrexone and naloxone injections become ineffective in less than a single day, with durations of action lasting 1–2 h [88,89][52][53]. A single injection of MCAM has a duration of action of thirteen days, reaching peak concentration 15–45 min after injection with a half-life of roughly 70 min [19,24,105][19][24][54]. Currently, MCAM’s pharmacokinetic properties are not fully understood, but the effectiveness at low plasma levels suggests that pharmacodynamic properties, rather than pharmacokinetic factors, play a prominent role in its long-lasting effects [19]. The evidence for pseudo-irreversible binding includes its non-reversible, insurmountable, and time-dependent antagonism of MORs [106][55]. A recent report with human embryonic kidney (HEK) cells expressing human opioid receptors showed that in addition to pseudo-irreversible orthosteric antagonism of MORs directly blocking binding, MCAM also utilized allosteric antagonism at an unknown site at a lower affinity, which alters ligand affinity and/or intrinsic efficacy of MOR agonists [106][55]. MCAM contains a weak Michael acceptor group that non-covalently binds to the MOR orthosteric site [106][55]. This suggests no true irreversible binding despite its seemingly irreversible effects. The pseudo-irreversible binding effectively incapacitates MORs; thus, cells need to synthesize nascent MORs to reestablish previous functionality [106][55]. Due to this, MCAM possesses a uniquely long DOA. As for MCAM’s interaction with DOR and KOR, the MOA was consistent in the opioid receptor expressing HEK cells, and in vivo, with simple competitive antagonism [106][55].
Repeated administration of MCAM every twelve days in rodents remained effective for over two months without altering the duration of opioid withdrawal with no major ADRs and no decrease in effectiveness, suggesting positive potential for long-term OUD treatment [19,21,99,113][19][21][56][57]. Naltrexone, naloxone, and MCAM are effective for acute reversal and prevention of respiratory depression and other overdose symptoms due to their effects on opioid receptors, but only MCAM prevents renarcotization in the hours and days following emergency intervention [19,48,104,105,114,115][19][54][58][59][60][61]. Naltrexone and naloxone bind competitively, meaning higher amounts of an agonist will overcome their intended effects, requiring a higher dose of either therapy to reverse initial and subsequent overdoses post-antagonist injection [105][54]. MCAM binds non-competitively, making it insurmountable and therefore more effective at blocking effects of opioids in the short- and long-term [19,24,106,114][19][24][55][60]. Additionally, MCAM is naloxone-insensitive with no notable drug interactions, meaning that there is a possibility that the two drugs could be administered concurrently for immediate rescue and prevent subsequent renarcotization [106][55]. With over-the-counter availability of naloxone, overdose-related deaths have decreased, but subsequent renarcotization and therefore consequent overdoses leading to death remains an issue [88,106][52][55]. If a shorter acting formulation of MCAM was combined with naloxone, renarcotization risk could significantly decrease and potentially further reduce opioid overdose-related deaths without inducing withdrawal. Naloxone would provide immediate rescue, and MCAM would prevent subsequent renarcotization. An extended-release or longer acting naloxone formulation retains the risk of renarcotization due to being surmountable [106][55]. Because the DOA differs between subcutaneous and intravenous methods of administration [104][59], it may be plausible that a different administration method could have a short enough duration to prevent renarcotization, but losing its effect before withdrawal is precipitated. MCAM can act as a preventative therapy for opioid misuse, indicating possible use at discharge from treatment facilities following a detoxification period, as well as use during ongoing therapeutic intervention [22,24,48,114][22][24][58][60]. Its prolonged DOA results in a long period before needing the next dose, which is hypothesized to relatively prevent patient noncompliance that is seen with extended-release naltrexone for outpatient treatment, including eliminating the possibility of an individual removing an implant [22,24][22][24]. In cases where effects lasting roughly five days or less are needed, such as preventing renarcotization in the hours and few days following an overdose but not for long-term treatment of OUD, intravenous administration of MCAM would be preferable because this method’s DOA is roughly 5 days [104,105][54][59]. There is discussion of creating an oral pill form of MCAM, an extended-release form, and faster acting intranasal and intramuscular formulations, but further study of the drug is needed before these will be developed [19,22,105][19][22][54]. MCAM also blocks the physiological and behavioral effects of MOR agonists such as unfavorable impacts of sensitivity to mechanical stimulation, gastrointestinal motility, and appetite [21,22,25,107][21][22][25][62]. MCAM does not impact memory and other cognition [112][51]. For these reasons, the adverse effect profile is encouraging. However, it is important to recognize that no testing has been conducted in humans [108][48]. It is currently unknown if long-term blockade of the MOR would attenuate endorphin and enkephalin signaling sufficiently to alter mood. Given the widespread impact of opioid overdoses [1,2][1][2], novel strategies are desperately needed.

References

  1. More than a Million Americans Have Died from Overdoses during the Opioid Epidemic. Available online: https://www.npr.org/2021/12/30/1069062738/more-than-a-million-americans-have-died-from-overdoses-during-the-opioid-epidemi (accessed on 23 January 2022).
  2. Coussens, N.P.; Sittampalam, G.S.; Jonson, S.G.; Hall, M.D.; Gorby, H.E.; Tamiz, A.P.; McManus, O.B.; Felder, C.C.; Rasmussen, K. The Opioid Crisis and the Future of Addiction and Pain Therapeutics. J. Pharmacol. Exp. Ther. 2019, 371, 396–408.
  3. Bechara, A.; Berridge, K.C.; Bickel, W.K.; Morón, J.A.; Williams, S.B.; Stein, J.S. A Neurobehavioral Approach to Addiction: Implications for the Opioid Epidemic and the Psychology of Addiction. Psychol. Sci. Public Interest 2019, 20, 96–127.
  4. Torralva, R.; Janowsky, A. Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis. J. Pharmacol. Exp. Ther. 2019, 371, 453–475.
  5. Hoffman, K.A.; Ponce Terashima, J.; McCarty, D. Opioid Use Disorder and Treatment: Challenges and Opportunities. BMC Health Serv. Res. 2019, 19, 884.
  6. Raehal, K.M.; Bohn, L.M. Mu Opioid Receptor Regulation and Opiate Responsiveness. AAPS J. 2005, 7, E587–E591.
  7. Pan, Z.Z. Mu-Opposing Actions of the Kappa-Opioid Receptor. Trends Pharmacol. Sci. 1998, 19, 94–98.
  8. Tofighi, B.; Williams, A.R.; Chemi, C.; Suhail-Sindhu, S.; Dickson, V.; Lee, J.D. Patient Barriers and Facilitators to Medications for Opioid Use Disorder in Primary Care: An in-Depth Qualitative Survey on Buprenorphine and Extended-Release Naltrexone. Subst. Use Misuse 2019, 54, 2409–2419.
  9. Skolnick, P. On the Front Lines of the Opioid Epidemic: Rescue by Naloxone. Eur. J. Pharmacol. 2018, 835, 147–153.
  10. Ryan, S.A.; Dunne, R.B. Pharmacokinetic Properties of Intranasal and Injectable Formulations of Naloxone for Community Use: A Systematic Review. Pain Manag. 2018, 8, 231–245.
  11. Hammerslag, L.R.; Hofford, R.S.; Kang, Q.; Kryscio, R.J.; Beckmann, J.S.; Bardo, M.T. Changes in Fentanyl Demand Following Naltrexone, Morphine, and Buprenorphine in Male Rats. Drug Alcohol Depend. 2020, 207, 107804.
  12. Moss, R.B.; Carlo, D.J. Higher Doses of Naloxone Are Needed in the Synthetic Opioid Era. Subst. Abuse Treat. Prev. Policy 2019, 14, 6.
  13. DEA: “Lazarus Parties” or “Narcan Parties” are Real. Available online: https://foxsanantonio.com/news/yami-investigates/dea-lazarus-parties-or-narcan-parties-are-real (accessed on 23 January 2022).
  14. Minozzi, S.; Amato, L.; Vecchi, S.; Davoli, M.; Kirchmayer, U.; Verster, A. Oral Naltrexone Maintenance Treatment for Opioid Dependence. Cochrane Database Syst. Rev. 2011, 4, CD001333.
  15. Mattick, R.P.; Kimber, J.; Breen, C.; Davoli, M. Buprenorphine Maintenance versus Placebo or Methadone Maintenance for Opioid Dependence. Cochrane Database Syst. Rev. 2004, 3, CD002207.
  16. Hswen, Y.; Zhang, A.; Brownstein, J.S. Leveraging Black-Market Street Buprenorphine Pricing to Increase Capacity to Treat Opioid Addiction, 2010–2018. Prev. Med. 2020, 137, 106105.
  17. Simpson, K.J.; Moran, M.T.; McCall, K.L.; Herbert, J.; Foster, M.L.; Simoyan, O.M.; Shah, D.T.; Desrosiers, C.; Nichols, S.D.; Piper, B.J. Increasing Heroin, Cocaine, and Buprenorphine Arrests Reported to the Maine Diversion Alert Program. Forensic Sci. Int. 2019, 303, 109924.
  18. Sordo, L.; Barrio, G.; Bravo, M.J.; Indave, B.I.; Degenhardt, L.; Wiessing, L.; Ferri, M.; Pastor-Barriuso, R. Mortality Risk during and after Opioid Substitution Treatment: Systematic Review and Meta-Analysis of Cohort Studies. BMJ 2017, 357, j1550.
  19. Maguire, D.R.; Gerak, L.R.; Sanchez, J.J.; Javors, M.A.; Disney, A.; Husbands, S.M.; France, C.P. Effects of Acute and Repeated Treatment with Methocinnamox, a Mu Opioid Receptor Antagonist, on Fentanyl Self-Administration in Rhesus Monkeys. Neuropsychopharmacology 2020, 45, 1986–1993.
  20. Broadbear, J.H.; Sumpter, T.L.; Burke, T.F.; Husbands, S.M.; Lewis, J.W.; Woods, J.H.; Traynor, J.R. Methocinnamox Is a Potent, Long-Lasting, and Selective Antagonist of Morphine-Mediated Antinociception in the Mouse: Comparison with Clocinnamox, Beta-Funaltrexamine, and Beta-Chlornaltrexamine. J. Pharmacol. Exp. Ther. 2000, 294, 933–940.
  21. Gerak, L.R.; Gould, G.G.; Daws, L.C.; France, C.P. Methocinnamox Produces Sustained Antagonism of the Antinociceptive Effects of Morphine and Persistent Decreases in DAMGO Binding to μ Opioid Receptors in Rat Cortex. FASEB J. 2020, 34, 1.
  22. Maguire, D.R.; Gerak, L.R.; Woods, J.H.; Husbands, S.M.; Disney, A.; France, C.P. Long-Lasting Effects of Methocinnamox on Opioid Self-Administration in Rhesus Monkeys. J. Pharmacol. Exp. Ther. 2019, 368, 88–99.
  23. Zamora, J.C.; Kotipalli, V.; Jennings, E.M.; Disney, A.; Husbands, S.; Winger, G.; Clarke, W.P.; Woods, J.H.; Berg, K.A. Methocinnamox (MCAM) Is a Selective, Long Acting Antagonist at Mu Opioid Receptors In Vitro. FASEB J. 2019, 33, 498.8.
  24. Townsend, E.A. The Lasting Impact of Methocinnamox on Opioid Self-Administration. Neuropsychopharmacology 2020, 45, 1963–1964.
  25. Minervini, V.; France, C. Long-Term Antagonism of Mu Opioid Receptors by Methocinnamox (MCAM) without Adverse Effects on Memory. FASEB J. 2020, 34, 1.
  26. Gerak, L.R.; Latham, E.A.; Woods, J.H.; Disney, A.; Husbands, S.M.; France, C.P. Methocinnamox: Sustained Antagonism of the Antinociceptive Effects of Morphine and Not Spiradoline in Rats. FASEB J. 2019, 33, 498.10.
  27. Jennings, E.M.; Disney, A.; Husbands, S.; Winger, G.; Berg, K.A.; Clarke, W.P.; Woods, J.H. Methocinnamox (MCAM) Is an Effective Long-Term Antagonist of Peripheral Mu, but Not Kappa or Delta Opioid Receptors In Vivo. FASEB J. 2019, 33, 498.9.
  28. Bidlack, J.M. Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence. Adv. Pharmacol. 2014, 69, 387–418.
  29. Manglik, A.; Lin, H.; Aryal, D.K.; McCorvy, J.D.; Dengler, D.; Corder, G.; Levit, A.; Kling, R.C.; Bernat, V.; Hübner, H.; et al. Structure-Based Discovery of Opioid Analgesics with Reduced Side Effects. Nature 2016, 537, 185–190.
  30. Mafi, A.; Kim, S.-K.; Goddard, W.A. Mechanism of β-Arrestin Recruitment by the μ-Opioid G Protein-Coupled Receptor. Proc. Natl. Acad. Sci. USA 2020, 117, 16346–16355.
  31. Gibula-Tarlowska, E.; Kotlinska, J.H. Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance. Biomolecules 2020, 10, 1376.
  32. Al-Hasani, R.; Bruchas, M.R. Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior. Anesthesiology 2011, 115, 1363–1381.
  33. Corder, G.; Castro, D.C.; Bruchas, M.R.; Scherrer, G. Endogenous and Exogenous Opioids in Pain. Annu. Rev. Neurosci. 2018, 41, 453–473.
  34. Mondal, D.; Kolev, V.; Warshel, A. Exploring the Activation Pathway and Gi-Coupling Specificity of the μ-Opioid Receptor. Proc. Natl. Acad. Sci. USA 2020, 117, 26218–26225.
  35. Smrcka, A.V. G Protein Βγ Subunits: Central Mediators of G Protein-Coupled Receptor Signaling. Cell Mol. Life Sci. 2008, 65, 2191–2214.
  36. Shenoy, S.S.; Lui, F. Biochemistry, Endogenous Opioids; StatPearls Publishing: Treasure Island, FL, USA, 2020. Available online: https://www.ncbi.nlm.nih.gov/books/NBK532899/ (accessed on 23 January 2022).
  37. National Academies of Sciences, Engineering and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Medication-Assisted Treatment for Opioid Use Disorder; Mancher, M.; Leshner, A.I. The Effectiveness of Medication-Based Treatment for Opioid Use Disorder; National Academies Press: Washington, DC, USA, 2019. Available online: https://www.ncbi.nlm.nih.gov/books/NBK541393/ (accessed on 23 January 2022).
  38. Lipiński, P.F.J.; Kosson, P.; Matalińska, J.; Roszkowski, P.; Czarnocki, Z.; Jarończyk, M.; Misicka, A.; Dobrowolski, J.C.; Sadlej, J. Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis. Molecules 2019, 24, 740.
  39. Minervini, V.; Lu, H.Y.; Padarti, J.; Osteicoechea, D.C.; France, C.P. Interactions between kappa and mu opioid receptor agonists: Effects of the ratio of drugs in mixtures. Psychopharmacology 2018, 235, 2245–2256.
  40. Navratilova, E.; Ji, G.; Phelps, C.; Qu, C.; Hein, M.; Yakhnitsa, V.; Neugebauer, V.; Porreca, F. Kappa Opioid Signaling in the Central Nucleus of the Amygdala Promotes Disinhibition and Aversiveness of Chronic Neuropathic Pain. Pain 2019, 160, 824–832.
  41. Zhou, W.; Li, Y.; Meng, X.; Liu, A.; Mao, Y.; Zhu, X.; Meng, Q.; Jin, Y.; Zhang, Z.; Tao, W. Switching of Delta Opioid Receptor Subtypes in Central Amygdala Microcircuits Is Associated with Anxiety States in Pain. J. Biol. Chem. 2021, 296, 100277.
  42. Al-Eitan, L.N.; Rababa’h, D.M.; Alghamdi, M.A. Genetic Susceptibility of Opioid Receptor Genes Polymorphism to Drug Addiction: A Candidate-Gene Association Study. BMC Psychiatry 2021, 21, 5.
  43. Liu, S.S.; Pickens, S.; Burma, N.E.; Ibarra-Lecue, I.; Yang, H.; Xue, L.; Cook, C.; Hakimian, J.K.; Severino, A.L.; Lueptow, L.; et al. Kappa Opioid Receptors Drive a Tonic Aversive Component of Chronic Pain. J. Neurosci. 2019, 39, 4162–4178.
  44. Massaly, N.; Copits, B.A.; Wilson-Poe, A.R.; Hipólito, L.; Markovic, T.; Yoon, H.J.; Liu, S.; Walicki, M.C.; Bhatti, D.L.; Sirohi, S.; et al. Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus Accumbens Kappa Opioid System. Neuron 2019, 102, 564–573.
  45. Rosenblum, A.; Marsch, L.A.; Joseph, H.; Portenoy, R.K. Opioids and the Treatment of Chronic Pain: Controversies, Current Status, and Future Directions. Exp. Clin. Psychopharmacol. 2008, 16, 405–416.
  46. Mercadante, S.; Arcuri, E.; Santoni, A. Opioid-Induced Tolerance and Hyperalgesia. CNS Drugs 2019, 33, 943–955.
  47. Kosten, T.R.; George, T.P. The Neurobiology of Opioid Dependence: Implications for Treatment. Sci. Pract. Perspect. 2002, 1, 13–20.
  48. Something better than Naloxone. Available online: https://www.wqad.com/article/news/health/your-health/your-health-mcam/526-cda2622a-69a3-4962-885a-a2185e9507d6 (accessed on 3 April 2022).
  49. National Institute on Drug Abuse—A Novel Opioid Receptor Antagonist for Treating Abuse and Overdose. Available online: https://taggs.hhs.gov/Detail/AwardDetail?arg_AwardNum=R01DA048417&arg_ProgOfficeCode=114 (accessed on 14 February 2021).
  50. National Institute of Health—Funded Projects. Available online: https://www.heal.nih.gov/funding/awarded (accessed on 14 February 2021).
  51. Compound Summary Methocinnamox. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/46877713 (accessed on 15 May 2021).
  52. Rzasa Lynn, R.; Galinkin, J. Naloxone Dosage for Opioid Reversal: Current Evidence and Clinical Implications. Ther. Adv. Drug Saf. 2018, 9, 63–88.
  53. Schumacher, M.A.; Basbaum, A.I.; Naidu, R.K. Opioid Agonists & Antagonists. In Basic & Clinical Pharmacology; Katzung, B.G., Ed.; McGraw-Hill Education: New York, NY, USA, 2017; Available online: https://accessmedicine.mhmedical.com/content.aspx?bookid=2249§ionid=175220393 (accessed on 14 February 2021).
  54. Gerak, L.R.; Maguire, D.R.; Woods, J.H.; Husbands, S.M.; Disney, A.; France, C.P. Reversal and Prevention of the Respiratory-Depressant Effects of Heroin by the Novel μ-Opioid Receptor Antagonist Methocinnamox in Rhesus Monkeys. J. Pharmacol. Exp. Ther. 2019, 368, 229–236.
  55. Zamora, J.C.; Smith, H.R.; Jennings, E.M.; Chavera, T.S.; Kotipalli, V.; Jay, A.; Husbands, S.M.; Disney, A.; Berg, K.A.; Clarke, W.P. Long-term Antagonism and Allosteric Regulation of Mu Opioid Receptors by the Novel Ligand, Methocinnamox. Pharmacol. Res. Perspect. 2021, 9, e00887.
  56. Methadone. Available online: https://go.drugbank.com/drugs/DB00333 (accessed on 26 January 2022).
  57. Maguire, D.; Gerak, L.; Disney, A.; Husbands, S.; France, C. Effects of Acute and Repeated Methocinnamox Treatment on Fentanyl Self-administration in Rhesus Monkeys. FASEB J. 2020, 34, 1.
  58. Volkow, N.D.; Blanco, C. The Changing Opioid Crisis: Development, Challenges and Opportunities. Mol. Psychiatry 2021, 26, 218–233.
  59. Jimenez, V.M.; Castaneda, G.; France, C.P. Methocinnamox (MCAM) Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats. J. Pharmacol. Exp. Ther. 2021, 377, 29–38.
  60. Minervini, V.; Disney, A.; Husbands, S.M.; France, C.P. Methocinnamox (MCAM) Antagonizes the Behavioral Suppressant Effects of Morphine without Impairing Delayed Matching-to-Sample Accuracy in Rhesus Monkeys. Psychopharmacology 2020, 237, 3057–3065.
  61. Jimenez, V.; Maguire, D.; Gerak, L.; France, C. Methocinnamox (MCAM) Reverses and Provides Extended Protection from Fentanyl-Induced Respiratory Depression in Awake Unrestrained Rats. FASEB J. 2020, 34, 1.
  62. Gerak, L.R.; Minervini, V.; Latham, E.; Ghodrati, S.; Lillis, K.V.; Wooden, J.; Disney, A.; Husbands, S.M.; France, C.P. Methocinnamox Produces Long-Lasting Antagonism of the Behavioral Effects of µ-Opioid Receptor Agonists but Not Prolonged Precipitated Withdrawal in Rats. J. Pharmacol. Exp. Ther. 2019, 371, 507–516.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Academic Video Service
Feedback