On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

Fürst, Susanna; Zádori, Zoltán; Zádor, Ferenc; Király, Kornél; Balogh, Mihály; László, Szilvia B.; Hutka, Barbara; Mohammadzadeh, Amir; Calabrese, Chiara; Galambos, Anna Rita; Riba, Pál; Romualdi, Patrizia; Benyhe, Sándor; Tı́már, József; Schmidhammer, Helmut; Spetea, Mariana; Al-Khrasani, Mahmoud

doi:10.3390/molecules25112473

Cited by 22 publications

(31 citation statements)

References 145 publications

(246 reference statements)

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“…The peripheral opioid system plays multiple roles, for example in the g.i. tract and in nociceptor neurons, the latter involved in peripheral analgesia [ 37 ]. PAMORAs including methylnaltrexone, naloxegol, alvimopan, and naldemdine are in clinical use to treat opioid-induced bowel dysfunction and constipation [ 15 , 38 ].…”

Section: Peripherally Active μ Opioid Receptor Antagonists (Pamoramentioning

confidence: 99%

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

2020

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Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose–response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

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Section: Peripherally Active μ Opioid Receptor Antagonists (Pamoramentioning

confidence: 99%

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

2020

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“…The peripheral opioid system plays multiple roles, for example in the g.i. tract and in nociceptor neurons, the latter involved in peripheral analgesia (37). PAMORAs including methylnaltrexone, naloxegol, alvimopan, and naldemidine are in clinical use to treat opioid-induced bowel dysfunction and constipation (15,38).…”

Section: Peripherally Active Mu Opioid Receptor Antagonists (Pamora) mentioning

confidence: 99%

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

Sadée

Oberdick

Wang

2020

Preprint

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Opioid analgesics are effective pain therapeutics but cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct m opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-m) to a ligand-free active form (MOR-m*), which mediates MOR signaling. Moreover, MOR-m converts spontaneously to MOR-m* (basal signaling). Persistent upregulation of MOR-m* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-m and MOR-m* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6b-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-m*, naltrexone but not 6b-naltrexol suppresses MOR-m*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-m*with high potency, whereas 6BN must compete with agonists at MOR-m, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose-response curve may also result from opposing effects on MOR-m and MOR-m*. In contrast, we find that 6b-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6b-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

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“…A significant and prolonged duration of the antinociceptive effect (up to 4 h) with a peripheral site of action was shown after oral administration of HS-731 to rats with carrageenaninduced inflammatory pain [32]. Recent data were reported on the absence of analgesic tolerance for HS-731 in rats upon chronic s.c. treatment for 14 days [23]. a Binding affinities (K i , nM) to the opioid receptors in the rat brain were determined in competitive radioligand binding assays; data from [30].…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Characterization of the Pharmacological Profile of HS-731, a Peripherally Acting Opioid Analgesic, at the µ-, δ-, κ-Opioid and Nociceptin Receptors

et al. 2022

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Accumulated preclinical and clinical data show that peripheral restricted opioids provide pain relief with reduced side effects. The peripherally acting opioid analgesic HS-731 is a potent dual μ-/δ-opioid receptor (MOR/DOR) full agonist, and a weak, partial agonist at the κ-opioid receptor (KOR). However, its binding mode at the opioid receptors remains elusive. Here, we present a comprehensive in silico evaluation of HS-731 binding at all opioid receptors. We provide insights into dynamic interaction patterns explaining the different binding and activity of HS-731 on the opioid receptors. For this purpose, we conducted docking, performed molecular dynamics (MD) simulations and generated dynamic pharmacophores (dynophores). Our results highlight two residues important for HS-731 recognition at the classical opioid receptors (MOR, DOR and KOR), particular the conserved residue 5.39 (K) and the non-conserved residue 6.58 (MOR: K, DOR: W and KOR: E). Furthermore, we assume a salt bridge between the transmembrane helices (TM) 5 and 6 via K2275.39 and E2976.58 to be responsible for the partial agonism of HS-731 at the KOR. Additionally, we experimentally demonstrated the absence of affinity of HS-731 to the nociceptin/orphanin FQ peptide (NOP) receptor. We consider the morphinan phenol Y1303.33 responsible for this affinity lack. Y1303.33 points deep into the NOP receptor binding pocket preventing HS-731 binding to the orthosteric binding pocket. These findings provide significant structural insights into HS-731 interaction pattern with the opioid receptors that are important for understanding the pharmacology of this peripheral opioid analgesic.

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On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

Cited by 22 publications

References 145 publications

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

Mechanistic Characterization of the Pharmacological Profile of HS-731, a Peripherally Acting Opioid Analgesic, at the µ-, δ-, κ-Opioid and Nociceptin Receptors

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