Replacement of current opioid drugs focusing on MOR-related strategies

Busserolles, Jérôme; Lolignier, Stéphane; Kerckhove, Nicolas; Bertin, Célian; Authier, Nicolas; Eschalier, Alain

doi:10.1016/j.pharmthera.2020.107519

Cited by 25 publications

(24 citation statements)

References 228 publications

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“…All desirable and unwanted opioid side effects largely stem from the activation of MORs that are distributed either in the CNS or in the periphery [97]. A general assumption was that central analgesic tolerance is the consequence of a decrease in the central MORs response to opioid analgesics; however, the involvement of peripheral MORs in the development of central analgesic tolerance has also gained attention recently [112,113].…”

Section: The Consequence Of Mors Activation On Primary Sensory Neuronsmentioning

confidence: 99%

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

et al. 2020

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There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.

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Section: The Consequence Of Mors Activation On Primary Sensory Neuronsmentioning

confidence: 99%

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

et al. 2020

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“…The pharmacological differences produced by activation of the three opioid receptors encourage the search for compounds that produce analgesia without the deleterious side effects of morphine or other clinically used opioid analgesics. Despite more than 60 years of effort to understand the pharmacological intricacies of the opioid receptor family [ 1 , 2 , 3 , 4 , 5 , 6 ], most current clinically-used opioid analgesics are mu-opioid receptor (MOR) agonists and retain serious side effects [ 4 , 7 , 8 , 9 ]. Analgesic effects can also be mediated through other members of the opioid receptor family, such as the kappa-opioid receptor (KOR) and delta-opioid receptor (DOR), and the related nociceptin/orphanin FQ peptide receptor (NOP receptor) [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite more than 60 years of effort to understand the pharmacological intricacies of the opioid receptor family [ 1 , 2 , 3 , 4 , 5 , 6 ], most current clinically-used opioid analgesics are mu-opioid receptor (MOR) agonists and retain serious side effects [ 4 , 7 , 8 , 9 ]. Analgesic effects can also be mediated through other members of the opioid receptor family, such as the kappa-opioid receptor (KOR) and delta-opioid receptor (DOR), and the related nociceptin/orphanin FQ peptide receptor (NOP receptor) [ 9 , 10 , 11 ]. There is a growing interest for the generation of multifunctional ligands: novel opioid analgesics that can bind with high affinity and activate multiple receptors, opioid or otherwise [ 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed μ-, κ- and δ-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics

McLaughlin

Rayala

Bunnell

et al. 2022

IJMS

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The design and development of analgesics with mixed-opioid receptor interactions has been reported to decrease side effects, minimizing respiratory depression and reinforcing properties to generate safer analgesic therapeutics. We synthesized bis-cyclic guanidine heterocyclic peptidomimetics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for the mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR) across the series, with compound 1968-22 displaying good affinity for all three receptors. Central intracerebroventricular (i.c.v.) administration of 1968-22 produced dose-dependent, opioid receptor-mediated antinociception in the mouse 55 °C warm-water tail-withdrawal assay, and 1968-22 also produced significant antinociception up to 80 min after oral administration (10 mg/kg, p.o.). Compound 1968-22 was detected in the brain 5 min after intravenous administration and was shown to be stable in the blood for at least 30 min. Central administration of 1968-22 did not produce significant respiratory depression, locomotor effects or conditioned place preference or aversion. The data suggest these bis-cyclic guanidine heterocyclic peptidomimetics with multifunctional opioid receptor activity may hold potential as new analgesics with fewer liabilities of use.

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“…Opioids are the strongest painkillers and they are commonly used for severe pain after surgery, trauma or associated with cancer; yet, their application is limited due to their severe side effects including addiction, respiratory depression and constipation. Misuse of both prescription and non-prescription opioids have dramatically increased worldwide 1 .…”

Section: Introductionmentioning

confidence: 99%

Amelioration of injury-induced tissue acidosis by a nonsteroidal analgesic attenuates antinociceptive effects of the pH-dependent opioid agonist NFEPP

Celik

Negrete

Rosso

et al. 2022

Sci Rep

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Opioid agonists are powerful drugs for managing pain. However, their central side effects are limiting their use and drugs with similar potency, but a lower risk profile are needed. (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) is a novel opioid agonist that preferentially activates opioid receptors at acidic extracellular pH. NFEPP was designed to activate peripheral opioid receptors in injured tissue, therefore precluding side effects elicited at normal pH in brain or intestinal wall. Considering the common combination of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) in multimodal analgesia, we investigated the interaction between NFEPP and a widely prescribed prototypical NSAID, diclofenac (DCF), in a rat model of unilateral hindpaw inflammation induced by complete Freund’s adjuvant. We evaluated the effects of systemically applied DCF on the paw tissue pH, on the expression of inflammatory mediators in immune cells from inflamed paws and on the expression of opioid receptors in dorsal root ganglia. Additionally, we investigated the antinociceptive efficacy of NFEPP injected into the inflamed paws after DCF treatment. We found that DCF reduced inflammation-induced nociceptive responses and tissue acidosis, but did not change the mRNA expression of IL-1β, TNF-α, IL-6, IL-4, NGF, or of mu-, delta-, or kappa-opioid receptors. The treatment with DCF moderately reduced the antinociceptive efficacy of NFEPP, suggesting a correlation between an increase in local tissue pH and the decreased antinociceptive effect of this pH-sensitive opioid agonist.

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Replacement of current opioid drugs focusing on MOR-related strategies

Cited by 25 publications

References 228 publications

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

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

Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed μ-, κ- and δ-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics

Amelioration of injury-induced tissue acidosis by a nonsteroidal analgesic attenuates antinociceptive effects of the pH-dependent opioid agonist NFEPP

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