The Life Cycle of the Mu-Opioid Receptor

Cuitavi, Javier; Hipólito, Lucía; Canals, Meritxell

doi:10.1016/j.tibs.2020.10.002

Cited by 35 publications

(37 citation statements)

References 105 publications

(118 reference statements)

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“…[42][43][44] However, recent studies have raised concerns about this hypothesis. 43,45,46 Mice lacking β-arrestin2 were reported to retain respiratory depression mediated by morphine, 47 and mice with MOR C-tail mutations that inhibit arrestin recruitment still show respiratory depression as well as tolerance 48 in contrast to previous reports 49 .…”

Section: Discussionmentioning

confidence: 91%

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

Chakraborty

DiBerto

Faouzi

et al. 2021

Preprint

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Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that kratom and its natural products (mitragynine) and semi-synthetic analogs (7-hydroxy mitragynine (7OH) and mitragynine pseudoindoxyl) are mu opioid receptor (MOR) agonists that show minimal beta-arrestin2 recruitment. To further investigate the structure activity relationships of G-protein potency, efficacy, and beta-arrestin2 recruitment, we diversified the mitragynine/7OH templates at the C9, -10 and -12 positions of the aromatic ring of the indole moiety. Three lead C9 analogs, synthesized by swapping the 9-methoxy group with varied substituents, namely phenyl (SC11), methyl (SC12), 3-furanyl (SC13), were further characterized using a panel of in vitro and ex vivo electrophysiology assays. All three compounds were partial agonists with lower efficacy than both DAMGO and morphine in heterologous G-protein assays and synaptic physiology. SC11-13 also showed lower recruitment of both β-arrestin subtypes compared to DAMGO, and in assays with limited MOR receptor reserve, the G-protein efficacy of SC11, SC12 and SC13 was comparable to buprenorphine. In mouse models, at equianalgesic doses SC13 showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning. Taken together, these results suggest that MOR agonists with a G-protein efficacy profile similar to buprenorphine can be developed into opioids that are effective analgesics with greatly reduced liabilities.

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Section: Discussionmentioning

confidence: 91%

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

Chakraborty

DiBerto

Faouzi

et al. 2021

Preprint

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“…For example, murine estrogen and µ-opioid receptors share 88% and 94% sequence homology with their respective human counterparts. 123 , 124 Of note, the latter modulate ancient behaviors such as pain perception, produce a similar spectrum of splice variants across species and facilitate redundant cellular responses, underlining the evolutionary conserved advantage conferred by the implementation of this system. 124 Consistently, other indispensable mediators such as steroid hormones are also conserved as exemplified by the identical structure of mouse and human testosterone.…”

Section: Osteocalcinmentioning

confidence: 99%

Skeletal endocrinology: where evolutionary advantage meets disease

et al. 2021

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The regulation of whole-body homeostasis by the skeleton is mediated by its capacity to secrete endocrine signaling molecules. Although bone-derived hormones confer several adaptive benefits, their physiological functions also involve trade-offs, thus eventually contributing to disease. In this manuscript, we discuss the origins and functions of two of the best-studied skeletal mediators, fibroblast growth factor 23 and osteocalcin, in an evolutionary context. Moreover, we provide a theoretical framework seeking to explain the broad involvement of these two hormones in amniote physiology as well as their potential to fuel the development and progression of diseases. Vice versa, we outline which perturbations might be amenable to manipulation of these systems and discuss limitations and ongoing challenges in skeletal endocrine research. Finally, we summarize unresolved questions and potential future studies in this thriving field.

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“…MORs are also involved in euphoria, sedation, meiosis, addiction, truncal rigidity, nausea, and respiratory control in the central nervous system. [ 6 ]…”

Section: O Pioid R Eceptorsmentioning

confidence: 99%

Fentanyl-Induced Respiratory Depression

Udayakumar

2021

Anesthesia Essays &Amp; Researches

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Opioid-related respiratory depression is a serious clinical problem as it can cause multiple deaths and anoxic brain injury. Genetic variations influence the safety and clinical efficacy of fentanyl. Pharmacogenetic studies help in identifying single-nucleotide polymorphisms (SNPs) associated with fentanyl causing respiratory depression and aid clinician in personalized pain medicine. This narrative review gives an insight of the common SNPs associated with fentanyl.

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The Life Cycle of the Mu-Opioid Receptor

Cited by 35 publications

References 105 publications

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

Skeletal endocrinology: where evolutionary advantage meets disease

Fentanyl-Induced Respiratory Depression

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