Mu-opioid Receptor (MOR) Biased Agonists Induce Biphasic Dose-dependent Hyperalgesia and Analgesia, and Hyperalgesic Priming in the Rat

Araldi, Dionéia; Ferrari, Luiz F.; Levine, Jon D.

doi:10.1016/j.neuroscience.2018.10.015

Cited by 32 publications

(32 citation statements)

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“…It has been well documented that the peripheral activation of Gi-coupled receptors in DRG neurons may induce hyperalgesia and promote mechanical pain (Araldi et al, 2016(Araldi et al, , 2018Yudin and Rohacs, 2018). Intradermal hind paw injection of the migraine drug sumatriptan for example evoked both an acute hyperalgesia 30 minutes after its injection, and hyperalgesic priming, potentiating the effect of PGE2, an effect that developed several days after the injection of the drug (Araldi et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Many different Gi-coupled receptors, such as GABAB and opioid receptors are expressed in DRG neurons; their activation generally reduces excitability, and exert analgesic effects (Yudin and Rohacs, 2018). Activation of many Gi-coupled receptors however was shown to induce mechanical hypersensitivity, the mechanism of which is not understood (Araldi et al, 2016(Araldi et al, , 2018Yudin and Rohacs, 2018) Here we found that activation of Gi-coupled receptors potentiated native Piezo2-mediated currents in DRG neurons and heterologous expressed Piezo2 channels in HEK293 cells without affecting the number of channels at the plasma membrane. Surprisingly, the currents of the closely related Piezo1 channels were inhibited after activation of Gi-coupled receptors in HEK293 cells.…”

Section: Introductionmentioning

confidence: 99%

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Gi-Coupled Receptor Activation Potentiates Piezo2 Currents via Gβγ

Rosario

Yudin

et al. 2019

Preprint

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SUMMARYDysregulation of mechanosensitive Piezo2 channels is a hallmark of mechanical allodynia, yet the cellular mechanisms that sensitize mechanoreceptors are still poorly understood. Activation of Gi-coupled receptors sensitizes Piezo2 currents, but whether Gi-coupled receptors regulate the activity of Piezo2 channels is not known. Here, we found that activation of Gi-coupled receptors potentiates Piezo2 currents in dorsal root ganglion (DRG) neurons and in heterologous systems, but inhibits Piezo1 currents in heterologous systems. The potentiation, or inhibition of Piezo currents is abolished when blocking Gβγ with the c-terminal domain of the beta-adrenergic kinase (βARKct). Pharmacological inhibition of kinases downstream of Gβγ, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), also abolished the potentiation of Piezo2 currents. Hence, our studies illustrate an indirect mechanism of action of Gβγ to sensitize Piezo2 currents after activation of Gi-coupled receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gi-Coupled Receptor Activation Potentiates Piezo2 Currents via Gβγ

Rosario

Yudin

et al. 2019

Preprint

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“…[2][3][4] However, recent investigations of these biased agonists indicate that side effects, including constipation and respiratory depression, may still be retained. [5][6][7][8] Thus, there is a need for greater understanding of how opioid receptor regulation and signaling underlie the control of physiological processes, including GI motility.…”

Section: See Editorial On Page 553mentioning

confidence: 99%

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

DiCello

Carbone

Saito

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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G protein-coupled receptors physically and functionally interact, leading to unique signaling. We report that delta and mu opioid receptors are coexpressed and functionally interact in myenteric neurons. Our findings have implications for opioid-based therapies for motility disorders and pain. BACKGROUND & AIMS:Functional interactions between the mu opioid receptor (MOR) and delta opioid receptor (DOR) represent a potential target for novel analgesics and may drive the effects of the clinically approved drug eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome. Although the enteric nervous system (ENS) is a likely site of action, the coexpression and potential interaction between MOR and DOR in the ENS are largely undefined. In the present study, we have characterized the distribution of MOR in the mouse ENS and examined MOR-DOR interactions by using pharmacologic and cell biology techniques.METHODS: MOR and DOR expression was defined by using MORmCherry and MORmCherry-DOR-eGFP knockin mice. MOR-DOR interactions were assessed by using DOR-eGFP internalization assays and by pharmacologic analysis of neurogenic contractions of the colon. RESULTS:Although MOR was expressed by approximately half of all myenteric neurons, MOR-positive submucosal neurons were rarely observed. There was extensive overlap between MOR and DOR in both excitatory and inhibitory pathways involved in the coordination of intestinal motility. MOR and DOR can functionally interact, as shown through heterologous desensitization of MORdependent responses by DOR agonists. Functional evidence suggests that MOR and DOR may not exist as heteromers in the ENS. Pharmacologic studies show no evidence of cooperativity between MOR and DOR. DOR internalizes independently of MOR in myenteric neurons, and MOR-evoked contractions are unaffected by the sequestration of DOR. CONCLUSIONS:Collectively, these findings demonstrate that although MOR and DOR are coexpressed in the ENS and functionally interact, they are unlikely to exist as heteromers under physiological conditions. (Cell Mol Gastroenterol Hepatol 2020;9:465-483; https://doi.

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“…We have recently shown that depending on the opioid used, and its dose and route of administration, opioids are capable of inducing acute hyperalgesia, even after a single administration (Araldi et al, 2015(Araldi et al, , 2018b(Araldi et al, ,c, 2019Ferrari et al, 2019). In particular, clinically used -opioid receptor (MOR) agonists, fentanyl (Araldi et al, 2018c) and morphine (Araldi et al, 2019;Ferrari et al, 2019), as well as the highly selective MOR agonist, DAMGO (Araldi et al, 2015(Araldi et al, , 2017(Araldi et al, , 2018a, produce OIH and hyperalgesic priming, a form of nociceptor neuroplasticity characterized by a persistent increase in responsivity of nociceptors to proalgesic mediators (Ferrari et al, 2010;Joseph and Levine, 2010b;Alvarez et al, 2014;Araldi et al, 2015;Khomula et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia

2019

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Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 g/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 g, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, 2 d after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E 2 (PGE 2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5 nM) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a-opioid receptor (MOR)-dependent increase in [Ca 2ϩ ] i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4 ϩ and IB4 Ϫ neurons. This sensitizing effect of fentanyl was reversed in weakly IB4 ϩ DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH.

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Mu-opioid Receptor (MOR) Biased Agonists Induce Biphasic Dose-dependent Hyperalgesia and Analgesia, and Hyperalgesic Priming in the Rat

Cited by 32 publications

References 58 publications

Gi-Coupled Receptor Activation Potentiates Piezo2 Currents via Gβγ

Gi-Coupled Receptor Activation Potentiates Piezo2 Currents via Gβγ

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia

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