Neuronal calcium signaling in chronic pain

Hagenston, Anna M.; Simonetti, Manuela

doi:10.1007/s00441-014-1942-5

Cited by 32 publications

(43 citation statements)

References 244 publications

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“…A versatile intracellular second messenger, Ca 2ϩ is known to modulate neuronal function, producing both fast and slow/delayed changes in excitability (Hagenston and Simonetti, 2014;Zhang et al, 2014;Bernard-Marissal et al, 2018;Luarte et al, 2018;Bandura and Feng, 2019). However, since an increase in [Ca 2ϩ ] i in response to fentanyl is not a direct measure of nociceptor sensitization, we also studied changes in electrical excitability, in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Calcium signals play an important role in the regulation of neuronal function (Kostyuk and Verkhratsky, 1994;Berridge et al, 2000;Hagenston and Simonetti, 2014;Luarte et al, 2018; Bandura and Feng, 2019), including type I hyperalgesic priming (Ferrari et al, 2013a;Araldi et al, 2018c). Altered calcium signaling in nociceptors can reflect both neuronal plasticity and changes in electrophysiological properties, including sensitization (Shutov et al, 2006;Khomula et al, 2013;Yu et al, 2015;Pan et al, 2016).…”

Section: Mor-mediated Increased [Ca 2؉ ] I In Sensory Neurons From Prmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Mor-mediated Increased [Ca 2؉ ] I In Sensory Neurons From Prmentioning

confidence: 99%

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

2019

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“…The exact effect of increased ER luminal Ca 2+ on neuronal function is difficult to predict primarily because Ca 2+ plays such a varied role inside the cell(50). However, aberrant Ca 2+ dynamics have been closely linked to painful phenotypes(51,52). We found small diameter sensory neurons in EAE to have increased CICR and KCl mediated cytosolic Ca 2+ transients.…”

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confidence: 77%

ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

Yousuf¹,

Samtleben²,

Lamothe

et al. 2020

Preprint

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AcknowledgementsWe would like to thank Drs. Simonetta Sipione, Christine Webber, and Jason Plemel (University of Alberta) for graciously sharing select equipment and software. ABSTRACTNeuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post-mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4phenylbutyric acid (4-PBA), reduced pain hypersensitivity. In vitro, 4-PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca 2+ transients in putative DRG nociceptors. We went to assess disease-mediated changes in the functional properties of Ca 2+ -sensitive BK-type K + channels in DRG neurons. We found that the conductance-voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.

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“…We previously demonstrated that a deficiency in mitochondrial function in sensory neurons prevents the resolution of inflammatory pain 12 . Moreover, in chronic pain neuronal mitochondrial functions, such as OxPhos and Ca 2+ buffering, are impaired 21,22 . Indeed, oxygen consumption in DRG neurons was reduced during the peak of inflammatory pain and resolved at day 3 (Supplemental data fig.…”

Section: Main Textmentioning

confidence: 99%

Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain

Raoof

Vlist

Willemen

et al. 2020

Preprint

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The current paradigm states that inflammatory pain passively resolves following the cessation of the inflammatory insult. Yet, in a substantial proportion of patients with inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, spontaneous or treatment-induced resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain 1-5 . Mechanistic insight as how inflammatory pain is resolved is lacking.Here we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. To resolve pain, macrophages transfer mitochondria to sensory neurons. This transfer requires expression of CD200 Receptor (CD200R) on macrophages and the noncanonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain and suggests a new direction for treatment of chronic pain.

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Neuronal calcium signaling in chronic pain

Cited by 32 publications

References 244 publications

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

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

ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain

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