Distinct Terminal and Cell Body Mechanisms in the Nociceptor Mediate Hyperalgesic Priming

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

doi:10.1523/jneurosci.5085-14.2015

Cited by 55 publications

(39 citation statements)

References 66 publications

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“…Moreover, disrupting CPEB and/or poly(A) tail-mediated regulation of translation block the development of hyperalgesic priming [1,2,9]. Experiments in this model system support the hypothesis that the mechanism of priming initiation requires local translation in the nociceptor axons that are proximal to the initial insult but not in the nociceptor cell bodies [72]. Human experimental data using NGF injection also support the view that local translation is required for nociceptor sensitization [11,12].…”

Section: Targeting Translation For Therapeutic Development Of Next-gementioning

confidence: 80%

Translational Control Mechanisms in Persistent Pain

Khoutorsky

Price

2018

Trends in Neurosciences

101

114

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Persistent pain, which is poorly treated and estimated to afflict one third of the world’s population, is largely mediated by the sensitization of nociceptive neurons. This sensitization involves de novo gene expression to support biochemical and structural changes required to maintain amplified pain signaling that frequently persists even after injury to tissue resolves. While transcription-dependent changes in gene expression are important, recent work demonstrates that activity-dependent regulation of mRNA translation is key to controlling the cellular proteome and the development and maintenance of persistent pain. In this review, we highlight recent advances in translational regulation of gene expression in nociceptive circuits, with a focus on key signaling pathways and mRNA targets that may be tractable for the creation of next-generation pain therapeutics.

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Section: Targeting Translation For Therapeutic Development Of Next-gementioning

confidence: 80%

Translational Control Mechanisms in Persistent Pain

Khoutorsky

Price

2018

Trends in Neurosciences

101

114

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“…in vitro. Of note, in this regard, this sensitization can be mediated by PKC, a calcium-independent kinase (Khasar et al, 1999;Aley et al, 2000;Parada et al, 2005;Reichling and Levine, 2009;Ferrari et al, 2015a) which is a MOR second messenger (Chu et al, 2010). At the same time, the fraction of responders, in excitability (60% of small-diameter DRG neurons), may be greater than the upper limit of MOR-expressing DRG neurons (39% of DRG neurons of all sizes).…”

Section: Discussionmentioning

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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“…6,7,32 Furthermore, CaMKIIα has been reported to contribute to hyperalgesia priming for transition from acute to chronic pain. 14,15 …”

Section: Discussionmentioning

confidence: 99%

CaMKIIα underlies spontaneous and evoked pain behaviors in Berkeley sickle cell transgenic mice

Chen¹,

Tian²,

Yang³

et al. 2016

PAIN

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Pain is one of the most challenging and stressful conditions to patients with sickle cell disease (SCD) and their clinicians. Patients with SCD start experiencing pain as early as three months old and continue having it throughout their lives. Although many aspects of the disease are well understood, little progress has been made in understanding and treating pain in SCD. This study aimed to investigate the functional involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) in the persistent and refractory pain associated with SCD. We found non-evoked ongoing pain as well as evoked hypersensitivity to mechanical and thermal stimuli were present in Berkeley sickle cell transgenic mice (BERK mice), but not non-sickle control littermates. Prominent activation of CaMKIIα was observed in the dorsal root ganglia and spinal cord dorsal horn region of BERK mice. Intrathecal administration of KN93, a selective inhibitor of CaMKII, significantly attenuated mechanical allodynia and heat hyperalgesia in BERK mice. Meanwhile, spinal inhibition of CaMKII elicited conditioned place preference in the BERK mice, indicating the contribution of CaMKII in the ongoing spontaneous pain of SCD. We further targeted CaMKIIα by siRNA knockdown. Both evoked pain and ongoing spontaneous pain were effectively attenuated in BERK mice. These findings elucidated, for the first time, an essential role of CaMKIIα as a cellular mechanism in the development and maintenance of spontaneous and evoked pain in SCD, which can potentially offer new targets for pharmacological intervention of pain in SCD.

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Distinct Terminal and Cell Body Mechanisms in the Nociceptor Mediate Hyperalgesic Priming

Cited by 55 publications

References 66 publications

Translational Control Mechanisms in Persistent Pain

Translational Control Mechanisms in Persistent Pain

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

CaMKIIα underlies spontaneous and evoked pain behaviors in Berkeley sickle cell transgenic mice

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