Comparison of P2X and TRPV1 Receptors in Ganglia or Primary Culture of Trigeminal Neurons and their Modulation by NGF or Serotonin

Simonetti, Manuela; Fabbro, Alessandra; D'Arco, Marianna; Zweyer, Marina; Nistri, Andrea; Giniatullin, Rashid; Fabbretti, Elsa

doi:10.1186/1744-8069-2-11

Cited by 95 publications

(139 citation statements)

References 53 publications

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“…Since these receptors are strongly expressed by the vast majority of nociceptors in the trigeminal ganglion without concomitant expression of other P2X receptors [70,71], this test system offers an advantageous opportunity to explore new antagonists and their potential value in dealing with trigeminal pain, an issue to be further studied with in vivo preclinical experiments. Thus, this work represents a starting point for a structure-based design of P2X3 antagonists as a strategy for the development of novel Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cultures of TG sensory neurons were prepared from C57Bl/6 wild type mice (P10-14) as previously described [70]. In brief, TG were rapidly excised and enzymatically dissociated in F12 Medium (Invitrogen Corp, Milan, Italy) containing 0.25 mg/mL trypsin, 1 mg/mL collagenase, 0.2 mL DNAse (Sigma, Milan, Italy) at 37°C for 12 min.…”

Section: Trigeminal Ganglia Culture Neuronsmentioning

confidence: 99%

“…Currents were recorded from small/medium size mouse TG neurons (nociceptors that strongly express native P2X3 receptors [70]) as previously described [70,82] in whole cell voltage clamp configuration, at a holding potential of −65 mV after correction for liquid junction potential. Cells were continuously superfused at room temperature with control solution containing (in mM): 152 NaCl, 5 KCl, 1 MgCl 2 , 2 CaCl 2 , 10 glucose, 10 HEPES; pH 7.4 adjusted with NaOH.…”

Section: Patch Clamp Recordingsmentioning

confidence: 99%

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2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Ben

Marchenkova

Thomas

et al. 2016

Purinergic Signalling

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Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2′,3′-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized. These new compounds were functionally evaluated on native P2X3 receptors from mouse trigeminal ganglion (TG) sensory neurons using patch clamp recordings under voltage clamp configuration. Our data show that some of these molecules are potent (nanomolar range) and reversible inhibitors of P2X3 receptors, without any apparent effect on trigeminal GABA A and 5-HT 3 receptors, whose membrane currents were unaffected by the tested compounds.

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Section: Resultsmentioning

confidence: 99%

Section: Trigeminal Ganglia Culture Neuronsmentioning

confidence: 99%

Section: Patch Clamp Recordingsmentioning

confidence: 99%

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2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Ben

Marchenkova

Thomas

et al. 2016

Purinergic Signalling

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“…NGF signaling also increases the anterograde transport of TRPV1 from the cell body to the peripheral terminals of nociceptors (Ji et al, 2002). In cultured TG neurons, chronic application of NGF led to an increase in TRPV1 expression (Simonetti et al, 2006). NGF in the DRG neurons activates p38, which in turn increases TRPV1 translation (Ji et al, 2002).…”

Section: Trpv1 Expression In Tg Neuronsmentioning

confidence: 99%

Nerve Growth Factor Contribution via Transient Receptor Potential Vanilloid 1 to Ectopic Orofacial Pain

Shinoda¹,

Asano²,

Omagari³

et al. 2011

J. Neurosci.

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It is well known that oral inflammation causes tenderness in temporomandibular joints or masseter muscles. The exact mechanism of such an orofacial ectopic hyperalgesia remains unclear. Here, we investigated the functional significance of interaction of nerve growth factor (NGF) and transient receptor potential vanilloid 1 (TRPV1) in relation to heat hyperalgesia in the whisker pad skin caused by complete Freund's adjuvant (CFA) injection into the lower lip. CFA injection induced heat hyperalgesia of the ipsilateral whisker pad skin. Moreover, it leads to enhancement of spontaneous activity and heat responses in trigeminal ganglion (TG) neurons that was elicited by heat stimulation of the whisker pad skin. The heat hyperalgesia was dose-dependently reversed by intraperitoneal TRPV1 antagonist administration, also diminished by neutralizing anti-NGF antibody administration into the lower lip and intraganglionic administration of K252a, a tyrosine kinase receptor inhibitor. Nerve fibers in bundle of mandibular nerve and TG neurons that innervates the whisker pad skin and lower lip both expressed labeled NGF, which was administrated into the lower lip. Moreover, the NGF concentrations in ophthalmic-maxillary and mandibular divisions of the TG increased after CFA injection into the lower lip. The number of TRPV1-positive neurons that innervates the whisker pad skin and lower lip was increased after CFA injection into the lower lip, and this increase was annulled by anti-NGF administration. The present findings suggest that inflammation in the lower lip induces release of NGF that regulates TRPV1 expression in TG neurons. This TRPV1 overexpression may underlie ectopic heat hyperalgesia in the whisker pad skin.

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“…Loaded cells were imaged with an excitation light of 488 nm (exposure time 100 ms, binning 2) and emission intensity ≥520 nm. ATP, ADP, AMP, and adenosine were applied via the fast perfusion system (Rapid Solution Changer RSC-200, BioLogic Science Instruments, Grenoble, France) followed by delivery of 50 mM KCl as a marker for neurons [31] and ionomycin (Abcam, USA) for signal normalization [32]. The function of P2X7 receptors was evaluated with the specific P2X7 antagonist A839977 (Tocris, UK).…”

Section: Live Cell Imagingmentioning

confidence: 99%

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions

Yegutkin

Guerrero-Toro

Kılınç

et al. 2016

Purinergic Signalling

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Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pronociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca 2+ transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pronociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.

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Comparison of P2X and TRPV1 Receptors in Ganglia or Primary Culture of Trigeminal Neurons and their Modulation by NGF or Serotonin

Cited by 95 publications

References 53 publications

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Nerve Growth Factor Contribution via Transient Receptor Potential Vanilloid 1 to Ectopic Orofacial Pain

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions

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