Figure - available via license: Creative Commons Attribution 3.0 Unported
Content may be subject to copyright.
A, Representative traces of currents induced by pulse application of α,β-meATP (10 µM, 2 s), capsaicin (1 µM, 3 s), or GABA (10 µM, 2 s) to TG neurons in control conditions or after application of BNP (100 ng/ml, 10 min) to the same cells. Histograms show average current density values of P2X3, TRPV1 or GABA-mediated responses (n=12, 12, 11, respectively). B, Histograms show average current density values of P2X3, TRPV1 or GABA-mediated responses in control conditions (n=52, 73, 123, respectively) or after 2 h application of 100 ng/ml BNP (n=42, 53, 119).
Source publication
Important pain transducers of noxious stimuli are small- and medium-diameter sensory neurons that express transient receptor vanilloid-1 (TRPV1) channels and/or adenosine triphosphate (ATP)-gated P2X3 receptors whose activity is upregulated by endogenous neuropeptides in acute and chronic pain models. Little is known about the role of endogenous mo...
Similar publications
- [...]
Backgrouds: ATP and P2X receptors play important roles in the modulation of trigeminal neuropathic pain, while the role of G protein-coupled P2Y2 receptors and the underlying mechanisms are less clear. The threshold and frequency of action potentials, fast inactivating transient K+ channels (IA) are important regulators of membrane excitability in...
Citations
... In acute and chronic pain models, small-and medium-diameter sensory neurons, which express transient receptor vanilloid-1 (TRPV1) channels and/or adenosine triphosphate (ATP)-gated P2X3 receptors, are the important pain transducers of noxious stimuli [57]. In women with EM, TRPV1 receptor expression has been demonstrated to be elevated in endometriotic lesions and correlated with pain [36,37,57]. ...
... In acute and chronic pain models, small-and medium-diameter sensory neurons, which express transient receptor vanilloid-1 (TRPV1) channels and/or adenosine triphosphate (ATP)-gated P2X3 receptors, are the important pain transducers of noxious stimuli [57]. In women with EM, TRPV1 receptor expression has been demonstrated to be elevated in endometriotic lesions and correlated with pain [36,37,57]. ...
Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.
... Most natriuretic peptide receptors that act as guanylyl cyclases (including NRPA and NRPC) inhibit the activity of the neurons in which they are expressed 158,159 . Indeed, intrathecal injection of BNP inhibits nociceptive transmission 160 , while exogenous application of BNP inhibits the excitability of primary nociceptors [161][162][163] , suggesting that BNP may be a negative modulator of nociceptive transmission under certain inflammatory pain conditions. Furthermore, intrathecal or intradermal injection of BNP at picomolar or nanomolar concentration fails to induce immediate scratching behaviour in mice, indicating that administration of BNP alone at a physiologically relevant concentration does not stimulate pruriceptive transmission 154,155,160 . ...
Itch is one of the most primal sensations, being both ubiquitous and important for the well-being of animals. For more than a century, a desire to understand how itch is encoded by the nervous system has prompted the advancement of many theories. Within the past 15 years, our understanding of the molecular and neural mechanisms of itch has undergone a major transformation, and this remarkable progress continues today without any sign of abating. Here I describe accumulating evidence that indicates that itch is distinguished from pain through the actions of itch-specific neuropeptides that relay itch information to the spinal cord. According to this model, classical neurotransmitters transmit, inhibit and modulate itch information in a context-, space- and time-dependent manner but do not encode itch specificity. Gastrin-releasing peptide (GRP) is proposed to be a key itch-specific neuropeptide, with spinal neurons expressing GRP receptor (GRPR) functioning as a key part of a convergent circuit for the conveyance of peripheral itch information to the brain.
... However, airway injury induced by particulate matter inhalation has been predominantly associated with P2Y-mediated signaling in epithelial cells leading to enhanced mucociliary clearance. On the other hand, P2X receptors have a prominent role in sensory nerves, as their activation triggers defensive responses such as cough [56,[60][61][62][63][64][65]. Most of the studies addressing ATP-mediated signaling are related to ATP release upon cell damage [66]. ...
Because of their low cost and easy production, silica nanoparticles (SiNPs) are widely used in multiple manufacturing applications as anti-caking, densifying and hydrophobic agents. However, this has increased the exposure levels of the general population and has raised concerns about the toxicity of this nanomaterial. SiNPs affect the function of the airway epithelium, but the biochemical pathways targeted by these particles remain largely unknown. Here we investigated the effects of SiNPs on the responses of 16HBE14o- cultured human bronchial epithelial (16HBE) cells to the damage-associated molecular pattern ATP, using fluorometric measurements of intracellular Ca2+ concentration. Upon stimulation with extracellular ATP, these cells displayed a concentration-dependent increase in intracellular Ca2+, which was mediated by release from intracellular stores. SiNPs inhibited the Ca2+ responses to ATP within minutes of application and at low micromolar concentrations, which are significantly faster and more potent than those previously reported for the induction of cellular toxicity and pro-inflammatory responses. SiNPs-induced inhibition is independent from the increase in intracellular Ca2+ they produce, is largely irreversible and occurs via a non-competitive mechanism. These findings suggest that SiNPs reduce the ability of airway epithelial cells to mount ATP-dependent protective responses.
... Through binding to its specific receptors on the cell surface, NPR-A (also known as NPR1 or GC-A) and NPR-C, ANP exerts a fundamental role in the modulation of cardiovascular homeostasis (Potter et al., 2009). ANP, brain NP (BNP), and C-type NP (CNP) are structurally related peptides belonging to members of the NP family that are widely distributed in the mammalian central nervous system (CNS) (Cao and Yang, 2008;Mahinrad et al., 2016), especially in peripheral sensory organs such as the dorsal root, trigeminal, retinal, and cochlear ganglia (Lamprecht and Meyer zum Gottesberge, 1988;Furuta et al., 1995;Abdelalim and Tooyama, 2010;Xu et al., 2010;Loo et al., 2012;Abdelalim et al., 2013;Vilotti et al., 2013;Fitzakerley and Trachte, 2018). Recent research has shown the involvement of the BNP/NPR-A signaling pathway in the modulation of nociceptive processing for pain and itch responses (Solinski et al., 2019). ...
Sensorineural hearing loss (SNHL) is a dominant public health issue affecting millions of people around the globe, which is correlated with the irreversible deterioration of the hair cells and spiral ganglion neurons (SGNs) within the cochlea. Strategies using bioactive molecules that regulate neurite regeneration and neuronal survival to reestablish connections between auditory epithelium or implanted electrodes and SGN neurites would become attractive therapeutic candidates for SNHL. As an intracellular second messenger, cyclic guanosine-3’,5’-monophosphate (cGMP) can be synthesized through activation of particulate guanylate cyclase-coupled natriuretic peptide receptor by natriuretic peptides, which in turn modulates multiple aspects of neuronal functions including neuronal development and neuronal survival. As a cardiac-derived hormone, atrial natriuretic peptide (ANP), and its specific receptors (NPR-A and NPR-C) are broadly expressed in the nervous system where they might be involved in the maintenance of diverse neural functions. Despite former literatures and our reports indicating the existence of ANP and its receptors within the inner ear, particularly in the spiral ganglion, their potential regulatory mechanisms underlying functional properties of auditory neurons are still incompletely understood. Our recently published investigation revealed that ANP could promote the neurite outgrowth of SGNs by activating NPR-A/cGMP/PKG cascade in a dose-dependent manner. In the present research, the influence of ANP and its receptor-mediated downstream signaling pathways on neurite outgrowth, neurite attraction, and neuronal survival of SGNs in vitro was evaluated by employing cultures of organotypic explant and dissociated neuron from postnatal rats. Our data indicated that ANP could support and attract neurite outgrowth of SGNs and possess a high capacity to improve neuronal survival of SGNs against glutamate-induced excitotoxicity by triggering the NPR-A/cGMP/PKG pathway. The neuroregenerative and neuroprotective effects of ANP/NPRA/cGMP/PKG-dependent signaling on SGNs would represent an attractive therapeutic candidate for hearing impairment.
... Endogenous neuropeptides upregulate their activity in acute and chronic pain. Vilotti et al reported that, BNP was a negative regulator of trigeminal sensory neuron excitability on TRPV1 and P2X3 receptors [19]. Our results for the increased pain threshold under sacubitril treatment may contribute to these previous studies. ...
Background:
We hypothesized that renin-angiotensin system and neprilysin (NEP) inhibition can modulate the nociceptive parameters on hypertensive rats. The aim of this study is to assess the preventive and therapeutic effects of ramipril and sacubitril on the pain hypersensitivities, and their interaction mechanisms with high blood pressure.
Methods:
Antinociceptive effects of ramipril and sacubitril were compared with those of diclofenac. Threshold of pain assesments were recorded before drugs administration. After a 18 days treatment, normotensive and dexamethasone-induced hypertensive rats were evaluated on thermal hyperalgesia and mechanical allodynia tests. Blood pressure of rats were verified by mean arterial pressure measurement.
Results:
Hypertensive rats showed significantly high pain threshold on thermal plantar test compared to that of normotensives. Among hypertensive rats, pain hypersensitivity was lowest in diclofenac group, followed by sacubitril group, while ramipril caused increased thermal and mechanical hypersensitivities.
Conclusion:
We found that NEP inhibition may play a role in nociception in hypertensive rats. NEP inhibitors may be suitable choice for the management of hypertension and pain because of their therapeutic and preventive effects on nociception and arterial blood pressure.
... It has been reported that brain natriuretic peptide (BNP), which is produced by cardiac cells, is elevated in migraine (Uzar et al., 2011). However, BNP is reported to negatively regulate sensory neuron excitability (Vilotti et al., 2013). Further investigations are necessary to elucidate the role of BNP, RAS and hypertension in migraine. ...
Migraine is one of the most prevalent and disabling neurovascular disorders worldwide. However, despite the increase in awareness and research, the understanding of migraine pathophysiology and treatment options remain limited. For centuries, migraine was considered to be a vascular disorder. In fact, the throbbing, pulsating quality of the headache is thought to be caused by mechanical changes in vessels. Moreover, the most successful migraine treatments act on the vasculature and induction of migraine can be accomplished with vasoactive agents. However, over the past 20 years, the emphasis has shifted to the neural imbalances associated with migraine, and vascular changes have generally been viewed as an epiphenomenon that is neither sufficient nor necessary to induce migraine. With the clinical success of peripherally-acting antibodies that target calcitonin gene-related peptide (CGRP) and its receptor for preventing migraine, this neurocentric view warrants a critical re-evaluation. This review will highlight the likely importance of the vasculature in migraine.
... From one animal we used both TG to produce two or three cultures. As previously reported in detail Nair et al., 2010;Vilotti et al., 2013), trigeminal neurons were superfused continuously (2 mL/min) with physiological solution containing (in mM): 152 NaCl, 5 KCl, 1 MgCl 2 , 2 CaCl 2 , 10 glucose, and 10 HEPES (pH adjusted to 7.4 with NaOH). Cells were patch-clamped in the whole-cell configuration using pipettes with a resistance of 3e4 MU when filled with the following solution (in mM): 140 KCl, 0.5 CaCl 2 , 2 MgCl 2 , 2 Mg 2 ATP 3 , 2 GTP, 10 HEPES, and 10 EGTA (pH adjusted to 7.2 with KOH). ...
... Cells were patch-clamped in the whole-cell configuration using pipettes with a resistance of 3e4 MU when filled with the following solution (in mM): 140 KCl, 0.5 CaCl 2 , 2 MgCl 2 , 2 Mg 2 ATP 3 , 2 GTP, 10 HEPES, and 10 EGTA (pH adjusted to 7.2 with KOH). Recordings were performed on small-and medium-size neurons (capacitance < 22 pF; cell body diameter 15e25 mm) that all express functional GABA A receptors and mostly (about 80%) express functional P2X3 receptors Vilotti et al., 2013). Cells were held at À65 mV after correcting for the liquid junction potential; currents were filtered at 1 kHz using an Axopatch 200B amplifier (Molecular Devices, Sunnyvale, CA, USA) and acquired by means of a DigiData 1200 Interface and pClamp 8.2 software (Molecular Devices, Sunnyvale, CA, USA). ...
... To induce P2X3 receptor currents, the synthetic agonist a,b-methylene-adenosine-5 0triphosphate (a,b-meATP; Sigma) was applied (2 s) at the concentration of 10 mM to evoke near maximal responses Franceschini et al., 2013;Nair et al., 2010), using a fast superfusion system (Rapid Solution Changer RSC-200; BioLogic Science Instruments, Claix, France). GABA was applied with 2-s pulses (Fabbro and Nistri, 2004;Vilotti et al., 2013) at various concentrations to obtain dose/response curves. For systematic testing the 10 mM concentration was employed. ...
Endocannabinoids are suggested to control pain, even though their clinical use is not fully validated and the underlying mechanisms are incompletely understood. To clarify the targets of endocannabinoid actions, we studied how activation of the endocannabinoid CB1 receptor (CB1R) affects neuronal responses in two in vitro preparations of rodents, namely the trigeminal sensory ganglion (TG) in culture and a coronal slice of the cerebral cortex. On TG small-medium size neurons, we tested whether submicromolar concentrations of the endogenous CB1R agonist anandamide (AEA) modulated inhibitory GABAA receptors and excitatory ATP-gated P2X3 receptors. AEA reversibly depressed GABA-mediated membrane currents without altering P2X3 receptor responses. The AEA antagonism was non-competitive, prevented by the CB1R antagonist AM-251, mimicked by the other cannabinoids 2-arachidonylglycerol and WIN 55,212-2, and insensitive to TRPV1 blocker capsazepine. AEA inhibited the potentiation of GABAergic responses by the cAMP activator forskolin, in line with the canonical inhibition of cAMP synthesis by CB1Rs. In the cerebral cortex, AEA or WIN 55,212-2 did not affect electrically-evoked local field potentials or characteristics of cortical spreading depolarization (CSD) elicited by high potassium application. The GABAA receptor blocker gabazine, however, strongly enhanced field potentials without affecting CSD properties, suggesting that CSD was not dominantly controlled by GABAergic mechanisms. Our data propose that, despite the widespread expression of CB1Rs peripherally and centrally, the functional effects of AEA are region-specific and depend on CB1R coupling to downstream effectors. Future studies concerned with the mechanisms of AEA analgesia should perhaps be directed to discrete subcortical nuclei processing trigeminal inputs.
... In the peritoneal inflammatory microenvironment of women with endometriosis, various inflammatory mediators are thought to activate nociceptive receptors on the afferent neurons by stimulating sensory nerve fibers within the lesions, leading to the sensitization of sensory neurons, and thus triggering pain signal cascade [16,17]. In acute and chronic pain models, small-and medium-diameter sensory neurons, which express transient receptor vanilloid-1 (TRPV1) channels and/or adenosine triphosphate (ATP)-gated P2X3 receptors, are the important pain transducers of noxious stimuli [18]. In women with endometriosis, TRPV1 receptor expression has been demonstrated to be elevated in endometriotic lesions, and correlated with endometriosis pain [16,[18][19][20]. ...
... In acute and chronic pain models, small-and medium-diameter sensory neurons, which express transient receptor vanilloid-1 (TRPV1) channels and/or adenosine triphosphate (ATP)-gated P2X3 receptors, are the important pain transducers of noxious stimuli [18]. In women with endometriosis, TRPV1 receptor expression has been demonstrated to be elevated in endometriotic lesions, and correlated with endometriosis pain [16,[18][19][20]. However, almost no studies on the role of the P2X3 receptor in endometriosis pain have been reported, although TRPV1 and P2X3 are both cation ion channels, and both are regulated by estrogen [21][22][23]. ...
The purinergic receptor P2X ligand-gated ion channel 3 (P2X3) is crucially involved in peripheral nociceptive processes of somatic and visceral pain. Endometriosis pain is considered as a kind of inflammatory and neuropathic pain. However, whether P2X3 is involved in endometriosis pain has not been reported up to date. Here, we aimed to determine whether P2X3 expression in endometriotic lesions is involved in endometriosis pain, which is regulated by inflammatory mediators through extracellular regulated protein kinases (ERK) signalling pathway. We found that P2X3 expressions in endometriosis endometrium and endometriotic lesions were both significantly higher as compared with control endometrium (P<0.05), and both positively correlated with pain (P<0.05). The expression levels of phosphorylated –ERK (p-ERK), phosphorylated-cAMP-response element binding protein (p-CREB), and P2X3 in endometriotic stromal cells (ESCs) were all significantly increased in comparison to the initial levels after treated with interleukin (IL)-1β (P<0.05) or adenosine triphosphate (ATP) (P<0.05), respectively, and did not increase after the ESCs were pre-treated with ERK1/2 inhibitor. Additionally, P2X3 and calcitonin gene related peptide (CGRP) were co-expressed in endometriotic lesions. These obtained results suggest that P2X3 might be involved in endometriosis pain signal transduction via ERK signal pathway.
... Biotinylated and input samples were processed for Western blotting using antibodies against HCN1-4 (1:1000). Positive control for biotinylation assay of membrane expression was obtained by checking the surface expression of the transferrin receptor (Vilotti et al., 2013) detected with an antibody purchased from Santa Cruz Biotechnology (1:1000, Heidelberg, Germany). ...
Transgenic knock-in (KI) mice that express CaV2.1 channels containing an R192Q gain-of-function mutation in the ?1A subunit known to cause familial hemiplegic migraine type-1 in patients, exhibit key disease characteristics and provide a useful tool to investigate pathophysiological mechanisms of pain transduction. Previously, KI trigeminal sensory neurons were shown to exhibit constitutive hyperexcitability due to up-regulation of ATP-gated P2X3 receptors that trigger spike activity at a more negative threshold. This implies that intrinsic neuronal conductances may shape action potential generation in response to ATP, which could act as a mediator of migraine headache. Here we investigated whether the hyperpolarization-activated conductance Ih, mediated by HCN channels, contributes to sub-threshold behavior and firing in wildtype (WT) and KI trigeminal ganglia (TG) neurons. Whereas most WT and KI trigeminal neurons expressed Ih current, blocked by the specific inhibitor ZD7288, it was smaller in KI neurons despite similar activation and deactivation kinetics. HCN1 and HCN2 were the most abundantly expressed subunits in TG, both in situ and in culture. In KI TG neurons, HCN2 subunits were predominantly present in the cytoplasm, not at the plasma membrane, likely accounting for the smaller Ih of such cells. ZD7288 hyperpolarized the membrane potential, thereby raising the firing threshold, and prolonging the spike trajectory to generate fewer spikes due to P2X3 receptor activation. The low amplitude of Ih in KI TG neurons suggests that down-regulation of Ih current in sub-threshold behavior acts as a compensatory mechanism to limit sensory hyperexcitability, manifested under certain stressful stimuli.
... A previous study found that BNP inhibited the excitability of small dorsal root ganglion (DRG) neurons, pain receptors in the peripheral nervous system, and inflammatory pain induced by CFA and formalin through activating the NPRA/PKG/BK Ca channel pathway [18]. A recent study found that functional NPRA is expressed in almost all the trigeminal ganglion (TG) neurons at the membrane level [19]. Chronic activation of NPRA by BNP down-regulated the excitability of TG neurons. ...
Background:
A previous study found that brain natriuretic peptide (BNP) inhibited inflammatory pain via activating its receptor natriuretic peptide receptor A (NPRA) in nociceptive sensory neurons. A recent study found that functional NPRA is expressed in almost all the trigeminal ganglion (TG) neurons at membrane level suggesting a potentially important role for BNP in migraine pathophysiology.
Methods:
An inflammatory pain model was produced by subcutaneous injection of BmK I, a sodium channel-specific modulator from venom of Chinese scorpion Buthus martensi Karsch. Quantitative PCR, Western Blot, and immunohistochemistry were used to detect mRNA and protein expression of BNP and NPRA in dorsal root ganglion (DRG) and dorsal horn of spinal cord. Whole-cell patch clamping experiments were conducted to record large-conductance Ca(2+)-activated K(+) (BKCa) currents of membrane excitability of DRG neurons. Spontaneous and evoked pain behaviors were examined.
Results:
The mRNA and protein expression of BNP and NPRA was up-regulated in DRG and dorsal horn of spinal cord after BmK I injection. The BNP and NPRA was preferentially expressed in small-sized DRG neurons among which BNP was expressed in both CGRP-positive and IB4-positive neurons while NPRA was preferentially expressed in CGRP-positive neurons. BNP increased the open probability of BKCa channels and suppressed the membrane excitability of small-sized DRG neurons. Intrathecal injection of BNP significantly inhibited BmK-induced pain behaviors including both spontaneous and evoked pain behaviors.
Conclusions:
These results suggested that BNP might play an important role as an endogenous pain reliever in BmK I-induced inflammatory pain condition. It is also suggested that BNP might play a similar role in other pathophysiological pain conditions including migraine.
