P2X3 receptors contribute to muscle pain induced by static contraction by a mechanism dependent on neutrophil migration

Aquino, Bruna de Melo; Santos, Diogo Francisco da Silva dos; Jorge, Carolina Ocanha; Marques, Aline Carolina Salgado; Teixeira, Juliana Maia; Parada, Carlos Amílcar; Oliveira, Maria Cláudia G.

doi:10.1007/s11302-019-09659-0

Cited by 13 publications

(5 citation statements)

References 79 publications

(115 reference statements)

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“…Elevated neurotransmitter release and peptide co-release with ATP are thought to cause peripheral and central sensitization [ 51 , 58 ]. Because P2X3R is sensitive to nanomolar ATP concentrations, purinergic signal transduction can be adjusted using varying ATP concentrations [ 59 ]. ATP modulates pain sensitivity via changes in sensory neuron voltage-gated ion channels activity, including CaV and NaV [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Electroacupuncture alleviates diabetic neuropathic pain in rats by suppressing P2X3 receptor expression in dorsal root ganglia

Fei

Tai

et al. 2020

Purinergic Signalling

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Diabetic neuropathic pain (DNP) is a troublesome diabetes complication all over the world. P2X3 receptor (P2X3R), a purinergic receptor from dorsal root ganglion (DRG), has important roles in neuropathic pain pathology and nociceptive sensations. Here, we investigated the involvement of DRG P2X3R and the effect of 2 Hz electroacupuncture (EA) on DNP. We monitored the rats’ body weight, fasting blood glucose level, paw withdrawal thresholds, and paw withdrawal latency, and evaluated P2X3R expression in DRG. We found that P2X3R expression is upregulated on DNP, while 2 Hz EA is analgesic against DNP and suppresses P2X3R expression in DRG. To evaluate P2X3R involvement in pain modulation, we then treated the animals with A317491, a P2X3R specific antagonist, or α β-me ATP, a P2X3R agonist. We found that A317491 alleviates hyperalgesia, while α β-me ATP blocks EA’s analgesic effects. Our findings indicated that 2 Hz EA alleviates DNP, possibly by suppressing P2X3R upregulation in DRG.

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Section: Discussionmentioning

confidence: 99%

Electroacupuncture alleviates diabetic neuropathic pain in rats by suppressing P2X3 receptor expression in dorsal root ganglia

Fei

Tai

et al. 2020

Purinergic Signalling

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“…We have recently demonstrated that P2X3 receptors expressed on gastrocnemius muscle and spinal cord dorsal horn seem to be essential to the development of the acute mechanical muscle hyperalgesia induced by static contraction of the gastrocnemius muscle [26]. It is important to point out that the long-term static contraction produces musculoskeletal pain by similar mechanisms to carrageenan, such as final inflammatory mediators and neutrophil migration [14,27,28].…”

Section: Discussionmentioning

confidence: 99%

“…The maintenance of chronic muscle pain seems to involve more lasting modifications, such as modulation of nociceptive afferent fibers by kinase activation cascade and/or in the expression of some receptors in the nociceptive fibers [11][12][13]. It is interesting to point out that P2X3 receptor, one of the most important receptors related to transmission and modulation of nociceptive signals (Oliveira-Fusaro et al 2017;Teixeira et al 2016), including the nociceptive muscle tissue signaling [14,15], has an involvement with the PKC signaling pathway [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…We have recently demonstrated that the intramuscular and intrathecal pharmacological blockade of P2X3 receptors previously to static contraction of gastrocnemius muscle prevents the development of acute mechanical muscle hyperalgesia [14]. It is important to point out that the long-term static contraction of the gastrocnemius muscle induced a local inflammation.…”

Section: Introductionmentioning

confidence: 99%

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P2X3 receptors contribute to transition from acute to chronic muscle pain

Jorge

Azambuja

Gomes

et al. 2020

Purinergic Signalling

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This study aimed to evaluate whether the development and/or maintenance of chronic-latent muscle hyperalgesia is modulated by P2X3 receptors. We also evaluate the expression of P2X3 receptors and PKCε of dorsal root ganglions during these processes. A mouse model of chronic-latent muscle hyperalgesia, induced by carrageenan and evidenced by PGE 2 , was used. Mechanical muscle hyperalgesia was measured by Randall-Selitto analgesimeter. The involvement of P2X3 receptors was analyzed by using the selective P2X3 receptors antagonist A-317491 by intramuscular or intrathecal injections. Expression of P2X3 and PKCε in dorsal root ganglion (L4-S1) were evaluated by Western blotting. Intrathecal blockade of P2X3 receptors previously to carrageenan prevented the development and maintenance of acute and chronic-latent muscle hyperalgesia, while intramuscular blockade of P2X3 receptors previously to carrageenan only reduced the acute muscle hyperalgesia and had no effect on chronic-latent muscle hyperalgesia. Intrathecal, but not intramuscular, blockade of P2X3 receptors immediately before PGE 2 , in animals previously sensitized by carrageenan, reversed the chronic-latent muscle hyperalgesia. There was an increase in total and phosphorylated PKCε 48 h after the beginning of acute muscle hyperalgesia, and in P2X3 receptors at the period of chronic muscle hyperalgesia. P2X3 receptors expressed on spinal cord dorsal horn contribute to transition from acute to chronic muscle pain. We also suggest an interaction of PKCε and P2X3 receptors in this process. Therefore, we point out P2X3 receptors of the spinal cord dorsal horn as a pharmacological target to prevent the development or reverse the chronic muscle pain conditions.

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“…As an important transducer of nociceptive stimuli, purinergic receptor P2X ligand-gated ion channel 3 (P2 × 3) is a trimeric cation channel that is gated by extracellular ATP and predominantly localized in small-to medium-sized neurons of the DRG [49] and acts as an attractive potential therapeutic target [50]. P2 × 3 can be involved in different pain conditions [51]. Its activation contributes to acute nociceptive behavior, hyperalgesia, and allodynia [52][53][54].…”

Section: Introductionmentioning

confidence: 99%

The mechanisms of protease-activated receptor 2 in mediating pain behaviors through nonselective cation channel signaling

Yue

Wang

Lau

et al. 2020

Preprint

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Background: Activation of purinergic receptor P2X ligand-gated ion channel 3 (P2X3), transient receptor potential vanilloid type 1 (TRPV1), and transient receptor potential ankyrin 1 (TRPA1) by their specific ligands is a major mechanism contributing to magnified pain responses. The relationship between these nonselective cation channels and proteinase-activated receptor 2 (PAR2) activation mediated pain is still to be clarified.Methods: In this study, both in vitro model of dorsal root ganglion (DRG) neurons with PAR2 agonist SL-NH2 challenge and SL-NH2-induced pain rat model were used to approach these questions. The expression of P2X3, TRPV1, and TRPA1 in DRG neurons was investigated by quantitative real-time RT-PCR, Western blot, and immunofluorescence. The involvement of the PLCβ3/PKCε signaling pathway was also determined. The behavior test for mechanical allodynia and thermal hyperalgesia was performed. Results: SL-NH2 induced upregulation of P2X3, TRPV1, and TRPA1 through phosphorylation of phospholipase Cβ3 (PLCβ3) and protein kinase Cε (PKCε) signaling pathway in DRG neurons in vitro and in vivo. SL-NH2 also elevated the proportion of P2X3-, TRPV1-, and TRPA1-expressing neurons. The upregulation of P2X3, TRPV1, and TRPA1 and phosphorylation of PLCβ3 and PKCε in DRG neurons was paralleled with mechanical allodynia and thermal hyperalgesia behaviors in rats. Conclusions: The data of the present study imply that SL-NH2 as a noxious stimulus activates PAR2 which induces TRPV1, TRPA1, and P2X3 upregulation through PLCβ3/PKCε signaling pathway, thereby decreasing activation thresholds and increasing excitability, resulting in sustained nociceptive activity in DRG neurons, and then causing mechanical allodynia and thermal hyperalgesia behaviors. These data expanded our knowledge about PAR2-mediated pain sensitivity and its relationship with TRPV1, TRPA1, and P2X3 and provided new opportunities on management of pain behaviors.

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P2X3 receptors contribute to muscle pain induced by static contraction by a mechanism dependent on neutrophil migration

Cited by 13 publications

References 79 publications

Electroacupuncture alleviates diabetic neuropathic pain in rats by suppressing P2X3 receptor expression in dorsal root ganglia

Electroacupuncture alleviates diabetic neuropathic pain in rats by suppressing P2X3 receptor expression in dorsal root ganglia

P2X3 receptors contribute to transition from acute to chronic muscle pain

The mechanisms of protease-activated receptor 2 in mediating pain behaviors through nonselective cation channel signaling

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