Blocking PAR2 attenuates oxaliplatin-induced neuropathic pain via TRPV1 and releases of substance P and CGRP in superficial dorsal horn of spinal cord

Chen, Kun; Zhang, Zhifa; Liao, Ming‐Feng; Yao, Wenlong; Wang, Juan; Wang, Xueren

doi:10.1016/j.jns.2015.03.029

Cited by 50 publications

(42 citation statements)

References 39 publications

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“…In addition, increased SP and TNF- α mRNA expression was observed in spinal cord. These results are consistent with those reported previously [7–10], suggesting that spinal glial activation and increased production of proinflammatory cytokines and excitatory neurotransmitters might contribute to the maintenance of OXL-induced chronic neuropathic pain in rats.…”

Section: Discussionsupporting

confidence: 93%

“…This dysfunction arises from the activation of glia and increased production of glial-derived proinflammatory cytokine (tumor necrosis factor- α , TNF- α ), resulting in modified neurotransmission [9]. The modified release of excitatory neurotransmitter (substance P, SP) also contributes to OXL-induced neuropathic pain [10]. This dysfunction increases peripheral nerve injury-induced central sensitization in the spinal cord [7–10].…”

Section: Background or Introductionmentioning

confidence: 99%

“…The modified release of excitatory neurotransmitter (substance P, SP) also contributes to OXL-induced neuropathic pain [10]. This dysfunction increases peripheral nerve injury-induced central sensitization in the spinal cord [7–10]. …”

Section: Background or Introductionmentioning

confidence: 99%

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Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain

Deng

Jia

Lin

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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One of the main dose-limiting complications of the chemotherapeutic agent oxaliplatin (OXL) is painful neuropathy. Glial activation and nociceptive sensitization may be responsible for the mechanism of neuropathic pain. The Traditional Chinese Medicine (TCM) Wen-luo-tong (WLT) has been widely used in China to treat chemotherapy induced neuropathic pain. However, there is no study on the effects of WLT on spinal glial activation induced by OXL. In this study, a rat model of OXL-induced chronic neuropathic pain was established and WLT was administrated. Pain behavioral tests and morphometric examination of dorsal root ganglia (DRG) were conducted. Glial fibrillary acidic protein (GFAP) immunostaining was performed, glial activation was evaluated, and the excitatory neurotransmitter substance P (SP) and glial-derived proinflammatory cytokine tumor necrosis factor-α (TNF-α) were analyzed. WLT treatment alleviated OXL-induced mechanical allodynia and mechanical hyperalgesia. Changes in the somatic, nuclear, and nucleolar areas of neurons in DRG were prevented. In the spinal dorsal horn, hypertrophy and activation of GFAP-positive astrocytes were averted, and the level of GFAP mRNA decreased significantly. Additionally, TNF-α mRNA and protein levels decreased. Collectively, these results indicate that WLT reversed both glial activation in the spinal dorsal horn and nociceptive sensitization during OXL-induced chronic neuropathic pain in rats.

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Section: Discussionsupporting

confidence: 93%

Section: Background or Introductionmentioning

confidence: 99%

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Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain

Deng

Jia

Lin

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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“…, Chen et al . ). The synthesis and release of this molecule is increased upon noxious stimulation of dental pulp nerves by thermal, mechanical and chemical stimuli (Sacerdote & Levrini ).…”

Section: Discussionmentioning

confidence: 97%

Activation of orexin‐1 receptors in the ventrolateral periaqueductal grey matter (vlPAG) modulates pulpal nociception and the induction of substance P in vlPAG and trigeminal nucleus caudalis

et al. 2018

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“…It is well documented that the upregulation of P2 × 3 is known to contribute to purinergic pain-sensing system [65]. In a different neuropathological perspective, PAR2-related pain sensitivity maybe attributed to the upregulation or activation of TRPV1 [66,67] and TRPA1 [46,68,69] in DRG neurons.…”

Section: Sl-nh2 Elicited P2 × 3 Trpv1 and Trpa1 Expression In Drg Nmentioning

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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Blocking PAR2 attenuates oxaliplatin-induced neuropathic pain via TRPV1 and releases of substance P and CGRP in superficial dorsal horn of spinal cord

Cited by 50 publications

References 39 publications

Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain

Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain

Activation of orexin‐1 receptors in the ventrolateral periaqueductal grey matter (vlPAG) modulates pulpal nociception and the induction of substance P in vlPAG and trigeminal nucleus caudalis

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

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