- Open Access
PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain
© Bao et al.; licensee BioMed Central Ltd. 2014
- Received: 13 December 2013
- Accepted: 28 April 2014
- Published: 5 May 2014
Bone cancer pain is currently a major clinical challenge for the management of cancer patients, and the cellular and molecular mechanisms underlying the spinal sensitization remain unclear. While several studies demonstrated the critical role of proteinase-activated receptor (PAR2) in the pathogenesis of several types of inflammatory or neuropathic pain, the involvement of spinal PAR2 and the pertinent signaling in the central sensitization is not determined yet in the rodent model of bone cancer pain.
Implantation of tumor cells into the tibias induced significant thermal hyperalgesia and mechanical allodynia, and enhanced glutamatergic strength in the ipsilateral dorsal horn. Significantly increased brain-derived neurotrophic factor (BDNF) expression was detected in the dorsal horn, and blockade of spinal BDNF signaling attenuated the enhancement of glutamatergic strength, thermal hyperalgesia and mechanical allodynia in the rats with bone cancer pain. Significantly increased spinal PAR2 expression was also observed, and inhibition of PAR2 signaling ameliorated BDNF upsurge, enhanced glutamatergic strength, and thermal hyperalgesia and mechanical allodynia. Inhibition of NF-κB pathway, the downstream of PAR2 signaling, also significantly decreased the spinal BDNF expression, glutamatergic strength of dorsal horn neurons, and thermal hyperalgesia and mechanical allodynia.
The present study demonstrated that activation of PAR2 triggered NF-κB signaling and significantly upregulated the BDNF function, which critically contributed to the enhancement of glutamatergic transmission in spinal dorsal horn and thermal and mechanical hypersensitivity in the rats with bone cancer. This indicated that PAR2 - NF-κB signaling might become a novel target for the treatment of pain in patients with bone cancer.
- Proteinase-activated receptor 2
- Brain-derived neurotrophic factor
- Nuclear factor-κB
- Glutamatergic transmission
- Bone cancer pain
Bone cancer pain is currently a major clinical challenge for the management of cancer patients, because the specific cellular and molecular mechanisms underlying bone cancer pain largely remain obscure [1, 2]. While lines of studies have demonstrated the remarkable sensitization of peripheral nociceptors in the bone, resulting from the tumor-induced acidosis and cytokine synthesis, emerging evidences indicated that the activation of astrocytes [3–5] and altered glutamatergic synaptogenesis [6, 7] existed in the spinal dorsal horn of the rodent model of bone cancer pain. Overwhelming evidences strongly suggest that brain-derived neurotrophic factor (BDNF) serves as one of the key regulators of synaptic plasticity in brain regions including cortex, hippocampus as well as spinal cord , and it is critically involved in the induction and maintenance of central sensitization in varieties types of pain . It was previously reported that the synthesis and release of BDNF was remarkably upregulated, which contributing to the central sensitization, in the spinal dorsal horn of the rodent with inflammatory or neuropathic pain [9, 10]. Currently, the role of BDNF in the induction and maintenance of enhanced spinal glutamatergic transmission has not been elucidated in the rodent model of bone cancer pain.
Proteinase-activated receptors (PARs) are a family of G-protein coupled receptors that are activated by proteases, which liberates a tethered ligand, by cleaving the N-terminus of the receptors, and initiates several intracellular signal pathways . Four subtypes of PARs exist. While PAR1, PAR3, and PAR4 are preferentially activated by thrombin, PAR2 is preferentially activated by trypsin and trypsin-like proteinases . All four PARs are expressed throughout the peripheral and central nerve system. In the spinal dorsal horn, PAR2 receptor is located in the microglia, astrocytes, neurons, and the terminals of afferent fibers originating from the dorsal root ganglions . Previous studies demonstrated the critical involvement of PAR2 in the pathogenesis of several types of inflammatory or neuropathic pain . Activation of PAR2 signaling participated in the induction of sensitization of peripheral nociceptors in the rodent model of bone cancer pain . However, it remains uncertain whether activation of spinal PAR2 signaling is critically involved in the central sensitization in the rodent model of bone cancer pain.
Besides triggering the mitogen-activated protein kinases signaling, including ERK1/2, p38 and JNK activity, the activation of G-protein couple receptor PAR2 also involves PLC-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and induction of the Ca2+/inositol 1,4,5-trisphosphate (IP3)/PKC signaling , which may in turn induce the phosphorylation of IKKα and IKKβ and result in the activation and nuclear translocation of NF-κB . Accumulating evidence demonstrated that peripheral inflammation or nerve injury induced remarkable NF-κB activity in the spinal dorsal horn, which contributing to the thermal hyperalgesia and mechanical allodynia in the rodent models of chronic pain [14, 15]. It was previously reported that upregulated NF-κB activity was required for the developmental and plasticity-associated synaptogenesis in the central neurons . Meanwhile, upregulation of NF-κB activity also facilitated the expression of BDNF in the central neurons . Here, the present study aims to elaborate the involvement of PAR2 - NF-κB signaling in the induction of enhanced spinal glutamatergic transmission and painful behaviors in the rats with bone cancer.
BDNF contributes to the enhanced glutamatergic strength in the rats with bone cancer pain
To determine the adaptation of glutamatergic transmission in the spinal dorsal horn of the rats with bone cancer pain, the whole cell-recording was performed in the ipsilateral laminae II neurons in spinal slices (L4-L5), and the glutamatergic EPSC was recorded in the presence of strychnine (2 μM) and bicuculline (10 μM). The EPSC was completely abolished by the perfusion of CNQX (10 μM) and APV (10 μM), confirm its glutamatergic components. Compared to that in the control rats, the input (intensity of stimuli) –output (amplitude of evoked EPSC) response was significantly left shifted (Figure 1B), indicating a significantly enhanced glutamatergic strength in the dorsal horn neurons in the rats with bone cancer pain.
BDNF, synthesized from central neurons and astrocytes, is critically involved in the glutamatergic synaptogenesis and synaptic plasticity in the brain . Here, we investigated the expression of BDNF in the dorsal horn, and its functional significance in the bone cancer-induced pain. As shown in Figure 1A, the expression of BDNF was significantly increased in the dorsal horn of the rats with bone cancer pain. The further electrophysiological recording studies revealed that intrathecal delivery of TrkB-Fc chimera (1.5 μg, day 3 to day 15), which quenching the endogenous BDNF, significantly ameliorated the increase of glutamatergic strength in the dorsal horn neurons of the rats with cancer-induced pain (Figure 1B). Behavioral studies demonstrated that inhibition of BDNF signaling by TrkB-Fc chimera also significantly attenuated the mechanical allodynia and thermal hyperalgesia in these modeled rats (Figure 1C). Note that blockade of the BDNF signaling failed to remarkably change basal glutamatergic transmission and pain behavior in the control rats (Figure 1B and C). These results suggested the critical involvement of BDNF signaling in the enhanced glutamatergic transmission in the dorsal horn neurons of the rats with bone cancer pain.
PAR2 mediated BDNF upregulation and glutamatergic sensitization in the rats with bone cancer pain
Then, FSLLRY-NH2 (10 μg, from day3 to day 15), the antagonist of PAR2, was daily delivered via the intrathecal catheter to determine its effect on BDNF function, glutamatergic strength and pain behavior in the rats with bone cancer. As shown in Figure 2B, blockade of PAR2 signaling by FSLLRY-NH2 significantly reversed the upregulation of spinal BDNF in the rats implanted with tumor cells, while it did not obviously change the expression of spinal BDNF in the control rats. This suggested a PAR2-mediated spinal BDNF upregulation in the setting of bone cancer pain.
Further recording results demonstrated that, as shown in Figure 2C, intrathecal delivery of FSLLRY-NH2 significantly attenuated the enhanced glutamatergic input–output response in the dorsal horn neurons of the rats with bone cancer, while it did not remarkably change the basal glutamatergic strength in the control rats (Figure 2C). It was also found that intrathecal delivery of FSLLRY-NH2 attenuated the increased expression of glutamate receptor subunits GluR1 and NR2B in the dorsal horn of the rats with bone cancer (Figure 2D). As well, behavioral studies also demonstrated that inhibition of PAR2 signaling by FSLLRY-NH2 significantly attenuated the mechanical allodynia and thermal hyperalgesia in these modeled rats (Figure 2E). Notably, intrathecal injection of scramble peptides in the same dose failed to affect the mechanical and thermal pain behaviors in either control or modeled rats (Figure 2F). These results suggested that upregulation of PAR2 signaling, via modulating the expression of BDNF, critically participated in the induction of enhanced spinal glutamatergic transmission and pain behavior in the rats with bone cancer.
NF-κB mediated BDNF upregulation and glutamatergic sensitization in the rats with bone cancer-induced pain
While inflammatory mediators and cytokines from peripheral nociceptors and surrounding immune and epithelial cells may remarkably sensitize the primary afferent fibers in the conditions of nociceptive and neuropathic pain , sensitization of nocisponsive neurons in spinal dorsal horn and supraspinal brain regions also significantly contributes to the persistent characteristics  and the negative affective components of sustained pain . Peripheral inflammation may drive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR1 membrane trafficking and induce hyperreactivity in the dorsal horn neurons . Peripheral nerve injury also significantly enhanced the excitatory glutamatergic transmission in the dorsal horn neurons, which contributing to the mechanical allodynia in the neuropathic pain . In the rodent model of bone cancer pain, the primary sensory afferents innervated in the bone marrow, mineralized bone, and the overlying periosteum was sensitized by the inflammatory microenvironment and injury of sensory and sympathetic fibers induced by proliferating tumor cells . Meanwhile, emerging evidences recently indicated that sensitization of dorsal horn nocisponsive neurons existed in the rodents with bone cancer pain. Increased expression and phosphorylation of NR2B, an N-methyl-D-aspartate receptor (NMDA) subunit, was reported in the dorsal horn of the bone cancer pain models [25–27]. In the present study, a remarkably increased input (stimulation intensity) – output (EPSC amplitude) response was observed in the dorsal horn neurons, which substantiating the enhanced spinal glutamatergic strength and central sensitization in the rodent with bone cancer pain.
Overwhelming evidences demonstrated that BDNF extensively participated in the neuronal development and the induction and maintenance of synaptic plasticity in several brain regions . As well, a growing body of evidence also suggested that BDNF was critically involved in spinal plasticity and central sensitization in varieties types of pain. Expression of BDNF was increased in the spinal dorsal horn of the rodent models of inflammatory or neuropathic pain . Enhanced BDNF-mediated signaling induces the phosphorylation of NMDA receptor subunits and sprouting of spinal nocisponsive fibers , and enhances the communication between microglia and neurons in the dorsal horn , thus contributing to the induction and maintenance of the sensitization of spinal neurons in the circumstance of chronic pain. Here, in the present study, a significantly increased BDNF in dorsal horn was revealed, and blocking BDNF signaling largely attenuated the enhanced glutamatergic strength and painful behavior in the rodent with bone cancer pain. This suggested a critical involvement of BDNF in the spinal sensitization and hypersensitivity to painful stimuli in the bone cancer pain.
Upon activation, PAR2 receptor may trigger several intracellular signal cascades involving MAPK signaling, PLC-mediated phospholipid signaling, and β-arrestin signaling . Among these, activation of PLC-mediated phospholipid signaling may induce the phosphorylation of IKKα and IKKβ and lead to activation and nuclear translocation of NF-κB [11, 18]. Activation of NF-κB - mediated signaling increased the histone acetylation and facilitated the expression of BDNF in the central neurons . Actually, it was recently implied that activation of PAR2 signaling was required for several inflammatory mediators-induced BDNF release from the microglia [32, 33]. Moreover, the present study demonstrated that inhibition the activity of either PAR2 or NF-κB largely attenuated the upregulation of BDNF in the dorsal horn, indicating that the PAR2 - NF-κB signaling critically participate in the spinal BDNF upregulation in the bone cancer pain.
PAR2 is expressed in the primary sensory neurons and nocisponsive neurons in the spinal dorsal horn. Increasing evidences suggested that activation of PAR2 signaling was extensively involved in the sensitization of peripheral nociceptors and dorsal horn neurons in inflammatory and neuropathic pain. Activation of PAR2 and downstream enzymes PLC, PKCϵ, and PKA resulted in the sensitization of peripheral nociceptors by decreasing the threshold of transient receptor potential (TRP) ion channels in the circumstances of peripheral inflammation [34, 35] or chemotherapeutic agent-induced neuropathic pain . Chronic compression of dorsal root ganglion (DRG) can activate PAR2 signaling, leading to increased nociceptor hyperexcitability and thermal hyperalgesia in the rodents [37, 38]. It was recently reported that activation of PAR2 signaling induced the sensitization of DRG neurons, which contributing to the thermal and mechanical hyperalgesia in the rodent model of bone cancer pain [12, 13]. The present study further revealed that activation of PAR2 signaling remarkably contributed to the enhanced glutamatergic strength in the dorsal horn neurons, which implying its role in the induction of central sensitization in bone cancer pain. The present study also suggested that activation of NF-κB signaling may underlie PAR2-mediated BDNF upregulation, central sensitization and behavioral hypersensitivity in the bone cancer pain.
The present study demonstrated that activation of PAR2 triggered NF-κB signaling and significantly upregulated the BDNF function, which substantially underlaid the enhancement of glutamatergic transmission in spinal dorsal horn and thermal and mechanical hypersensitivity in the rats with bone cancer pain. This indicated that PAR2 - NF-κB signaling might become a novel target for the treatment of pain in patients with bone cancer.
Animal model of bone cancer pain and drug delivery
Adult female Wistar rats (weighing 200–250 g) were purchased from the Institutional Center of Experiment Animals, and were housed in the standard lab conditions (22 ± 1°C and 12:12 h light cycle) with unrestricted free access to food and water. All animal experiments were approved by the Institutional Animal Care and Use Committee in China Academy of Chinese Medical Sciences, and were in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All surgery was performed under appropriate anesthesia, and all efforts were made to minimize suffering in the animals.
The rat model of bone cancer pain was established by implantation of Walker 256 rat mammary gland carcinoma cells into the right tibias, as previously reported . Briefly, suspensions of tumor cells in PBS was prepared as previously described . Tumor cell implantation was achieved by injecting the tumor cells (1 × 105 cells/μl, 5 μL) into the intramedullary space of the right tibia to induce bone cancer in rats under the anesthesia with pentobarbital (45 mg/kg). Boiled cells were injected with a similar procedure in the control group. The investigators who performed behavioral tests, immunoblotting, and electrophysiological recording were blinded to this procedure.
Intrathecal cannulation was performed as described previously . Intrathecal catheters (PE-10 polyethylene tubing) were implanted 1 week before any procedures. The catheters were advanced 8 cm caudally through an incision in the cisternal membrane and secured to the musculature at the incision site. Only animals with no evidence of neurological deficits after catheter insertion were studied. TrkB-Fc chimera (1.5 μg, R&D systems cat#: 688-TK-100) , FSLLRY-NH2 (10 μg, Tocris cat#: 4751) , pyrrolidine dithiocarbamate (PDTC, 1 μg, Sigma cat#: P8765) , or vehicle was administered in a volume of 10 μl followed by a 10-μl flush with normal saline. The drugs were given daily from day 3 to day 15 after carcinoma cell inoculation.
Mechanical allodynia and thermal hyperalgesia were assessed in rats to evaluate painful behavior induced by tumor cell implantation. Mechanical sensitivity was assessed by using a series of von Frey filaments with logarithmic incremental stiffness (Stoelting Co., Wood Dale, IL), and 50% probability paw withdrawal thresholds were calculated with the up-down method as previously described . In brief, the animals were placed individually beneath an inverted ventilated cage with a metal-mesh floor, and allowed to habituation for 30 minutes before testing. The filaments were applied to the plantar surface of the hindpaws for approximately 6 seconds in an ascending or descending order after a negative or positive withdrawal response, respectively. Six consecutive responses after the first change in response were used to calculate the paw withdrawal threshold (in grams). The maximum pressure was set as 16 g.
Thermal nociceptive thresholds were measured using radiant heat . Briefly, rats were placed into individual plastic cubicles mounted on a glass surface maintained at 30°C and allowed an hour habituation period. A thermal stimulus (a radiant heat source) was then delivered to the plantar surface of the hindpaws. The time for the rat to remove the paw from the thermal stimulus was electronically recorded as the paw withdrawal latency (PWL). The stimulus shut off automatically when the hind paw moved or after 16 seconds to prevent tissue damage. The intensity of the heat stimulus was maintained constant throughout all experiments.
Protein extraction and immunoblotting
After behavioral testing, the rats were deeply anesthetized with pentobarbital sodium (50 mg/kg), and the ipsilateral L4-L5 segments were quickly removed and homogenized in the lysis buffer (25 mM Tris–HCl, pH 7.6, 150 mM NaCl, 0.1% SDS, 1 mM PMSF, 1 mM NaF, 1 mM NaVO3, 1 μg/ml leupeptin, 1 μg/ml pepstatin, and 1 μg/ml aprotinin). The lysates were centrifuged at 14,000 rpm for 10 min at 4°C, and the protein concentrations in the supernatant were measured by using the Bio-Rad protein assay kit. The samples (containing 20 μg proteins) were separated on a 15% (for BDNF) or 7.5% (for other proteins) SDS-polyacrylamide gel, and blotted to a nitrocellulose membrane. The blots were incubated overnight at 4°C with a rabbit polyclonal anti-BDNF primary antibody (1:250; Santa Cruz Biotechnology cat#: sc-546), monoclonal anti-PAR2 antibody (1:1000; Millipore cat#: MABF243), polyclonal anti-NF-κB p65 (1:1000, Abcam cat#: ab7970), anti-phosphorylated NF-κB p65 (1:1000, Abcam cat#: ab106129), or monoclonal anti-β-actin antibody (1:2000; Santa Cruz Biotechnology, cat#: sc-81178). The membranes were washed extensively with Tris-buffered saline and incubated with horseradish peroxidase-conjugated anti-mouse and anti-rabbit IgG antibody (1:10,000; Jackson ImmunoResearch Laboratories Inc., West Grove, PA). The immunoreactivity was detected using enhanced chemiluminescence (ECL Advance Kit; Amersham Biosciences). The intensity of the bands was captured digitally and analyzed quantitatively with Image J software. The immunoreactivities of target proteins were normalized to that of β-actin.
Spinal cord slice preparation and electrophysiological recording
The rats were deeply anesthetized with inhalation of halothane, and the lumbar segment of the spinal cord was removed through laminectomy. The spinal tissue was immediately placed in ice-cold artificial cerebrospinal fluid containing (in mM): sucrose 230, KCl 3.5, MgCl2 1.5, CaCl2 2.0, NaH2PO4 1.2, glucose 12, and NaHCO3 25. Transverse spinal cord slices (400 μm) were cut with a vibratome (Technical Products International, St. Louis, MO), and incubated in Krebs’ solution (containing: 117 mM NaCl, 3.6 mM KCl, 1.2 mM MgCl2, 2.5 mM CaCl2, 1.2 mM NaH2PO4, 11 mM glucose, and 25 mM NaHCO3, bubbled with 95% O2 and 5% CO2) at 35°C for at least 1 h before the recording was performed.
Whole-cell recording on the spinal cord slices (L4-L5) was performed as described previously . The neurons in lamina II of the ipsilateral dorsal horn were visualized using an upright microscope with infrared illumination (BX50WI; Olympus, Tokyo). Whole-cell voltage-clamp recordings were performed using an Axopatch 200B amplifier (Molecular Devices) with 3–5 MΩ glass electrodes containing the following internal solution (in mM): K-gluconate, 126; NaCl, 5; MgCl2 1.2; EGTA, 0.5; Mg-ATP, 2; Na3GTP, 0.1; HEPES, 10; guanosine 5-O-(2-thiodiphosphate) 1; lidocaine N-ethyl bromide (QX314), 10; pH 7.3; 290 – 300 mOsmol. A seal resistance of ≥ 2 GΩ and an access resistance of 15 – 20 MΩ were considered acceptable. The series resistance was optimally compensated by ≥70% and constantly monitored throughout the experiments. The membrane potential was held at -60 mV throughout the experiment. Excitatory postsynaptic currents (EPSCs) in ipsilateral lamina II neurons were evoked by electrical stimulation (0.25 ms, 0.05 – 0.3 mA) of the dorsal root in the presence of strychnine (2 μM) and bicuculline (10 μM). The evoked EPSCs were filtered at 2 kHz, digitized at 10 kHz, and acquired and analyzed using pCLAMP 9.2 software (Molecular Devices).
All data were presented as means ± SEM. For analysis of immunoblotting data, differences between groups were compared by Student’s t-test or ANOVA followed by Fisher’s PLSD post hoc analysis. The electrophysiological and behavioral data were compared with two-way ANOVA with repeated measurements. The criterion for statistical significance was P < 0.05. Statistical tests were performed with SPSS 13.0 (SPSS, USA).
The current work was partially supported by the National Natural Science Foundation Project of China (No. 81273718 and No. 81302961).
- van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J: Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007, 18: 1437–1449. 10.1093/annonc/mdm056PubMedView ArticleGoogle Scholar
- Mantyh P: Bone cancer pain: causes, consequences, and therapeutic opportunities. Pain 2013,154(Suppl 1):S54–62.PubMedView ArticleGoogle Scholar
- Wang XW, Hu S, Mao-Ying QL, Li Q, Yang CJ, Zhang H, Mi WL, Wu GC, Wang YQ: Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats. Mol Brain 2012, 5: 21. 10.1186/1756-6606-5-21PubMed CentralPubMedView ArticleGoogle Scholar
- Mao-Ying QL, Wang XW, Yang CJ, Li X, Mi WL, Wu GC, Wang YQ: Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats. Mol Brain 2012, 5: 16. 10.1186/1756-6606-5-16PubMed CentralPubMedView ArticleGoogle Scholar
- Wang XW, Li TT, Zhao J, Mao-Ying QL, Zhang H, Hu S, Li Q, Mi WL, Wu GC, Zhang YQ, Wang YQ: Extracellular signal-regulated kinase activation in spinal astrocytes and microglia contributes to cancer-induced bone pain in rats. Neuroscience 2012, 217: 172–181.PubMedView ArticleGoogle Scholar
- Ke C, Li C, Huang X, Cao F, Shi D, He W, Bu H, Gao F, Cai T, Hinton AO Jr, Tian Y: Protocadherin20 promotes excitatory synaptogenesis in dorsal horn and contributes to bone cancer pain. Neuropharmacology 2013, 75C: 181–190.View ArticleGoogle Scholar
- Yanagisawa Y, Furue H, Kawamata T, Uta D, Yamamoto J, Furuse S, Katafuchi T, Imoto K, Iwamoto Y, Yoshimura M: Bone cancer induces a unique central sensitization through synaptic changes in a wide area of the spinal cord. Mol Pain 2010, 6: 38. 10.1186/1744-8069-6-38PubMed CentralPubMedView ArticleGoogle Scholar
- Lu Y, Christian K, Lu B: BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 2008, 89: 312–323. 10.1016/j.nlm.2007.08.018PubMed CentralPubMedView ArticleGoogle Scholar
- Trang T, Beggs S, Salter MW: Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain. Neuron Glia Biol 2011, 7: 99–108. 10.1017/S1740925X12000087PubMed CentralPubMedView ArticleGoogle Scholar
- Kobayashi H, Yokoyama M, Matsuoka Y, Omori M, Itano Y, Kaku R, Morita K, Ichikawa H: Expression changes of multiple brain-derived neurotrophic factor transcripts in selective spinal nerve ligation model and complete Freund’s adjuvant model. Brain Res 2008, 1206: 13–19.PubMedView ArticleGoogle Scholar
- Rothmeier AS, Ruf W: Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol 2012, 34: 133–149. 10.1007/s00281-011-0289-1PubMedView ArticleGoogle Scholar
- Bao Y, Hou W, Hua B: Protease-activated receptor 2 signalling pathways: a role in pain processing. Expert Opin Ther Targets 2014, 18: 15–27. 10.1517/14728222.2014.844792PubMedView ArticleGoogle Scholar
- Liu S, Liu YP, Yue DM, Liu GJ: Protease-activated receptor 2 in dorsal root ganglion contributes to peripheral sensitization of bone cancer pain. Eur J Pain 2013. doi:10.1002/j.1532–2149.2013.00372.xGoogle Scholar
- Lee KM, Kang BS, Lee HL, Son SJ, Hwang SH, Kim DS, Park JS, Cho HJ: Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci 2004, 19: 3375–3381. 10.1111/j.0953-816X.2004.03441.xPubMedView ArticleGoogle Scholar
- Sun T, Luo J, Jia M, Li H, Li K, Fu Z: Small interfering RNA-mediated knockdown of NF-kappaBp65 attenuates neuropathic pain following peripheral nerve injury in rats. Eur J Pharmacol 2012, 682: 79–85. 10.1016/j.ejphar.2012.02.017PubMedView ArticleGoogle Scholar
- Boersma MC, Dresselhaus EC, De Biase LM, Mihalas AB, Bergles DE, Meffert MK: A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis. J Neurosci 2011, 31: 5414–5425. 10.1523/JNEUROSCI.2456-10.2011PubMed CentralPubMedView ArticleGoogle Scholar
- Kairisalo M, Korhonen L, Sepp M, Pruunsild P, Kukkonen JP, Kivinen J, Timmusk T, Blomgren K, Lindholm D: NF-kappaB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein. Eur J Neurosci 2009, 30: 958–966. 10.1111/j.1460-9568.2009.06898.xPubMedView ArticleGoogle Scholar
- Sriwai W, Mahavadi S, Al-Shboul O, Grider JR, Murthy KS: Distinctive G protein-dependent signaling by protease-activated receptor 2 (PAR2) in Smooth muscle: feedback inhibition of RhoA by cAMP-Independent PKA. PLoS One 2013, 8: e66743. 10.1371/journal.pone.0066743PubMed CentralPubMedView ArticleGoogle Scholar
- Fu ES, Zhang YP, Sagen J, Candiotti KA, Morton PD, Liebl DJ, Bethea JR, Brambilla R: Transgenic inhibition of glial NF-kappa B reduces pain behavior and inflammation after peripheral nerve injury. Pain 2010, 148: 509–518. 10.1016/j.pain.2010.01.001PubMed CentralPubMedView ArticleGoogle Scholar
- Millan MJ: The induction of pain: an integrative review. Prog Neurobiol 1999, 57: 1–164. 10.1016/S0301-0082(98)00048-3PubMedView ArticleGoogle Scholar
- Tan AM, Waxman SG: Spinal cord injury, dendritic spine remodeling, and spinal memory mechanisms. Exp Neurol 2012, 235: 142–151. 10.1016/j.expneurol.2011.08.026PubMedView ArticleGoogle Scholar
- Bie B, Brown DL, Naguib M: Synaptic plasticity and pain aversion. Eur J Pharmacol 2011, 667: 26–31. 10.1016/j.ejphar.2011.05.080PubMedView ArticleGoogle Scholar
- Tao YX: AMPA receptor trafficking in inflammation-induced dorsal horn central sensitization. Neurosci Bull 2012, 28: 111–120. 10.1007/s12264-012-1204-zPubMed CentralPubMedView ArticleGoogle Scholar
- Chen SR, Zhou HY, Byun HS, Pan HL: Nerve injury increases GluA2-Lacking AMPA receptor prevalence in spinal cords: functional significance and signaling mechanisms. J Pharmacol Exp Ther 2013, 347: 765–772. 10.1124/jpet.113.208363PubMed CentralPubMedView ArticleGoogle Scholar
- Gu X, Zhang J, Ma Z, Wang J, Zhou X, Jin Y, Xia X, Gao Q, Mei F: The role of N-methyl-D-aspartate receptor subunit NR2B in spinal cord in cancer pain. Eur J Pain 2010, 14: 496–502. 10.1016/j.ejpain.2009.09.001PubMedView ArticleGoogle Scholar
- Zhang YK, Huang ZJ, Liu S, Liu YP, Song AA, Song XJ: WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest 2013, 123: 2268–2286. 10.1172/JCI65364PubMed CentralPubMedView ArticleGoogle Scholar
- Wang LN, Yang JP, Ji FH, Zhan Y, Jin XH, Xu QN, Wang XY, Zuo JL: Brain-derived neurotrophic factor modulates N-methyl-D-aspartate receptor activation in a rat model of cancer-induced bone pain. J Neurosci Res 2012, 90: 1249–1260. 10.1002/jnr.22815PubMedView ArticleGoogle Scholar
- Edelmann E, Lessmann V, Brigadski T: Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology 2013, 76 Pt C: 610–627.PubMedGoogle Scholar
- Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R: BDNF as a pain modulator. Prog Neurobiol 2008, 85: 297–317. 10.1016/j.pneurobio.2008.04.004PubMedView ArticleGoogle Scholar
- Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y: BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005, 438: 1017–1021. 10.1038/nature04223PubMedView ArticleGoogle Scholar
- Peng C, Aron L, Klein R, Li M, Wurst W, Prakash N, Le W: Pitx3 is a critical mediator of GDNF-induced BDNF expression in nigrostriatal dopaminergic neurons. J Neurosci 2011, 31: 12802–12815. 10.1523/JNEUROSCI.0898-11.2011PubMedView ArticleGoogle Scholar
- Yuan H, Zhu X, Zhou S, Chen Q, Zhu X, Ma X, He X, Tian M, Shi X: Role of mast cell activation in inducing microglial cells to release neurotrophin. J Neurosci Res 2010, 88: 1348–1354.PubMedGoogle Scholar
- Fan Y, Chen J, Ye J, Yan H, Cai Y: Proteinase-activated receptor 2 modulates corticotropin releasing hormone-induced brain-derived neurotrophic factor release from microglial cells. Cell Biol Int 2013,38(1):92–96.PubMedView ArticleGoogle Scholar
- Dai Y, Wang S, Tominaga M, Yamamoto S, Fukuoka T, Higashi T, Kobayashi K, Obata K, Yamanaka H, Noguchi K: Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Invest 2007, 117: 1979–1987. 10.1172/JCI30951PubMed CentralPubMedView ArticleGoogle Scholar
- Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, Lopez CB, Joseph EK, Levine JD, Liedtke W, Vanner S, Vergnolle N, Geppetti P, Bunnett NW: Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol 2007, 578: 715–733. 10.1113/jphysiol.2006.121111PubMed CentralPubMedView ArticleGoogle Scholar
- Chen Y, Yang C, Wang ZJ: Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience 2011, 193: 440–451.PubMedView ArticleGoogle Scholar
- Huang ZJ, Li HC, Cowan AA, Liu S, Zhang YK, Song XJ: Chronic compression or acute dissociation of dorsal root ganglion induces cAMP-dependent neuronal hyperexcitability through activation of PAR2. Pain 2012, 153: 1426–1437. 10.1016/j.pain.2012.03.025PubMedView ArticleGoogle Scholar
- Liu Q, Weng HJ, Patel KN, Tang Z, Bai H, Steinhoff M, Dong X: The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci Signal 2011, 4: ra45.PubMed CentralPubMedGoogle Scholar
- Liu S, Liu YP, Song WB, Song XJ: EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord. Pain 2013.Google Scholar
- Zhou HY, Chen SR, Chen H, Pan HL: The glutamatergic nature of TRPV1-expressing neurons in the spinal dorsal horn. J Neurochem 2009, 108: 305–318. 10.1111/j.1471-4159.2008.05772.xPubMed CentralPubMedView ArticleGoogle Scholar
- Mantilla CB, Gransee HM, Zhan WZ, Sieck GC: Motoneuron BDNF/TrkB signaling enhances functional recovery after cervical spinal cord injury. Exp Neurol 2013, 247: 101–109.PubMed CentralPubMedView ArticleGoogle Scholar
- Huang Z, Tao K, Zhu H, Miao X, Wang Z, Yu W, Lu Z: Acute PAR2 activation reduces GABAergic inhibition in the spinal dorsal horn. Brain Res 2011, 1425: 20–26.PubMedView ArticleGoogle Scholar
- Li L, Xie R, Hu S, Wang Y, Yu T, Xiao Y, Jiang X, Gu J, Hu CY, Xu GY: Upregulation of cystathionine beta-synthetase expression by nuclear factor-kappa B activation contributes to visceral hypersensitivity in adult rats with neonatal maternal deprivation. Mol Pain 2012, 8: 89. 10.1186/1744-8069-8-89PubMed CentralPubMedView ArticleGoogle Scholar
- Naguib M, Xu JJ, Diaz P, Brown DL, Cogdell D, Bie B, Hu J, Craig S, Hittelman WN: Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system. Anesth Analg 2012, 114: 1104–1120. 10.1213/ANE.0b013e31824b0191PubMed CentralPubMedView ArticleGoogle Scholar
- Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988, 32: 77–88. 10.1016/0304-3959(88)90026-7PubMedView ArticleGoogle Scholar
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