scholarly journals Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

2021 ◽  
Vol 22 (3) ◽  
pp. 991
Author(s):  
Petra Mrozkova ◽  
Diana Spicarova ◽  
Jiri Palecek
Keyword(s):  
Synaptic Transmission ◽  
Dorsal Horn ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Thermal Hyperalgesia ◽  
Dorsal Root Ganglion Neurons ◽  
Peripheral Inflammation ◽  
Transient Receptor Potential Vanilloid ◽  
Behavioral Experiments ◽  
Ganglion Neurons

The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.

scholarly journals Parvalbumin and TRPV1 receptor expression in dorsal root ganglion neurons after acute peripheral inflammation

2009 ◽  
pp. 305-309 ◽  
Author(s):  
G Zachařová ◽  
J Paleček
Keyword(s):  
Dorsal Root Ganglion ◽  
Synaptic Transmission ◽  
Dorsal Root ◽  
Receptor Expression ◽  
Dorsal Root Ganglion Neurons ◽  
Peripheral Inflammation ◽  
Transient Receptor Potential Vanilloid ◽  
Drg Neurons ◽  
Trpv1 Receptors ◽  
Ganglion Neurons

Expression of parvalbumin (PV) and transient receptor potential vanilloid (TRPV1) receptors in the lumbar dorsal root ganglion neurons (DRG) was evaluated in control animals and in rats after acute carageenan-induced knee joint inflammation. PV is a calcium binding protein that acts as a calcium buffer, affects intracellular calcium homeostasis and may thus influence signal transduction and synaptic transmission. TRPV1 receptors are viewed as molecular integrators of nociceptive stimuli and modulate spinal cord synaptic transmission beside their function in the peripheral nerve endings. In naive rats, 13 % of the L4 DRG neurons had PV immunopositivity (PV+) and 36 % expressed TRPV1 receptors (TRPV1+). The soma of the PV+ neurons was of medium to large size, while the TRPV1 receptors were expressed in small diameter neurons. The co-localization of the PV and TRPV1 immunoreactivity was minimal (0.2 %). There was no significant change in the PV+ (11 %), TRPV1+ (42 %) and PV+TRPV1+ (0.25 %) expression, or shift in the neuronal size distribution 28 h after the unilateral peripheral inflammation, both when compared to controls and when ipsilateral to contralateral sides were evaluated. Thus under the given experimental conditions, no change in somatic TRPV1 receptors and PV expression in L4 DRG neurons was found.

scholarly journals Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 775
Author(s):  
Xingjuan Chen ◽  
Yaqian Duan ◽  
Ashley Riley ◽  
Megan Welch ◽  
Fletcher White ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Dorsal Root Ganglion ◽  
Patch Clamp ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Dorsal Root Ganglion Neurons ◽  
Transient Receptor Potential Vanilloid ◽  
Drg Neurons ◽  
Ganglion Neurons

Individuals with end-stage diabetic peripheral neuropathy present with decreased pain sensation. Transient receptor potential vanilloid type 1 (TRPV1) is implicated in pain signaling and resides on sensory dorsal root ganglion (DRG) neurons. We investigated the expression and functional activity of TRPV1 in DRG neurons of the Ins2+/Akita mouse at 9 months of diabetes using immunohistochemistry, live single cell calcium imaging, and whole-cell patch-clamp electrophysiology. 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay was used to determine the level of Reactive Oxygen Species (ROS) in DRGs. Although TRPV1 expressing neuron percentage was increased in Ins2+/Akita DRGs at 9 months of diabetes compared to control, capsaicin-induced Ca2+ influx was smaller in isolated Ins2+/Akita DRG neurons, indicating impaired TRPV1 function. Consistently, capsaicin-induced Ca2+ influx was decreased in control DRG neurons cultured in the presence of 25 mM glucose for seven days versus those cultured with 5.5 mM glucose. The high glucose environment increased cytoplasmic ROS accumulation in cultured DRG neurons. Patch-clamp recordings revealed that capsaicin-activated currents decayed faster in isolated Ins2+/Akita DRG neurons as compared to those in control neurons. We propose that in poorly controlled diabetes, the accelerated rate of capsaicin-sensitive TRPV1 current decay in DRG neurons decreases overall TRPV1 activity and contributes to peripheral neuropathy.

CDK5 inhibits the clathrin-dependent internalization of TRPV1 by phosphorylating the clathrin adaptor protein AP2μ2

2019 ◽  
Vol 12 (585) ◽  
pp. eaaw2040 ◽  
Author(s):  
Jiao Liu ◽  
Junxia Du ◽  
Yun Wang
Keyword(s):  
Drug Targets ◽  
Transient Receptor Potential ◽  
Phosphorylation Site ◽  
Thermal Hyperalgesia ◽  
Adaptor Protein ◽  
Receptor Potential ◽  
Dorsal Root Ganglion Neurons ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor ◽  
Ganglion Neurons

Transient receptor potential vanilloid 1 (TRPV1), a nonselective, ligand-gated cation channel, responds to multiple noxious stimuli and is targeted by many kinases that influence its trafficking and activity. Studies on the internalization of TRPV1 have mainly focused on that induced by capsaicin or other agonists. Here, we report that constitutive internalization of TRPV1 occurred in a manner dependent on clathrin, dynamin, and adaptor protein complex 2 (AP2). The μ2 subunit of AP2 (AP2μ2) interacted directly with TRPV1 and was required for its constitutive internalization. Cyclin-dependent kinase 5 (CDK5) phosphorylated AP2μ2 at Ser45, which reduced the interaction between TRPV1 and AP2μ2, leading to decreased TRPV1 internalization. Intrathecal delivery of a cell-penetrating fusion peptide corresponding to the Cdk5 phosphorylation site in AP2μ2, which competed with AP2μ2 for phosphorylation by Cdk5, increased the abundance of TRPV1 on the surface of dorsal root ganglion neurons and reduced complete Freund’s adjuvant (CFA)–induced inflammatory thermal hyperalgesia in rats. In addition to describing a mechanism of TRPV1 constitutive internalization and its inhibition by CDK5, these findings demonstrate that CDK5 promotes inflammatory thermal hyperalgesia by reducing TRPV1 internalization, providing previously unidentified insights into the search for drug targets to treat pain.

scholarly journals Attenuation of TRPV1 and TRPV4 Expression and Function in Mouse Inflammatory Pain Models Using Electroacupuncture

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Wei-Hsin Chen ◽  
Jason T. C. Tzen ◽  
Ching Liang Hsieh ◽  
Yung Hsiang Chen ◽  
Tzu-Jou Lin ◽  
...  
Keyword(s):  
Inflammatory Pain ◽  
Transient Receptor Potential ◽  
Thermal Hyperalgesia ◽  
Receptor Potential ◽  
Dorsal Root Ganglion Neurons ◽  
Transient Receptor Potential Vanilloid ◽  
Pain Mechanisms ◽  
Electrophysiological Properties ◽  
Pain Models ◽  
Ganglion Neurons

Although pain is a major human affliction, our understanding of pain mechanisms is limited. TRPV1 (transient receptor potential vanilloid subtype 1) and TRPV4 are two crucial receptors involved in inflammatory pain, but their roles in EA- (electroacupuncture-) mediated analgesia are unknown. We injected mice with carrageenan (carra) or a complete Freund’s adjuvant (CFA) to model inflammatory pain and investigated the analgesic effect of EA using animal behavior tests, immunostaining, Western blotting, and a whole-cell recording technique. The inflammatory pain model mice developed both mechanical and thermal hyperalgesia. Notably, EA at the ST36 acupoint reversed these phenomena, indicating its curative effect in inflammatory pain. The protein levels of TRPV1 and TRPV4 in DRG (dorsal root ganglion) neurons were both increased at day 4 after the initiation of inflammatory pain and were attenuated by EA, as demonstrated by immunostaining and Western blot analysis. We verified DRG electrophysiological properties to confirm that EA ameliorated peripheral nerve hyperexcitation. Our results indicated that the AP (action potential) threshold, rise time, and fall time, and the percentage and amplitude of TRPV1 and TRPV4 were altered by EA, indicating that EA has an antinociceptive role in inflammatory pain. Our results demonstrate a novel role for EA in regulating TRPV1 and TRPV4 protein expression and nerve excitation in mouse inflammatory pain models.

scholarly journals Propofol Modulates Agonist-induced Transient Receptor Potential Vanilloid Subtype-1 Receptor Desensitization via  a Protein Kinase Cϵ-dependent Pathway in Mouse Dorsal Root Ganglion Sensory Neurons

2010 ◽  
Vol 113 (4) ◽  
pp. 833-844 ◽  
Author(s):  
Peter J. Wickley ◽  
Ryo Yuge ◽  
Mary S. Russell ◽  
Hongyu Zhang ◽  
Michael A. Sulak ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Dorsal Root Ganglion Neurons ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Transient Receptor ◽  
Ganglion Neurons

Background The activity of transient receptor potential vanilloid subtype-1 (TRPV1) receptors, key nociceptive transducers in dorsal root ganglion sensory neurons, is enhanced by protein kinase C epsilon (PKCepsilon) activation. The intravenous anesthetic propofol has been shown to activate PKCepsilon. Our objectives were to examine whether propofol modulates TRPV1 function in dorsal root ganglion neurons via activation of PKCepsilon. Methods Lumbar dorsal root ganglion neurons from wild-type and PKC& epsilon;-null mice were isolated and cultured for 24 h. Intracellular free Ca concentration was measured in neurons by using fura-2 acetoxymethyl ester. The duration of pain-associated behaviors was also assessed. Phosphorylation of PKCepsilon and TRPV1 and the cellular translocation of PKCepsilon from cytosol to membrane compartments were assessed by immunoblot analysis. Results In wild-type neurons, repeated stimulation with capsaicin (100 nm) progressively decreased the transient rise in intracellular free Ca concentration. After desensitization, exposure to propofol rescued the Ca response. The resensitizing effect of propofol was absent in neurons obtained from PKCepsilon-null mice. Moreover, the capsaicin-induced desensitization of TRPV1 was markedly attenuated in the presence of propofol in neurons from wild-type mice but not in neurons from PKCepsilon-null mice. Propofol also prolonged the duration of agonist-induced pain associated behaviors in wild-type mice. In addition, propofol increased phosphorylation of PKCepsilon as well as TRPV1 and stimulated translocation of PKCepsilon from cytosolic to membrane fraction. Discussion Our results indicate that propofol modulates TRPV1 sensitivity to capsaicin and that this most likely occurs through a PKCepsilon-mediated phosphorylation of TRPV1.

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