scholarly journals Intrathecal Resiniferatoxin Modulates TRPV1 in DRG Neurons and Reduces TNF-Induced Pain-Related Behavior

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
M. Leo ◽  
M. Schulte ◽  
L.-I. Schmitt ◽  
M. Schäfers ◽  
C. Kleinschnitz ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Intrathecal Injection ◽  
Thermal Hyperalgesia ◽  
Receptor Potential ◽  
Intrathecal Administration ◽  
Transient Receptor Potential Vanilloid ◽  
Therapeutic Approaches ◽  
Transient Receptor

Transient receptor potential vanilloid-1 (TRPV1) is a nonselective cation channel, predominantly expressed in sensory neurons. TRPV1 is known to play an important role in the pathogenesis of inflammatory and neuropathic pain states. Previous studies suggest interactions between tumor necrosis factor- (TNF-) alpha and TRPV1, resulting in a modulation of ion channel function and protein expression in sensory neurons. We examined the effect of intrathecal administration of the ultrapotent TRPV1 agonist resiniferatoxin (RTX) on TNF-induced pain-associated behavior of rats using von Frey and hot plate behavioral testing. Intrathecal injection of TNF induces mechanical allodynia (2 and 20 ng/kg) and thermal hyperalgesia (200 ng) 24 h after administration. The additional intrathecal administration of RTX (1.9 μg/kg) alleviates TNF-induced mechanical allodynia and thermal hyperalgesia 24 h after injection. In addition, TNF increases the TRPV1 protein level and number of TRPV1-expressing neurons. Both effects could be abolished by the administration of RTX. These results suggest that the involvement of TRPV1 in TNF-induced pain offers new TRPV1-based experimental therapeutic approaches and demonstrates the analgesic potential of RTX in inflammatory pain diseases.

scholarly journals Paclitaxel Induces Upregulation of Transient Receptor Potential Vanilloid 1 Expression in the Rat Spinal Cord

2020 ◽  
Vol 21 (12) ◽  
pp. 4341 ◽  
Author(s):  
Yukako Kamata ◽  
Toshie Kambe ◽  
Terumasa Chiba ◽  
Ken Yamamoto ◽  
Kazuyoshi Kawakami ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Thermal Hyperalgesia ◽  
Receptor Potential ◽  
Intrathecal Administration ◽  
Transient Receptor Potential Vanilloid ◽  
Rat Spinal Cord ◽  
Trpv1 Receptor ◽  
Transient Receptor

Painful peripheral neuropathy is a common adverse effect of paclitaxel (PTX) treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia, TRPV1 expression in the rat spinal cord was analyzed after intraperitoneal administration of 2 and 4 mg/kg PTX. PTX treatment increased the expression of TRPV1 protein in the spinal cord. Immunohistochemistry showed that PTX (4 mg/kg) treatment increased TRPV1 protein expression in the superficial layers of the spinal dorsal horn 14 days after treatment. Behavioral assessment using the paw withdrawal response showed that PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia after 14 days was significantly inhibited by oral or intrathecal administration of the TRPV1 antagonist AMG9810. We found that intrathecal administration of small interfering RNA (siRNA) to knock down TRPV1 protein expression in the spinal cord significantly decreased PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia. Together, these results demonstrate that TRPV1 receptor expression in spinal cord contributes, at least in part, to the development of PTX-induced painful peripheral neuropathy. TRPV1 receptor antagonists may be useful in the prevention and treatment of PTX-induced peripheral neuropathic pain.

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

2020 ◽  
Author(s):  
Yaping Yue ◽  
Na Wang ◽  
Yanming Lau ◽  
Yiran Fu ◽  
Hao Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Thermal Hyperalgesia ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Drg Neurons ◽  
Pain Behaviors ◽  
Transient Receptor

Abstract 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.

Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia

2008 ◽  
Vol 294 (5) ◽  
pp. G1288-G1298 ◽  
Author(s):  
Walter E. B. Sipe ◽  
Stuart M. Brierley ◽  
Christopher M. Martin ◽  
Benjamin D. Phillis ◽  
Francisco Bautista Cruz ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Action Potentials ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mechanical Hyperalgesia ◽  
Transient Receptor Potential Vanilloid ◽  
Afferent Neurons ◽  
Nociceptive Neurons ◽  
Afferent Fibers ◽  
Transient Receptor

Protease-activated receptor (PAR2) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR2 cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR2-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR2, and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4+/+ mice, intraluminal PAR2 activating peptide (PAR2-AP) exacerbated VMR to graded CRD from 6–24 h, indicative of mechanical hyperalgesia. PAR2-induced hyperalgesia was not observed in TRPV4−/− mice. PAR2-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4+/+ mice, but not from TRPV4−/− mice. The TRPV4 agonists 5′,6′-epoxyeicosatrienoic acid and 4α-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR2-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR2 increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR2-induced mechanical hyperalgesia and excitation of colonic afferent neurons.

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