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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 Oct 13; 193:440-51.N

Abstract

Paclitaxel chemotherapy is limited by a long-lasting painful neuropathy that lacks an effective therapy. In this study, we tested the hypothesis that paclitaxel may release mast cell tryptase, which activates protease-activated receptor 2 (PAR2) and, subsequently, protein kinases A and C, resulting in mechanical and thermal (both heat and cold) hypersensitivity. Correlating with the development of neuropathy after repeated administration of paclitaxel, mast cell tryptase activity was found to be increased in the spinal cord, dorsal root ganglia, and peripheral tissues in mice. FSLLRY-amide, a selective PAR2 antagonist, blocked paclitaxel-induced neuropathic pain behaviors in a dose- and time-dependent manner. In addition, blocking downstream signaling pathways of PAR2, including phospholipase C (PLC), protein kinase A (PKA), and protein kinase Cε (PKC), effectively attenuated paclitaxel-induced mechanical, heat, or cold hypersensitivity. Furthermore, sensitized pain response was selectively inhibited by antagonists of transient receptor potential (TRP) V1, TRPV4, or TRPA1. These results revealed specific cellular signaling pathways leading to paclitaxel-induced neuropathy, including the activation of PAR2 and downstream enzymes PLC, PKCε, and PKA and resultant sensitization of TRPV1, TRPV4, and TRPA1. Targeting one or more of these signaling molecules may present new opportunities for the treatment of paclitaxel-induced neuropathy.

Authors+Show Affiliations

Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois, Chicago, IL 60612, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21763756

Citation

Chen, Y, et al. "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, vol. 193, 2011, pp. 440-51.
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;193:440-51.
Chen, Y., Yang, C., & Wang, Z. J. (2011). 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, 193, 440-51. https://doi.org/10.1016/j.neuroscience.2011.06.085
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 Oct 13;193:440-51. PubMed PMID: 21763756.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Chen,Y, AU - Yang,C, AU - Wang,Z J, Y1 - 2011/07/14/ PY - 2011/04/05/received PY - 2011/06/28/revised PY - 2011/06/28/accepted PY - 2011/7/19/entrez PY - 2011/7/19/pubmed PY - 2012/1/19/medline SP - 440 EP - 51 JF - Neuroscience JO - Neuroscience VL - 193 N2 - Paclitaxel chemotherapy is limited by a long-lasting painful neuropathy that lacks an effective therapy. In this study, we tested the hypothesis that paclitaxel may release mast cell tryptase, which activates protease-activated receptor 2 (PAR2) and, subsequently, protein kinases A and C, resulting in mechanical and thermal (both heat and cold) hypersensitivity. Correlating with the development of neuropathy after repeated administration of paclitaxel, mast cell tryptase activity was found to be increased in the spinal cord, dorsal root ganglia, and peripheral tissues in mice. FSLLRY-amide, a selective PAR2 antagonist, blocked paclitaxel-induced neuropathic pain behaviors in a dose- and time-dependent manner. In addition, blocking downstream signaling pathways of PAR2, including phospholipase C (PLC), protein kinase A (PKA), and protein kinase Cε (PKC), effectively attenuated paclitaxel-induced mechanical, heat, or cold hypersensitivity. Furthermore, sensitized pain response was selectively inhibited by antagonists of transient receptor potential (TRP) V1, TRPV4, or TRPA1. These results revealed specific cellular signaling pathways leading to paclitaxel-induced neuropathy, including the activation of PAR2 and downstream enzymes PLC, PKCε, and PKA and resultant sensitization of TRPV1, TRPV4, and TRPA1. Targeting one or more of these signaling molecules may present new opportunities for the treatment of paclitaxel-induced neuropathy. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/21763756/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(11)00806-2 DB - PRIME DP - Unbound Medicine ER -