Role of nerve growth factor-tyrosine kinase receptor A signaling in paclitaxel-induced peripheral neuropathy in rats

• Published in: Biochemical and biophysical research communications Vol. 444; no. 3; pp. 415 - 419
• Main Authors: Nakahashi, Yusuke, Kamiya, Yoshinori, Funakoshi, Kengo, Miyazaki, Tomoyuki, Uchimoto, Kazuhiro, Tojo, Kentaro, Ogawa, Kenichi, Fukuoka, Tetsuo, Goto, Takahisa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.02.2014
• Subjects: Animals; Base Sequence; Brain-Derived Neurotrophic Factor - metabolism; DNA Primers; Dorsal root ganglia; Male; Nerve growth factor; Nerve Growth Factor - metabolism; Paclitaxel; Paclitaxel - pharmacology; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - enzymology; Peripheral Nervous System Diseases - metabolism; Peripheral neuropathy; Rats; Rats, Sprague-Dawley; Receptor, trkA - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Spinal dorsal horn; Tyrosine kinase receptor A; NEDD4-2; p75NTR; DH; BDNF; Nerve growth factor; I.P; NGF; Peripheral neuropathy; I.T; Tyrosine kinase receptor A; SNL; Spinal dorsal horn; TrkB; TrkA; Dorsal root ganglia; Paclitaxel; DRG; qPCR; SKIN; SN
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.01.082

•Paclitaxel administration induced painful neuropathy in rats.•NGF and trkA levels are increased in the DRG of paclitaxel-treated rats.•NGF and trkA increases are independent from Transcription or degradation.•Intrathecal administration of k252a partially attenuated pain behaviors. The mechanisms underlying paclitaxel-induced peripheral neuropathy remain unknown. Nerve growth factor (NGF) is a representative neurotrophic factor that maintains neuronal function, promotes survival, and mediates neuropathic pain. We investigated expression levels of NGF and its receptors in the dorsal root ganglia (DRG) and spinal dorsal horn (DH) following paclitaxel treatment. Intraperitoneal (I.P.) administration of paclitaxel induced significant mechanical hypersensitivity and cold allodynia in rats, significantly increased the expression of NGF and its receptor tyrosine kinase receptor A (trkA) in the DRG, and increased NGF expression in the DH. In contrast, paclitaxel treatment did not alter the mRNA levels of NGF or its receptors in the DRG, DH, sciatic nerve, or hindpaw skin. Moreover, expression of NEDD4-2, a negative regulator of trkA, was significantly increased in the DRG of paclitaxel-treated rats. Intrathecal (I.T.) administration of the tyrosine kinase receptor inhibitor k252a significantly alleviated mechanical hypersensitivity in paclitaxel-treated rats. Our results suggest that NGF–trkA signaling is involved in mechanical allodynia in paclitaxel-induced neuropathy.