Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. Src homology 2 domain-containing tyrosine phosphatase 1 (Shp-1) is a key phosphatase dephosphorylating TRPV1. In this study, we reported that Shp-1 colocalized with and bound to TRPV1 in nociceptive DRG neurons. Shp-1 inhibitors, including sodium stibogluconate and PTP inhibitor III, sensitized TRPV1 in cultured DRG neurons. In naive rats, intrathecal injection of Shp-1 inhibitors increased both TRPV1 and tyrosine-phosphorylated TRPV1 in DRGs and induced thermal hyperalgesia, which was abolished by pretreatment with TRPV1 antagonists capsazepine, BCTC, or AMG9810. Complete Freund's adjuvant (CFA)–induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.
The inhibition of protein-tyrosine phosphatase Shp-1 sensitized TRPV1 in rat dorsal root ganglions, decreased normal nociceptive throsholds, and aggravated inflammatory pain that was alleviated by Shp-1 overexpression.
aNeuroscience Research Institute, Peking University, Beijing, China
bClinical Molecular Laboratory, Peking University People's Hospital, Beijing, China
cDepartment of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China
dKey Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Beijing, China
Corresponding author. Address: Neuroscience Research Institute, Peking University, 38 Xueyuan Road, Beijing 100191, China. Tel.: +86-10-8280.5185. E-mail address: email@example.com (Y. Wan).
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Received July 18, 2014
Received in revised form November 18, 2014
Accepted December 17, 2014