Protease-activated receptor-1 and platelet-derived growth factor in spinal cord neurons are implicated in neuropathic pain after nerve injury.

Abstract

Recently, it has been reported that both thrombin-sensitive protease-activated receptor 1 (PAR-1) and platelet-derived growth factor (PDGF) are present not only in platelets, but also in the CNS, which indicates that they have various physiological functions. In this study, we evaluated whether PAR-1/PDGF in the spinal cord could contribute to the development of a neuropathic pain-like state in mice. Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were significantly suppressed by repeated intrathecal injection of hirudin, which is characterized as a specific and potent thrombin inhibitor. Furthermore, a single intrathecal injection of thrombin produced long-lasting hyperalgesia and allodynia, and these effects were also inhibited by hirudin in normal mice. In nerveligated mice, the increase in the binding of [35S]GTPgammaS to membranes of the spinal cord induced by thrombin and PAR-1-like immunoreactivity (IR) in the spinal cord were each greater than those in sham-operated mice. Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were also suppressed by repeated intrathecal injection of either the PDGF alpha receptor (PDGFRalpha)/Fc chimera protein or the PDGFR-dependent tyrosine kinase inhibitor AG17 [(3,5-di-tert-butyl-4-hydroxybenzylidene)-malononitrile]. Moreover, thermal hyperalgesia and tactile allodynia induced by thrombin in normal mice were virtually eliminated by intrathecal pretreatment with PDGFRalpha/Fc. In immunohistochemical studies, PAR-1-like IR-positive cells in the spinal dorsal horn were mostly colocated on PDGF-like IR-positive neuronal cells. These data provide novel evidence that PAR-1 and PDGF-A-mediated signaling pathway within spinal cord neurons may be directly implicated in neuropathic pain after nerve injury in mice.

• Authors: Minoru Narita, Aiko Usui, Michiko Narita, Keiichi Niikura, Hiroyuki Nozaki, Junaidi Khotib, Yasuyuki Nagumo, Yoshinori Yajima, Tsutomu Suzuki
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 25 Issue 43 Pg. 10000-9 (Oct 26 2005) ISSN: 1529-2401 [Electronic] United States
• PMID: 16251448 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Hirudins
• Platelet-Derived Growth Factor
• Receptor, PAR-1
• Mitogen-Activated Protein Kinase Kinases
• Thrombin

Topics

• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Functional Laterality
• Hirudin Therapy (methods)
• Hirudins (pharmacology)
• Immunohistochemistry (methods)
• Male
• Mice
• Mitogen-Activated Protein Kinase Kinases (pharmacology)
• Neuralgia (etiology, metabolism)
• Neurons (drug effects, metabolism)
• Pain Measurement (methods)
• Physical Stimulation
• Platelet-Derived Growth Factor (metabolism, therapeutic use)
• Receptor, PAR-1 (metabolism)
• Sciatic Neuropathy (complications, drug therapy, metabolism)
• Spinal Cord (cytology)
• Thrombin (therapeutic use)
• Time Factors