title: 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.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Tokyo 142-8501, Japan. narita@hoshi.ac.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Aiko
authors.initials: A
authors.lastname: Usui
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.forename: Keiichi
authors.initials: K
authors.lastname: Niikura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nozaki
authors.forename: Junaidi
authors.initials: J
authors.lastname: Khotib
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nagumo
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yajima
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007839:Functional Laterality; D024764:Hirudin Therapy / Q000379:methods; D006629:Hirudins / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000494:pharmacology; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D010812:Physical Stimulation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000627:therapeutic use; D044463:Receptor, PAR-1 / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology*; D013917:Thrombin / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D006629:Hirudins; D010982:Platelet-Derived Growth Factor; D044463:Receptor, PAR-1; D020929:Mitogen-Activated Protein Kinase Kinases; D013917:Thrombin