| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received November 22, 2002
Accepted after revision March 25, 2003
1 University of Minnesota, Department of Veterinary Pathobiology, 1988 Fitch Avenue, St Paul, MN 55108, USA
2 Department of Veterinary Pathobiology, 1988 Fitch Avenue Room 295, University of Minnesota, St Paul, MN 55108, USA
* To whom correspondence should be addressed. E-mail: larso011{at}umn.edu.
The CNS expresses many components of an extracellular protease signalling system, including the protease-activated receptor-1 (PAR-1) whose tethered ligand is generated by thrombin. Activation of PAR-1 potentiates NMDA receptor activity in hippocampal neurons. Because NMDA activity mediates hyperalgesia, we tested the hypothesis that PAR-1 receptors also regulate pain processing. In contrast to the potentiating effect of thrombin in the hippocampus, NMDA-induced behaviours and the transient mechanical hyperalgesia (von Frey fibres) induced by intrathecally injected NMDA in mice were inhibited by thrombin in a dose-related fashion. This anti-hyperalgesic effect was mimicked by SFLLRN, the natural ligand at PAR-1 binding sites, but not SLIGRL-amide, a PAR-2 agonist. The effects of SFLLRN were less potent and shorter in duration than that of thrombin, consistent with its more transient effect on PAR-1 sites. Both thrombin and SFLLRN inhibited acetic acid-induced abdominal stretch (writhing) behaviours, which were also sensitive to NMDA antagonism, but not hot plate or tail flick latencies, which were insensitive to NMDA antagonists. TFLLR-amide, a selective ligand for PAR-1 sites, mimicked the effects of thrombin while RLLFT-amide, an inactive, reverse peptide sequence, did not. In addition, the effect of TFLLR-amide was prevented by RWJ-56110, a PAR-1 antagonist. Thrombin and TFLLR-amide produced no oedema (Evans Blue extravasation) in the spinal cord that would account for these effects. Based on the reported ability of thrombin to mobilize endothelin-1 from astrocytes, we tested the role of this compound in thrombin's activity. BQ123, an endothelin A receptor antagonist, prevented thrombin's inhibition of writhing and NMDA-induced behaviours while BQ788, an endothelin B receptor antagonist, did not. Thus, activation of PAR-1 sites by thrombin in the CNS appears to inhibit NMDA-mediated nociception by a pathway involving endothelin type A receptors.
This article has been cited by other articles:
|
|
 |
|
  R. L. Zhang, C. Zhang, L. Zhang, C. Roberts, M. Lu, A. Kapke, Y. Cui, M. Ninomiya, T. Nagafuji, B. Albala, et al. Synergistic Effect of an Endothelin Type A Receptor Antagonist, S-0139, With rtPA on the Neuroprotection After Embolic Stroke Stroke, October 1, 2008; 39(10): 2830 - 2836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Narita, A. Usui, M. Narita, K. Niikura, H. Nozaki, J. Khotib, Y. Nagumo, Y. Yajima, and T. Suzuki Protease-Activated Receptor-1 and Platelet-Derived Growth Factor in Spinal Cord Neurons Are Implicated in Neuropathic Pain after Nerve Injury J. Neurosci., October 26, 2005; 25(43): 10000 - 10009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Steinhoff, J. Buddenkotte, V. Shpacovitch, A. Rattenholl, C. Moormann, N. Vergnolle, T. A. Luger, and M. D. Hollenberg Proteinase-Activated Receptors: Transducers of Proteinase-Mediated Signaling in Inflammation and Immune Response Endocr. Rev., February 1, 2005; 26(1): 1 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Benjamim, C. Canetti, F. Q. Cunha, S. L. Kunkel, and M. Peters-Golden Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis J. Immunol., February 1, 2005; 174(3): 1616 - 1620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Rohatgi, F. Sedehizade, K. G. Reymann, and G. Reiser Protease-Activated Receptors in Neuronal Development, Neurodegeneration, and Neuroprotection: Thrombin as Signaling Molecule in the Brain Neuroscientist, December 1, 2004; 10(6): 501 - 512. [Abstract] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
