Editors' ChoicePain

Cathepsin S's Cuts Cause Pain

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Science's STKE  26 Jun 2007:
Vol. 2007, Issue 392, pp. tw225
DOI: 10.1126/stke.3922007tw225

Chronic pain caused by damage to the nervous system (neuropathic pain) results in part from the immune response in the damaged tissue. Clark et al. provide new insight into how microglial cells (cells of the immune system that function in the central nervous system) contribute to such effects. After partial neuronal ligation of the sciatic nerve in rats, the authors noted (by immunofluorescence microscopy) increased abundance of the protease cathepsin S in microglial cells in the area of the spinal cord where the injured nerve fibers terminated. If they continuously exposed the spinal cord cells to an irreversible inhibitor of cathepsin S in vivo, the hyperalgesia (increased sensitivity to pain) and allodynia (sensation of pain from a stimulus that is not normally painful) experienced by the animals 7 to 14 days after injury was reduced. Administration of recombinant rat cathepsin S, on the other hand, increased hyperalgesia and allodynia in uninjured rats. The authors therefore searched for potential target molecules expected from their protein sequence to be susceptible to cleavage by cathepsin S. One such protein was the membrane-bound chemokine fractalkine, which is expressed on the surface of neuronal cells and activates receptors on microglial cells; the hypothetical cleavage event was expected to release the biologically active extracellular domain of the molecule. Indeed, exposure of cultured neurons to cathepsin S increased release of fractalkine into the culture medium. Furthermore, inhibiting the action of fractalkine with a neutralizing antibody in vivo reduced hyperalgesia and allodynia caused by administration of cathepsin S or fractalkine at the spinal cord. The allodynia produced by administration of cathepsin S was not observed in mice lacking the CX3CR1 receptor for fractalkine. Fractalkine presumably enhances release of other cytokines that enhance perception of pain. Thus the authors propose that blocking these events through inhibition of cathepsin S could provide a mechanism to therapeutically limit chronic pain.

A. K. Clark, P. K. Yip, J. Grist, C. Gentry, A. A. Staniland, F. Marchand, M. Dehvari, G. Wotherspoon, J. Winter, J. Ullah, S. Bevan, M. Malcangio, Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. U.S.A. 104, 10655-10660 (2007). [Abstract] [Full Text]

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