Glycinergic mediation of tactile allodynia induced by platelet-activating factor (PAF) through glutamate-NO-cyclic GMP signalling in spinal cord in mice
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Our previous study showed that intrathecal (i.t.) injection of platelet-activating factor (PAF) induced tactile allodynia, suggesting that spinal PAF is a mediator of neuropathic pain. The present study further examined the spinal molecules participating in PAF-induced tactile allodynia in mice. I.t. injection of L-arginine, NO donor (5-amino-3-morpholinyl-1,2,3-oxadiazolium (SIN-1) or 3,3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18)) or cGMP analog (8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate; pCPT-cGMP) induced tactile allodynia. PAF- and glutamate- but not SIN-1- or pCPT-cGMP-induced tactile allodynia was blocked by an NO synthase inhibitor. NO scavengers and guanylate cyclase inhibitors protected mice against the induction of allodynia by PAF, glutamate and SIN-1, but not by pCPT-cGMP. cGMP-dependent protein kinase (PKG) inhibitors blocked the allodynia induced by PAF, glutamate, SIN-1 and pCPT-cGMP. To identify signalling molecules through which PKG induces allodynia, glycine receptor α3 (GlyR α3) was knocked down by spinal transfection of siRNA for GlyR α3. A significant reduction of GlyR α3 expression in the spinal superficial layers of mice treated with GlyR α3 siRNA was confirmed by immunohistochemical and Western blotting analyses. Functional targeting of GlyR α3 was suggested by the loss of PGE2-induced thermal hyperalgesia and the enhancement of allodynia induced by bicuculline, a GABAA receptor antagonist in mice after GlyR α3 siRNA treatment. pCPT-cGMP, PAF, glutamate and SIN-1 all failed to induce allodynia after the knockdown of GlyR α3. These results suggest that the glutamate-NO-cGMP-PKG pathway in the spinal cord may be involved in the mechanism of PAF-induced tactile allodynia, and GlyR α3 could be a target molecule through which PKG induces allodynia.
- 2008-09-15
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