Involvement of TRPV4-NO-cGMP-PKG pathways in the development of thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats.

The aim of the present study was to test the hypothesis that the TRPV4-NO-cGMP-PKG cascade is involved in the maintenance of thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rats. CCD rats showed thermal hyperalgesia and increased nitrite production. Intrathecal administration of ruthenium red (TRPV4 antagonist, 0.1-1 nmol), TRPV4 antisense ODN (TRPV4 AS, 40 microg, daily for 7 days), N(G)-L-nitro-arginine methyl ester (l-NAME, inhibitor of NO synthase, 30-300 nmol), 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor, 50-100 nmol) or 8-(4-Chlorophenylthio) guanosine 3',5'-cyclic Monophosphothioate, Rp-Isomer sodium salt (Rp-8-pCPT-cGMPS, a PKG inhibitor, 25-50 nmol) induced a significant (P<0.001) and dose-dependent increase in the paw withdrawal latency (PWL) compared with control rats, respectively. Ruthenium red (1 nmol), TRPV4 AS (40 microg, daily for 7 days) or L-NAME (300 nmol) decreased nitrite (an index of nitric oxide formation) in the DRG of CCD rats. In addition, the phorbol ester 4alpha-phorbol 12,13-didecanoate (4alpha-PDD, TRPV4 synthetic activator, 1 nmol), co-administered with L-NAME (300 nmol), attenuated the suppressive effect of L-NAME on CCD-induced thermal hyperalgesia and nitrite production. Our data suggested that the TRPV4-NO-cGMP-PKG pathway could be involved in CCD-induced thermal hyperalgesia.