Involvement of endogenous nitric oxide in the mechanism of bradykinin-induced peripheral hyperalgesia

1 When N-G-nitro-L-arginine methyl ester (L-NAME, 0.1-10 nmol) or N-G-monomethyl-L-arginine (L-NMMA, 10 nmol-1 mu mol) was intradermally administered with bradykinin (BK, 3 nmol) into the instep of rat hind-paws, a dose-related suppression of BK-induced hyperalgesia, assessed by the paw-pressure test, was produced. 2 L-Arginine (1 mu mol) but not D-arginine (1 mu mol) reversed the suppressive effects of L-NAME (10 nmol) and L-NMMA (1 mu mol) on BK-induced hyperalgesia. 3 Concomitant intradermal administration of BK (3 nmol) with haemoglobin (1 nmol) significantly suppressed BK-induced hyperalgesia in the paw-pressure test. The BK-induced hyperalgesia was abolished by concomitant intradermal administration of either a guanylate cyclase inhibitor, methylene blue (10 nmol), or LY83583 (1 nmol). In addition, KT5823 (1 nmol) or R(p)-8-bromoguanosine-3':5'-cyclic monophosphothioate (R(p)-8-Br-cGMPS; 1 nmol), an inhibitor of cyclic GMP-dependent protein kinase, also significantly suppressed BK-induced hyperalgesia. 4 The carrageenin-induced hyperalgesia was significantly attenuated by L-NAME in a dose-dependent manner. 5 L-Arginine (1 mu mol), sodium nitroprusside (1 mu mol), dibutyryl cyclic GMP (1 mu mol) or 8-bromo cyclic GMP (1 mu mol) all failed to produce any significant relieving effect on the nociceptive threshold of rodent hind-paws. Concomitant administrations of each agent with a sub-threshold dose (0.1 nmol) of BK induced significant hyperalgesia. 6 R(p)-adenosine 3':5'-cyclic monophosphothioate (R(p)-cAMPS; 1 nmol), an inhibitor of cyclic AMP-dependent protein kinase, significantly suppressed BK-induced mechanical hyperalgesia. Concomitant administration of forskolin (1 nmol) with 8-bromo cyclic GMP (100 nmol) induced significant hyperalgesia. 7 In the superfusion experiment of a blister base on the instep of rodent hind-paws, intradermally administered BK (3 nmol) significantly increased the outflow of both cyclic GMP and cyclic AMP from the blister base. Concomitant administrations of L-NAME (10 nmol) with BK significantly reduced the BK-induced outflow of cyclic GMP without affecting the cyclic AMP content. 8 These results suggest that the NO - cyclic GMP pathway is involved in the mechanism of BK-induced hyperalgesia, and an activation of both cyclic GMP-and cyclic AMP-second messenger system plays an important role in the production of peripherally induced mechanical hyperalgesia.