Abstract
Signal transduction system involved in the mechanism of peripheral mechanical hyperalgesia was investigated. All drugs were administered intradermally into the instep of rat hind-paws. Bradykinin (BK)-induced hyperalgesia was significantly suppressed by NO-cGMP pathway inhibitors, as well as prostaglandins (PGs)-cAMP pathway inhibitors, in the paw-pressure test. Concomitant administration of BK with Rp-cAMPS, an inhibitor of cAMP-dependent protein kinase (A kinase), or Rp-8-Br-cGMPS, an inhibitor of cGMP-dependent protein kinase (G kinase) also abolished BK-induced hyperalgesia. Concomitant administration of 8-Br-cAMP (10 nmol) with 8-Br-cGMP (10 nmol) produced mechanical hyperalgesia synergistically. When administered alone, high dose of 8-Br-cAMP (30 and 100 nmol), but not 8-Br-cGMP, produced significant hyperalgesia. The hyperalgesia induced by high dose of 8-Br-cAMP was significantly attenuated by Rp-8-Br-cGMPS, as well as Rp-cAMPS. This result suggests that cross-activation of G kinase by cAMP also plays some role in the production of hyperalgesia. However, peripheral hyperalgesia induced by chemical mediators (BK, adenosine, serotonin and glutamate) or carrageenan was significantly suppressed by NO-cGMP pathway inhibitors. This suggests that G kinase is mainly activated through the NO-cGMP pathway in inflammatory state. In conclusion, an activation of both cGMP- and cAMP-second messenger system plays an important role in the production of peripherally induced mechanical hyperalgesia.
