Pharmacological modulation of secondary mediator systems - cyclic AMP and cyclic GMP - on inflammatory hyperalgesia

1 The objective of the present paper was to evaluate the relevance of neuro nal balance of cyclic AMP and cyclic GMP concentration for functional regul ation of nociceptor sensitivity during inflammation. 2 Injection of PGE(2) (10-100 ng paw(-1)) evoked a dose-dependent hyperalge sic effect which was mediated rin a cyclic AMP-activated protein kinase (PK A) inasmuch as hyperalgesia was blocked by the PKA inhibitor H89. 3 The PDE4 inhibitor rolipram and RP73401, but not PDE3 and PDE5 inhibitors potentiated the hyperalgesic effects of PGE(2). The hyperalgesic effect of dopamine was also enhanced by rolipram. Moreover, rolipram significantly p otentiated hyperalgesia induced by carrageenan, bradykinin, TNF alpha, IL-1 beta, IL-6 and IL-8. This suggests that neuronal cyclic AMP mediates the p rostanoid and sympathetic components of mechanical hyperalgesia. Moreover, in the neuron cyclic AMP is mainly metabolized by PDE4. 4 To examine the role of the NO/cyclic GMP pathway in modulating mechanical hyperalgesia, we tested the effects of the soluble guanylate cyclase inhib itor, ODQ. This substance counteracts the inhibitory effects of the NO dono r, SNAP, on the hyperalgesia induced by PGE(2). 5 The ODQ potentiated hyperalgesia induced by carrageenan, bradykinin, TNF alpha, IL-1 beta, IL-6 and IL-8. In contrast, ODQ had no significant effect on the hyperalgesia induced by PGE(2) and dopamine. This indicates that th e hyperalgesic cytokines may activate soluble guanylate cyclase, which down -regulate the ability of these substances to cause hyperalgesia. This event appears not to be mediated by prostaglandin or dopamine. 6 In conclusion, the results presented in this paper confirm an association between (i) hyperalgesia and elevated levels of cyclic AMP as well as (ii) antinociception and elevated levels of cyclic GMP. The intracellular level s of cyclic AMP that enhance hyperalgesia are controlled by the PDE4 isofor m and appear to result in activation of protein kinase A whereas the intrac ellular levels of cyclic GMP results from activation of a soluble guanylate cyclase.