The aim of this investigation was to evaluate the role played by cyclic nucleotides in the transduction of inflammatory pain and hyperalgesia. Unmyelinated afferents (n=79) were exposed to stable analogues of cyclic AMP and cyclic GMP, to inflammatory mediators and to Methylene Blue, an inhibitor of guanylyl cyclase. Analogues of cyclic AMP at a concentration of 1mM (n=9) but not 10μM (n=16) sensitized nociceptor responses to noxious heat and enhanced interstimulus activity. In addition, mechanical thresholds were moderately, but significantly lowered after superfusion of the cyclic AMP analogue (1mM). Addition of 10μM cyclic AMP analogue to a mixture of excitatory inflammatory mediators (serotonin, histamine, bradykinin and prostaglandin E₂, 10μM each) did not further increase nociceptor activity (n=15), in contrast to a previous report that cAMP sensitized bradykinin responses. Cyclic GMP analogues (10μM, 1mM) did not alter heat sensitivity or mechanical thresholds of polymodal C-fibres, nor did they enhance the ongoing activity that resulted from repeated heat stimulation. After inhibition of guanylyl cyclase with Methylene Blue, cyclic GMP analogues (1–10μM) did not alter nociceptor responses evoked by application of the mixture of inflammatory mediators. The findings indicate that polymodal nociceptor sensitization and excitation is independent of cyclic GMP. Cyclic AMP can obviously contribute to the increased heat sensitivity of inflamed tissue, whereas cyclic GMP might be of importance in the recruitment of “silent” nociceptors.