Sensitization of C-fibres by prostaglandin E(2) in the rat is inhibited by guanosine 5'-O-(2-thiodiphosphate), 2'.5'-dideoxyadenosine and Walsh inhibitor peptide

Behavioral studies have shown that mechanical hyperalgesia induced by intradermal injection of prostaglandin E(2) is blocked by inhibitors of the cAMP second messenger system. Similarly, injection of prostaglandin E(2) also induces a decrease in mechanical threshold and an increase in the number of action potentials elicited by test stimuli in most C-fibre nociceptors. This change is called sensitization. To further evaluate the degree of correlation between primary afferent sensitization and mechanical hyperalgesia, we conducted a study to evaluate the effect of agents known to block the cAMP second messenger system and behavioral manifestations of mechanical hyperalgesia following injection of prostaglandin E(2). The agents tested were guanosine 5'-O-(2-thiodiphosphate), an inhibitor of stimulatory guanine nucleotide-binding regulatory proteins; 2'.5'-dideoxyadenosine, an inhibitor of adenylyl cyclase; and Walsh Inhibitor Peptide, an inhibitor of cAMP-dependent protein kinase. Single fibre electrophysiologic studies of 138 C-fibres, innervating the dorsum of the hind paw, was done in male Sprague-Dawley rats. The number of spikes evoked by a 10 s application of a threshold von Frey hair were determined before and after intradermal injection of test agents administered alone and in combination with prostaglandin E(2). Injection of prostaglandin E(2) with the test agent vehicle (saline or distilled water) resulted in a significant decrease in von Frey hair threshold and an increase in the number of spikes generated in response to threshold von Frey hairs. In contrast, co-injection of prostaglandin E(2) with guanosine-5'-O-(2-thiodiphosphate), 2'.5'-dideoxyadenosine or Walsh inhibitor peptide did not result in a significant decrease in von Frey hair mechanical threshold or increase in the number of spikes generated to the threshold stimuli, compared with vehicle/prostaglandin E(2). It is suggested that guanosine 5'-O-(2-thiodiphosphate), 2'.5'-dideoxyadenosine and Walsh inhibitor protein inhibited prostaglandin E(2) sensitization of primary afferent C-fibres by inhibiting a stimulatory guanine nucleotide-binding regulatory protein, adenylyl cyclase, and protein kinase A, respectively. These results support the hypothesis that primary afferent sensitization by prostaglandin E(2), underlies prostaglandin E(2)-induced hyperalgesia.