ACTIVATION AND RECOVERY OF THE PGE(2)-MEDIATED SENSITIZATION OF THE CAPSAICIN RESPONSE IN RAT SENSORY NEURONS

Pro-inflammatory prostaglandins are known to enhance the sensitivity o f sensory neurons to various modalities of stimulation, including the excitatory chemical agent, capsaicin. In this report, we examined the capacity of prostaglandin E-2 (PGE(2)) to enhance the capsaicin respon se recorded from sensory neurons isolated from embryonic rats and grow n in culture. Previous work demonstrated that the cyclic adenosine 3', 5'-monophosphate pathway mediates initiation of the PGE(2)-induced sen sitization, however, little is known about the pathways regulating the recovery from sensitization. Therefore, we examined the neuronal tran sduction cascades that control the duration of sensitization. Treatmen t with PGE(2) enhanced the capsaicin-evoked current by two-to threefol d, however, this sensitization was transient even in the continued pre sence of prostaglandin. The duration of sensitization produced by PGE, was related inversely to the extracellular Ca2+ concentration with th e shortest recovery times observed in cells exposed to 2 mM Ca2+-Ringe r. Inclusion of the Ca2+ chelator, bis-(o-aminophenoxy)-N,N,N',N'-tetr aacetic acid, in the recording pipette greatly lengthened the period o f sensitization. Pretreatment with either the nitric oxide synthase in hibitor, nitro-l-arginine methyl ester (L-NAME), or the inhibitor of t he cyclic guanosine 3',5'-monophosphate (GMP)-dependent protein kinase , KT-5823, before the application of PGE(2) increased the duration of sensitization even in the presence of 2 mM Ca2+. In contrast, after at taining maximal sensitization in 2 mM Ca2+-Ringer containing L-NAME, t he addition of either nitric oxide donors (3-morpholinosydnonimine or s-nitroso-n-acetylpenicillamine) or 8-Br-cyclic GMP led to a rapid dec rease in the level of sensitization. In the absence of sensitization, nitric oxide-cyclic GMP modulating agents had no effect on the capsaic in-evoked current. Therefore, these results suggest that capsaicin-ind uced elevations in intracellular Ca2+ levels lead to an enhanced produ ction of cyclic GMP, via the nitric oxide pathway, that ultimately act ivates cyclic GMP-dependent protein kinase. This protein kinase inacti vates or terminates the sensitization produced by PGE(2) by an as yet unidentified mechanism.