Activation and Recovery of the PGE₂-Mediated Sensitization of the Capsaicin Response in Rat Sensory Neurons

Abstract

Pro-inflammatory prostaglandins are known to enhance the sensitivity of sensory neurons to various modalities of stimulation, including the excitatory chemical agent, capsaicin. In this report, we examined the capacity of prostaglandin E2 (PGE2) to enhance the capsaicin response recorded from sensory neurons isolated from embryonic rats and grown in culture. Previous work demonstrated that the cyclic adenosine 3',5'-monophosphate pathway mediates initiation of the PGE2-induced sensitization, however, little is known about the pathways regulating the recovery from sensitization. Therefore, we examined the neuronal transduction cascades that control the duration of sensitization. Treatment with PGE2 enhanced the capsaicin-evoked current by two- to threefold, however, this sensitization was transient even in the continued presence of prostaglandin. The duration of sensitization produced by PGE2 was related inversely to the extracellular Ca2+ concentration with the shortest recovery times observed in cells exposed to 2 mM Ca2+-Ringer. Inclusion of the Ca2+ chelator, bis-(o-aminophenoxy)-N, N,N',N'-tetraacetic acid, in the recording pipette greatly lengthened the period of sensitization. Pretreatment with either the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME), or the inhibitor of the cyclic guanosine 3', 5'-monophosphate (GMP)-dependent protein kinase, KT-5823, before the application of PGE2 increased the duration of sensitization even in the presence of 2 mM Ca2+. In contrast, after attaining maximal sensitization in 2 mM Ca2+-Ringer containing L-NAME, the addition of either nitric oxide donors (3-morpholinosydnonimine or s-nitroso-n-acetylpenicillamine) or 8-Br-cyclic GMP led to a rapid decrease in the level of sensitization. In the absence of sensitization, nitric oxide-cyclic GMP modulating agents had no effect on the capsaicin-evoked current. Therefore, these results suggest that capsaicin-induced elevations in intracellular Ca2+ levels lead to an enhanced production of cyclic GMP, via the nitric oxide pathway, that ultimately activates cyclic GMP-dependent protein kinase. This protein kinase inactivates or terminates the sensitization produced by PGE2 by an as yet unidentified mechanism.

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

“…Recordings were made using the perforated patch-clamp technique (Horn and Marty 1988;Rae et al 1991;Lopshire and Nicol 1997). Briefly, a cover slip with the sensory neurons was placed in a recording chamber where neurons were bathed in normal Ringers of the following composition (in mM): 140 NaCl, 5 KCl, 2 CaCl 2 , 1 MgCl 2 , 10 HEPES and 10 glucose, pH at 7.4 with NaOH.…”

Prostaglandin E2 Has No Effect on Two Components of Tetrodotoxin-Resistant Na+ Current in Mouse Dorsal Root Ganglion

“…Upregulation of the capsaicin-induced inward current by PGE 2 There may be a possibility that our experimental condition includes some unidentified fatal defect in producing the effect of PGE 2 . We finally examined this possibility by checking the effect of PGE 2 on the capsaicin-induced inward current, since this current is also known to be upregulated by PGE 2 (29). As shown in Fig.…”

Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype

“…This is partly due to the fact that PGs facilitate nociception at different levels of integration (13). They do not only sensitize peripheral nociceptors (14)(15)(16) but can also lead to changes in the central, particularly spinal, processing of nociceptive input (17,18). It is hence still unclear which PGs and which PG receptors mediate pain sensitization in the periphery and in the spinal cord, respectively, and to what extent the 2 sites contribute to inflammatory hyperalgesia.…”