ACTIVATION AND RECOVERY OF THE PGE2 -MEDIATED SENSITIZATION OF THE
CAPSAICIN RESPONSE IN RAT SENSORY NEURONS.
J.C. LOPSHIRE and G.D. NICOL.
Medical Neurobiology Program and Department of Pharmacology and Toxicology
Indiana University School of Medicine, Indianapolis, IN USA 46202.
APStracts 4:175N, 1997.
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 AMP 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 2-3 fold, however, this
sensitization was transient even in the continued presence of prostaglandin.
The duration of sensitization produced by PGE2 was inversely related to the
extracellular Ca++ concentration with the shortest recovery times observed in
cells exposed to 2 mM Ca++-Ringer's. Inclusion of the Ca++ chelator, BAPTA, in
the recording pipette greatly lengthened the period of sensitization.
Pretreatment with either the nitric oxide synthase inhibitor, L-NAME, or the
inhibitor of the cyclic GMP-dependent protein kinase, KT-5823, prior to the
application of PGE2 increased the duration of sensitization even in the
presence of 2 mM Ca++. In contrast, after attaining maximal sensitization in 2
mM Ca++-Ringer's containing L-NAME, the addition of either nitric oxide donors
(SIN-1 or SNAP) 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 Ca++
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.
Received 9 May 1997; accepted in final form 30 July 1997.
APS Manuscript Number J384-7.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 28 August 1997