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Prostaglandin E, Enhances Bradykinin-Stimulated Release of Neuropeptides from Rat Sensory Neurons in Culture

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Prostaglandin E, Enhances Bradykinin-Stimulated Release of Neuropeptides from Rat Sensory Neurons in Culture The Journal of Neuroscience, August 1994, 14(E): 4987-4997 Prostaglandin E, Enhances Bradykinin-stimulated Release of Neuropeptides from Rat Sensory Neurons in Culture M. Ft. Vasko,l** W. B. Campbell,3 and K. J. Waite’ ‘Department of Pharmacology and Toxicology and 2Department of Anesth’esia, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120, and 3Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 Prostaglandins are known to enhance the inflammatory and of these agents produces symptoms characteristic of inflam- nociceptive actions of other chemical mediators of inflam- mation such as vasodilatation and swelling (seereview by Higgs mation such as bradykinin. One possible mechanism for this et al., 1984). Intradermal or intraarterial administration of bra- sensitizing action is that prostanoids augment the release dykinin also elicits nociceptive responsesin animal models of of neuroactive substances from sensory neurons. To initially pain and produces overt pain in man (Ferreira, 1972; Juan and test this hypothesis, we examined whether selected pros- Lembeck, 1974; Manning et al., 199 I ; seealso review by Dray taglandins could enhance the resting or bradykinin-evoked and Perkins, 1993). Administration of prostaglandins in con- release of immunoreactive substance P (ISP) and/or im- centrations similar to those found in inflammatory exudates munoreactive calcitonin gene-related peptide (ICGRP) from does not cause overt pain, but rather increasessensitivity to sensory neurons in culture. Bradykinin alone causes a con- noxious stimuli (Willis and Cornelsen, 1973; Ferreira et al., centration-dependent increase in the release of iSP and 1978; Juan, 1978; Taiwo and Levine, 1989). iCGRP from isolated sensory neurons, and this action is abol- Various components of inflammation result from activation ished in the absence of extracellular calcium. Pretreating the of small-diameter sensory neurons (Bayliss, 1901; Jancsoet al., neurons with PGE, (10 nM to 1 AM) potentiates the bradykinin- 1967; Kenins, 1981; Bessonand Chaouch, 1987; Szolcsanyi, evoked release of both iSP and iCGRP by approximately two- 1988). Thus, it is possiblethat the inflammatory and nociceptive to fourfold. At these concentrations, PGE, alone did not sig- effects of bradykinin and/or prostaglandins originate, in part, nificantly alter peptide release. Exposing the cultures to 1 from an action on these neurons. Indeed, bradykinin receptors AM PGF,,, is ineffective in altering either resting or bradykinin- are found on sensory neurons (Steranka et al., 1988) and the evoked peptide release. Sensory neurons in culture contain intraarterial administration ofbradykinin resultsin an increased cyclooxygenase-like immunoreactivity, suggesting that the firing of small-diameter sensory fibers (Beck and Handwerker, enzyme that converts arachidonic acid to prostaglandins is 1974;Juan and Lembeck, 1974; Kanaka et al., 1985; Kumazawa present. In addition, pretreating cultures with W-arachidon- et al., 199I ). Furthermore, in sensoryneurons grown in culture, ic acid yields radiolabeled eicosanoids that cochromato- bradykinin causesan increase in cell firing (Baccaglini and Ho- graph with known prostaglandin standards. Preexposing cul- gan, 1983) suggestinga direct excitatory action of this agent. tures to indomethacin abolishes the production of Prostaglandins also affect sensory neurons, although the ac- prostaglandins and attenuates the bradykinin-stimulated re- tions are largely to sensitize the neurons to other stimuli. For lease of iSP and ICGRP. This implies that the synthesis of example, Handwerker (1976) showed that prostaglandin E, prostaglandins contributes to the bradykinin-evoked release (PGE,) or prostaglandin E, (PGE,) increased the number of of peptides. The augmentation of bradykinin-induced re- dischargesevoked by thermal stimulation in C-fibers. Similarly, lease of iSP and iCGRP by PGE, may be one mechanism to prostanoids sensitize A-6 fibers (Pateromichelakis and Rood, account for the inflammatory and hyperalgesic actions of 1982) and increasethe firing of group III and IV afferent fibers this eicosanoid. in responseto mechanical stimulation (Mense, 1981; Schaible [Key words: calcitonin gene-related peptide, bradykinin, and Schmidt, 1988). PGE, and PGE, also enhancethe activation release, prostaglandin E2, dorsal root ganglia, sensory neu- of small-diameter sensory nerve fibers elicited by endogenous ron, substance P] or exogenousinflammatory agentssuch as potassium, bradyki- nin, or capsaicin (Chahl and Iggo, 1972: Baccaglini and Hogan, Prostaglandinsand bradykinin are important mediators of var- 1983; Yanagisawa et al., 1986; Schaible and Schmidt, 1988; ious components of the inflammatory responseincluding en- Grubb et al., 199 1). hancedsensitivity to noxious stimuli. Exogenousadministration Although prostaglandinscan increasethe bradykinin-induced excitability of sensory neurons, the question remains as to whether these agents can enhance the bradykinin-stimulated Received Nov. 2, 1993: revised Jan. 27, 1994; accepted Feb. 17, 1994. releaseof neurotransmitters from these neurons. This question This work was supported by PHS I -P60 AR20582- 15 and PHS 1 -ROl DA07 176, and the Showalter Research Trust. We thank Dr. Grant Nicol for the numerous is important becausethe releaseof neuroactive peptides such hours of discussion regarding this work. as substanceP (SP) or calcitonin gene-related peptide (CGRP) Correspondence should be addressed to M. R. Vasko, Ph. D., Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Bam- from sensory nerve terminals in peripheral tissuesmay initiate hill Drive, Indianapolis, IN 46202-5 120. neurogenicinflammation (Foreman, 1987; Payan, 1989) where- Copyright 0 1994 Society for Neuroscience 0270-6474/94/144987-l 1$05,00/O as releaseat terminals in the dorsal spinal cord may enhance 4988 Vasko et al. * PGE, and Bradykinin on Peptide Release pain signaling (Cuello, 1987; Oku et al., 1987; Kuraishi et al., The cells were counted using a hemocytometer and approximately 1988). Thus, augmentation of peptide release by prostaglandins 125,000 cells were added to individual wells of a 24-well Falcon culture dish coated with 0.5 mg/ml rat-tail collagen. Additional medium was may be a mechanism to account for the inflammatory and hy- added to make a final volume of 0.5 ml/well. The wells were incubated peralgesic actions of these agents. We therefore examined the at 37°C in a 5% CO?, 95% air atmosphere, and the medium was changed effects of low concentrations of prostaglandins on the resting every 2 d. and bradykinin-evoked release of SP-like and CGRP-like im- Peptide release protocol. After 9-l 2 d in culture, release studies were munoreactive substances (iSP, iCGRP) from rat sensory neu- performed using a modification of our previously described method (Nicol et al., 1992). The medium was gently aspirated from the culture rons grown in culture. We utilized isolated sensory neurons as dish and the cells washed with 0.5 ml of HEPES buffer consisting of (in a model for studying modulation of release because it allows mM) 22.5 HEPES, 135 NaCI, 3.5 KCI, 1 MgCI,, 2.5 CaCI,, 3.3 glucose, the determination of the direct effects of prostaglandins and 0.1% bovine serum albumin, and 0.003% bacitracin, pH 7.4 and main- bradykinin on peptide release with minimal interference from tained at 36-37°C. Cells were then incubated for three consecutive 10 min periods with 0.4 ml of HEPES buffer. The initial incubation was other neuronal input and from non-neuronal tissues. with HEPES buffer in the absence or presence of PGE?, or PGF2,, to Our results indicate that exposing the neuronal cultures to measure resting release (referred to in the text as basal release). This nanomolar concentrations of PGEz results in a significant en- was followed by incubating the cells for IO min in buffer containing hancement of the bradykinin-stimulated release of both pep- bradykinin in the absence or presence of eicosanoids or 50 mM KC1 substituted for equimolar NaCI. The cells were subsequently exposed tides. Furthermore, the release ofpeptides evoked by bradykinin to HEPES buffer alone to reestablish basal release. Durina each incu- alone is attenuated but not eliminated by pretreating cultures bation, the cells were maintained at 37°C in a 5% CO, environment. with indomethacin. These results and the observation that the After each 10 min incubation, the buffer was removed, aliquoted, and isolated sensory neurons have the capability of synthesizing assayed for iSP and iCGRP as described below. prostaglandins suggest that a component ofthe bradykinin stim- The effect of a drug pretreatment was compared between wells of neurons exposed to a test substance and bradykinin and wells of neurons ulation involves prostaglandins. dissociated and plated at the same time exposed to bradykinin and Preliminary findings from these studies have appeared in ab- vehicle. The vehicle, 1-methyl-2-pyrrolidinone, did not alter either the stract form (Waite and Vasko, 199 1, 1992). basal or bradykinin-stimulated release of iSP or iCGRP. To determine the dependence of release on extracellular calcium, cells were exposed to HEPES buffer minus CaCI, containing 3 mM EGTA during the release protocol. The calculated free calcium concentration using this buffer Materials and Methods was approximately 0.1 nM (Caldwell, 1970). assuming a contamination Materials. All experiments were performed using
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