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Inhibitory Effects of Glutamate-Stimulated Astrocytes on Action Potentials Evoked by Bradykinin in Cultured Dorsal Root Ganglion Neurons

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Inhibitory Effects of Glutamate-Stimulated Astrocytes on Action Potentials Evoked by Bradykinin in Cultured Dorsal Root Ganglion Neurons Tokai J Exp Clin Med., Vol. 39, No. 1, pp. 14-24, 2014 Inhibitory Effects of Glutamate-stimulated Astrocytes on Action Potentials Evoked by Bradykinin in Cultured Dorsal Root Ganglion Neurons Kazuo SUZUKI, Minehisa ONO and Kenji TONAKA Department of Biomedical Engineering, Tokai University (Received September 26, 2013; Accepted January 20, 2014) Patch-clamp and Ca2+-imaging techniques have revealed that astrocytes have dynamic properties including ion channel activity and release of neurotransmitters, such as adenosine triphosphate (ATP) and glutamate. Here, we used the patch-clamp technique to determine whether ATP and glutamate is able to modulate the bradykinin (BK) response in neurons cultured with astrocytes in the mouse dorsal root ganglia (DRG) in order to clarify the role of astrocytes in nociceptive signal transmission. Astrocytes were identified using a fluorescent anti-GFAP antibody. The membrane potential of astrocytes was about －39 mV. The application of glutamic acid (GA) to the bath evoked the opening of two types of Cl－ channel in the astrocyte cell membrane with a unit conductance of about 380 pS and 35 pS in the cell-attached mode, respectively. ATP application evoked the opening of two types of astrocyte K+ channel with a unit conductance of about 60 pS and 29 pS, respectively. Application of BK to the neuron evoked an action potential (spike). Concomitant BK application with ATP increased the frequency of BK-evoked neuron spikes when neurons coexisted with astrocytes. Stimulation of BK with GA inhibited the BK-evoked spike under similar conditions. The application of furosemide, a potent cotransporter (Na+-K+-2Cl－) inhibitor, prior to stimulation of BK with GA blocked inhibition of the spike. It is thought that inhibition of the spike is related to Cl－ movement from astrocytes. Key words: astrocyte, glutamate, chloride channel, allodynia, dorsal root ganglion ganglia (DRG) are activated by BK [10]. In the present INTRODUCTION study, the electrophysiological properties of cultured Glial cells (glia), including astrocytes and oligoden- astrocytes were investigated using the patch-clamp drocytes, have traditionally been considered the sup- technique. Specifically, we studied the inhibitory ef- porting cells of the nervous system. However, recently fects of glutamate-stimulated astrocytes on the action developed patch-clamp techniques and Ca2+-imaging potentials of cultured neurons stimulated by BK in the technology have revealed that astrocytes have dynamic cell body when neurons coexisted with astrocytes. properties, including ion channel activity, release of MATERIALS AND METHODS neurotransmitters such as ATP and glutamate, as well as signal transmission in the neuronal network of the Cells central nervous system [1, 2]. Free nerve endings of The following procedures were performed in ac- pain sensory cells are activated or sensitized by pain-re- cordance with the Guidelines for the Care and Use lated stimuli and also by compounds that are released of Animals for Science Purposes at Tokai University. locally in damaged tissue [3, 4]. Of these compounds, Mice (Jcl: ICR; age, 7-8 weeks; male) were obtained bradykinin (BK), prostaglandins (PG) and amines acti- from CLEA Japan (Shizuoka, Japan). Animals had free vate the pain sensory endings, and are thought to play access to water and food until the day of the experi- a role in pain associated with injury and inammation ment. Mice were killed by section of the neck above [3, 4]. It has been suggested that glial cells contribute the spinal column under anesthesia with diethyl ether. to enhanced pain. Activated glial cells release pain- About 40-45 DRG were aseptically removed from each enhancing substances, such as nitric oxide (NO), ATP, mouse. DRG were dissociated in 2 ml of Ham＇s F12 PG, excitatory amino acids (EAA), interleukins (IL1, medium with 0.2% collagenase at 37ºC for 90 min in IL6) and tumor necrosis factor (TNF) [5]. a shaking bath. After a further 15 min of incubation On the other hand, it has been reported that gluta- in Ca2+ - and Mg2+ -free Hank＇s balanced salt solution mate microinjection into the lateral reticular nucleus (HBSS) containing 0.25% trypsin, tissue was triturated [6] and the nucleus raphe magnus [7] in the medulla, in HBSS containing a trypsin inhibitor (0.05 mg/ml) and the locus coeruleus/subcoeruleus in the pons [7, and was added to a 30% Percoll solution. It was then 8], reduced the neuronal response to skin heating. subjected to density gradient centrifugation at 200 x Glutamate microinjection into the locus coeruleus in g for 4 min, resulting in a yield of more than 5 x 104 the dorsolateral pons reduced the nociceptive tail-ick neurons per mouse with high purity. The dispersed reex [9]. Our previous study demonstrated that free neurons were washed three times with F12 containing nerve endings of cultured neurons from dorsal root 10% fetal bovine serum (FBS), and were seeded onto Kazuo SUZUKI, Department of Biomedical Engineering, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan Tel: +81-463-93-1121 Fax: +81-463-93-1167 E-mail: [email protected] ―14― K. SUZUKI et al. / Glutamate-stimulated Astrocyte Inhibits Nociceptive Signal Transmission 35-mm culture dishes coated with poly-L-lysine. Cell (KS609; Sony, Tokyo, Japan) for subsequent replay and density was adjusted to 3 x 103 cells/cm2. DRG neurons analysis. Current amplitude was obtained by measur- were kept in medium and were allowed to adhere to ing the amplitude of the current on the recorder chart the substrate for 4 h in a humidied atmosphere con- with Vernier calipers. taining 5% CO2 at 37ºC. Culture solution containing cellular debris was removed and replaced with fresh Chemicals medium containing 10% FBS and 100 ng/ml 7S nerve Percoll and mouse nerve growth factor (7S growth factor (NGF). After 24 h, culture solution was mNGF) were purchased from Amersham Biosciences removed and replaced with serum-free Ham＇s F12 (Piscataway, NJ) and Alomone Labs (Jerusalem, Israel), culture medium containing 5 µg/ml insulin, 5 µg/ml respectively. Pyridoxal phosphate-6-azo-tetrasodium transferrin, 2 nM progesterone, 0.1 mM putrescine, salt, DL-2-amino-3-phosphonopropionic acid, and 3 mM selenium and 100 ng/ml NGF. Medium was NS102 were obtained from Sigma. changed every other day. In DRG culture, cells smaller RESULTS than 25 µm in diameter were used in all experiments. Cell size (smaller than 25 µm), resting potential char- 1. Electrophysiological properties of astrocytes acteristics (around －45 mV), and long spike duration Chloride channels (10-15 ms), indicated that the cells used in the experi- Glial astrocytes were identified using an antibody ments were unmyelinated C-bers [10]. against GFAP and were visualized with a fluorescent In order to extract astrocytes, the layer including secondary antibody. A polygonal shaped cell was used astrocytes and tissue debris was separated from above for patch-clamp recording. Membrane potential (intra- the Percoll layer in the centrifuge tube. It was then cellular potential) was recorded using current-clamp subjected to density gradient centrifugation, as de- mode in the whole-cell configuration of the patch- scribed above, to remove tissue debris. Dispersed astro- clamp technique. The membrane potential was －39.5 cytes were seeded onto 35-mm culture dishes coated ± 1.7mV (mean ± SEM, n = 33). DRG astrocytes were with poly-L-lysine. Same medium without NGF was mostly silent with respect to ion channel activity. In used as a culture solution. To culture neurons with as- the central nervous system, glutamate is known to act trocytes, neurons were seeded onto astrocytes that had as a neurotransmitter, and in astrocytes, it induces a been cultured for 5-7 days in culture dishes. Neurons response resulting in Ca2+-changes [1, 11]. Glutamate＇s accompanied by astrocytes were cultured for 3-4 days ability to evoke the opening of the Cl－ channels in in the same culture medium with NGF, as described DRG astrocytes was assessed. When glutamic acid (GA) for the neuron-culture methods, and the patch-clamp (20 µM, final concentration) was added to the bath experiment was performed. solution, single-channel currents were observed in the Glial cells were identied by uorescence microsco- cell-attached conguration using a pipette containing py (TMD-EFQ; Nikon, Tokyo, Japan) and a rabbit poly- Na+-rich solution, which contained 2.5 mM Ca2+ (Fig. clonal antibody against glial fibrillary acidic protein 1A). The unitary conductance of the single-channel (GFAP) (G9269; Sigma, St. Louis, MO). Binding was was about 380.6 ± 21.8 pS (mean ± SEM, n = 8). The detected with fluorescein-conjugated goat anti-rabbit Cl－ equilibrium potential was about －30 mV under secondary antibody (anti-rabbit IgG FITC conjugate, the quasi-physiological ion concentration, given that F1262; Sigma) using UV irradiation. Cells were fixed the internal Cl－ concentration of glial cells is about 40 using 4% paraformaldehyde in phosphate buffered sa- mM [12]. The membrane potential of astrocytes was line for 15 min, and then using acid alcohol (methanol) about －39 mV, and the reversal (null) potential was at －20ºC for 10 min prior to incubation with primary between 0 mV and －10 mV of the pipette potential antibody (60 min) and secondary antibody (30 min). (VP) (Fig. 1B). This channel must be Cl－ selective, as in this experimental situation, the only ion with a Patch-clamp recordings reversal potential of around 0 mV of VP is Cl－. Membrane potentials (intracellular potential) and Ca2+-sensitivity of the Cl－ channel was assessed un- single-channel currents were recorded using the patch- der conditions when the Cl－ channel was certain to be clamp technique. Voltage recordings were obtained by observed using a pipette containing Na+-rich solution the whole-cell current-clamp method. Single-channel (145 mM Cl－); the patch membrane was excised to current recordings were obtained using the voltage- create an inside-out conguration.
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