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ANESTHETIC PHARMACOLOGY

The Effects of General Anesthetics on P2X₇ and P2Y Receptors in a Rat Microglial Cell Line

Mika Nakanishi, MD^*, Takashi Mori, MD, PhD^*, Kiyonobu Nishikawa, MD, PhD^*, Makoto Sawada, PhD, Miyuki Kuno, MD, PhD, and Akira Asada, MD, PhD^*

From the *Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; Department of Brain Science, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan; and Department of Physiology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Address correspondence to Mika Nakanishi, MD, Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, 1-5-7 Asahi-machi, Abeno-ku, Osaka 545-8586, Japan. Address e-mail to m1383144{at}med.osaka-cu.ac.jp.

BACKGROUND: Microglial cells play important roles in coordinating the inflammatory brain responses to hypoxia and trauma. Ionotropic P2X receptors and metabotropic P2Y receptors (P2YRs) expressed in microglia can be activated by extracellular adenosine triphosphate (ATP) derived from damaged cells or astrocytes, and participate in the signaling pathways evoked in brain insult. Although several inhaled and IV anesthetics produce neuroprotective effects through neuronal mechanisms, little is known about how general anesthetics modulate microglial responses in the pathological state. We examined the effects of various general anesthetics on purinergic responses in a rat microglial cell line.

METHODS: Currents were consistently activated by applications of ATP via a U-tube system under the whole-cell configuration. ATP-induced nondesensitizing currents observed after several applications of ATP exhibited characteristics of P2X₇ receptors. The P2YRs-mediated mobilization of intracellular Ca²⁺ was measured using a Ca²⁺-sensitive fluorescent dye (fura-2).

RESULTS: Inhaled anesthetics (sevoflurane, isoflurane, and halothane) at doses three times as high as minimum alveolar concentrations had no effect on the P2X₇Rs-mediated currents. IV anesthetics (ketamine, propofol, and thiopental) enhanced the P2X₇Rs-mediated currents reversibly. The potencies for activation of P2X₇Rs were not correlated with the octanol/buffer partition coefficients. Thiopental, at low concentrations, slightly inhibited the P2X₇Rs-mediated currents, suggesting its dual actions on P2X₇Rs. The P2YRs-mediated mobilization of intracellular Ca²⁺ was not affected by any of the general anesthetics tested.

CONCLUSIONS: Our results suggest that IV anesthetics, particularly thiopental and propofol, may modulate microglial functions through P2X₇Rs in pathological conditions.