Ultralow concentrations of bupivacaine exert anti‐inflammatory effects on inflammation‐reactive astrocytes

Bupivacaine is a widely used, local anesthetic agent that blocks voltage‐gated Na + channels when used for neuro‐axial blockades. Much lower concentrations of bupivacaine than in normal clinical use, < 10 −8   m , evoked Ca 2+ transients in astrocytes from rat cerebral cortex, that were inositol trisphosphate receptor‐dependent. We investigated whether bupivacaine exerts an influence on the Ca 2+ signaling and interleukin‐1β ( IL ‐1β) secretion in inflammation‐reactive astrocytes when used at ultralow concentrations, < 10 −8   m . Furthermore, we wanted to determine if bupivacaine interacts with the opioid‐, 5‐hydroxytryptamine‐ (5‐ HT ) and glutamate‐receptor systems. With respect to the μ‐opioid‐ and 5‐ HT ‐receptor systems, bupivacaine restored the inflammation‐reactive astrocytes to their normal non‐inflammatory levels. With respect to the glutamate‐receptor system, bupivacaine, in combination with an ultralow concentration of the μ‐opioid receptor antagonist naloxone and μ‐opioid receptor agonists, restored the inflammation‐reactive astrocytes to their normal non‐inflammatory levels. Ultralow concentrations of bupivacaine attenuated the inflammation‐induced upregulation of IL ‐1β secretion. The results indicate that bupivacaine interacts with the opioid‐, 5‐ HT ‐ and glutamate‐receptor systems by affecting Ca 2+ signaling and IL ‐1β release in inflammation‐reactive astrocytes. These results suggest that bupivacaine may be used at ultralow concentrations as an anti‐inflammatory drug, either alone or in combination with opioid agonists and ultralow concentrations of an opioid antagonist.