Bupivacaine inhibits activation of neuronal spinal extracellular receptor-activated kinase through selective effects on ionotropic receptors.
BACKGROUND
Central terminals of primary nociceptors release neurotransmitters glutamate and substance P, which bind to ionotropic or metabotropic receptors on spinal neurons to induce cellular responses. Extracellular signal-regulated kinases are activated by these receptors and are important modulators of pain at the dorsal horn. The authors investigated these pathways as potential targets for antinociceptive actions of local anesthetics.


METHODS
The effects of bupivacaine on the activation of extracellular receptor-activated kinase (phosphorylation to pERK) in rat spinal cord slices, induced by presynaptic release (capsaicin), by presynaptic or postsynaptic ionotropic or metabotropic receptor activation, or by activation of intracellular protein kinase C or protein kinase A and also by a receptor-independent Ca2+ ionophore, were quantitated by immunohistochemistry, counting pERK-positive neurons in the superficial dorsal horn.


RESULTS
Capsaicin (3 microm, 10 min)-stimulated pERK was reduced by bupivacaine (IC50 approximately 2 mm, approximately 0.05%), which similarly suppressed pERK induced by the ionotropic glutamate receptors for N-methyl-D-aspartate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid but not that induced by the metabotropic receptors for glutamate, bradykinin, or substance P. Extracellular receptor-activated kinase activation by the Ca2+ ionophore ionomycin was also sensitive to bupivacaine, but direct activation by protein kinase A or protein kinase C was not.


CONCLUSIONS
Bupivacaine inhibits pERK activation resulting from different modes of Ca2+ influx through the plasma membrane. This represents a postsynaptic mechanism of analgesia that occurs in parallel with impulse inhibition during neuraxial blockade.
Yanagidate
Fumi
F
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115-6110, USA.
Strichartz
Gary R
GR
D000775:Anesthesia, Spinal; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000779:Anesthetics, Local; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D002045:Bupivacaine