Actions of bupivacaine, a widely used local anesthetic, on NMDA receptor responses.
Meaghan A PaganelliGabriela K PopescuPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2015)
NMDA receptors mediate excitatory neurotransmission in brain and spinal cord and play a pivotal role in the neurological disease state of chronic pain, which is caused by central sensitization. Bupivacaine is the indicated local anesthetic in caudal, epidural, and spinal anesthesia and is widely used clinically to manage acute and chronic pain. In addition to blocking Na(+) channels, bupivacaine affects the activity of many other channels, including NMDA receptors. Importantly, bupivacaine inhibits NMDA receptor-mediated synaptic transmission in the dorsal horn of the spinal cord, an area critically involved in central sensitization. We used recombinant NMDA receptors expressed in HEK293 cells and found that increasing concentrations of bupivacaine decreased channel open probability in GluN2 subunit- and pH-independent manner by increasing the mean duration of closures and decreasing the mean duration of openings. Using kinetic modeling of one-channel currents, we attributed the observed current decrease to two main mechanisms: a voltage-dependent "foot-in-the-door" pore block and an allosteric gating effect. Further, the inhibition was state-independent because it occurred to the same degree whether the drug was applied before or after glutamate stimulation and was mediated by extracellular and intracellular inhibitory sites, via hydrophilic and hydrophobic pathways. These results predict that clinical doses of bupivacaine would decrease the peak and accelerate the decay of synaptic NMDA receptor currents during normal synaptic transmission. These quantitative predictions inform possible applications of bupivacaine as preventative and therapeutic approaches in chronic pain.
Keyphrases
- chronic pain
- pain management
- spinal cord
- postoperative pain
- neuropathic pain
- spinal cord injury
- emergency department
- resting state
- liver failure
- liquid chromatography
- white matter
- functional connectivity
- cell proliferation
- multiple sclerosis
- small molecule
- prefrontal cortex
- reactive oxygen species
- signaling pathway
- mass spectrometry
- cell cycle arrest
- hepatitis b virus