Faculty, Staff and Student Publications
Publication Date
8-20-2024
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abstract
Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids (e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to amplify opioid effects, increasing analgesia and overdose-related adverse outcomes, but in vitro proof of this amplification and its mechanism are lacking. We previously showed that after SCI, sensitivity to opioids is reduced by fourfold to sixfold in rat sensory neurons. Here, we demonstrate that after injury, gabapentinoids restore normal sensitivity of opioid inhibition of cyclic AMP (cAMP) generation, while reducing nociceptor hyperexcitability by inhibiting voltage-gated calcium channels (VGCCs). Increasing intracellular Ca2+ or activation of L-type VGCCs (L-VGCCs) suffices to mimic SCI effects on opioid sensitivity, in a manner dependent on the activity of the Raf1 proto-oncogene, serine/threonine-protein kinase C-Raf, but independent of neuronal depolarization. Together, our results provide a mechanism for potentiation of opioid effects by gabapentinoids after injury, via reduction of calcium influx through L-VGCCs, and suggest that other inhibitors targeting these channels may similarly enhance opioid treatment of neuropathic pain.
Keywords
Animals, Neuralgia, Cyclic AMP, Rats, Spinal Cord Injuries, Analgesics, Opioid, Gabapentin, Signal Transduction, Rats, Sprague-Dawley, Male, Calcium Channels, L-Type, Calcium, Pregabalin, Drug Synergism, Sensory Receptor Cells
DOI
10.1073/pnas.2405465121
PMID
39145932
PMCID
PMC11348325
PubMedCentral® Posted Date
8-15-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes