Mechanism of gabapentinoid potentiation of opioid effects on cyclic AMP signaling in neuropathic pain
成果类型：
Article
署名作者：
Garza-Carbajal, Anibal; Bavencoffe, Alexis; Herrera, Juan J.; Johnson, Kayla N.; Walters, Edgar T.; Dessauer, Carmen W.
署名单位：
University of Texas System; University of Texas Health Science Center Houston; University of Texas System; University of Texas Health Science Center Houston
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-9990
DOI：
10.1073/pnas.2405465121
发表日期：
2024-08-15
关键词：
calcium-channel blockers
dorsal-root ganglion
spinal-cord-injury
adenylyl-cyclase
primary nociceptors
opiate analgesia
n-type
morphine
subunit
phosphorylation
摘要：
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.