title: Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by Aβ-fiber stimulation.
abstract: Activation of Aβ-fibers is an intrinsic feature of spinal cord stimulation (SCS) pain therapy. Cannabinoid receptor type 1 (CB1) is important to neuronal plasticity and pain modulation, but its role in SCS-induced pain inhibition remains unclear. In this study, we showed that CB1 receptors are expressed in both excitatory and inhibitory interneurons in substantia gelatinosa (SG). Patch-clamp recording of the evoked excitatory postsynaptic currents (eEPSCs) in mice after spinal nerve ligation (SNL) showed that electrical stimulation of Aβ-fibers (Aβ-ES) using clinical SCS-like parameters (50 Hz, 0.2 millisecond, 10 μA) induced prolonged depression of eEPSCs to C-fiber inputs in SG neurons. Pretreatment with CB1 receptor antagonist AM251 (2 μM) reduced the inhibition of C-eEPSCs by Aβ-ES in both excitatory and inhibitory SG neurons. We further determined the net effect of Aβ-ES on spinal nociceptive transmission in vivo by recording spinal local field potential in SNL rats. Epidural SCS (50 Hz, Aβ-plateau, 5 minutes) attenuated C-fiber-evoked local field potential. This effect of SCS was partially reduced by spinal topical application of AM251 (25 μg, 50 μL), but not CB2 receptor antagonist AM630 (100 μg). Finally, intrathecal pretreatment with AM251 (50 μg, 15 μL) in SNL rats blocked the inhibition of behavioral mechanical hypersensitivity by SCS (50 Hz, 0.2 millisecond; 80% of motor threshold, 60 minutes). Our findings suggest that activation of spinal CB1 receptors may contribute to synaptic depression to high-threshold afferent inputs in SG neurons after Aβ-ES and may be involved in SCS-induced inhibition of spinal nociceptive transmission after nerve injury.
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Fei
authors: F
authors: Yang
authors: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Qian
authors: Q
authors: Xu
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Bin
authors: B
authors: Shu
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Vinod
authors: V
authors: Tiwari
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Shao-Qiu
authors: SQ
authors: He
authors: Neuromodulation Research, Medtronic Inc., Minneapolis, MN, USA.
authors: Louis P
authors: LP
authors: Vera-Portocarrero
authors: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Xinzhong
authors: X
authors: Dong
authors: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Bengt
authors: B
authors: Linderoth
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Srinivasa N
authors: SN
authors: Raja
authors: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors: Yun
authors: Y
authors: Wang
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Yun
authors: Y
authors: Guan
mesh_terms: D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D008026:Ligation / Q000009:adverse effects; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009413:Nerve Fibers, Myelinated / Q000502:physiology*; D009437:Neuralgia / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D009619:Nociceptors / Q000502:physiology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology; D013127:Spinal Nerves / Q000293:injuries; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D063386:Cannabinoid Receptor Agonists; D008164:Luminescent Proteins; D043884:Receptor, Cannabinoid, CB1; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1