Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats.
BACKGROUND
Spinal glia, particularly microglia and astrocytes, are of the utmost importance in the development and maintenance of chronic pain. A recent study from our laboratory revealed that gabapentin, a recommended first-line treatment for multiple neuropathic conditions, could also efficiently antagonize thermal hyperalgesia evoked by complete Freund's adjuvant (CFA)-induced monoarthritis (MA). In the present study, we investigated whether the spinal glia are involved in the anti-hyperalgesic effect of gabapentin and how this event occurs.


RESULTS
Unilateral intra-articular injection of CFA produced a robust activation of microglia and astrocytes. These cells exhibited large cell bodies, thick processes and increases in the ionized calcium binding adapter molecule 1 (Iba-1, a microglial marker) or the glia fibrillary acidic protein (GFAP, an astrocytic marker). These cells also displayed immunoreactive signals, and an upregulation of the voltage-gated calcium channels (VGCCs) α2/δ-1 subunit, CX3CL1 and CX3CR1 expression levels in the spinal cord. These changes were associated with the development of thermal hyperalgesia. Immunofluorescence staining showed that VGCC α2/δ-1 subunit, a proposed gabapentin target of action, was widely distributed in primary afferent fibers terminals and dorsal horn neurons. CX3CL1, a potential trigger to activate microglia, colocalized with VGCC α2/δ-1 subunits in the spinal dorsal horn. However, its receptor CX3CR1 was mainly expressed in the spinal microglia. Multiple intraperitoneal (i.p.) gabapentin injections (100 mg/kg, once daily for 4 days with the first injection 60 min before intra-articular CFA) suppressed the activation of spinal microglia, downregulated spinal VGCC α2/δ-1 subunits decreased CX3CL1 levels and blocked the development of thermal hyperalgesia in MA rats.


CONCLUSIONS
Here we provide the first evidence that gabapentin diminishes CX3CL1 signaling and spinal microglia activation induced by joint inflammation. We also show that the VGCC α2/δ-1 subunits might be involved in these events.
Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Jia-Le
JL
Yang
Bo
B
Xu
Shuang-Shuang
SS
Li
Wei-Shi
WS
Zhang
Hua
H
Xu
Xiao-Ming
XM
Deng
Yu-Qiu
YQ
Zhang
D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001168:Arthritis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000073883:CX3C Chemokine Receptor 1; D020746:Calcium Channels, L-Type / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D005620:Freund's Adjuvant; D000077206:Gabapentin; D006930:Hyperalgesia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007270:Injections, Intra-Articular; D007274:Injections, Intraperitoneal; D008159:Lumbar Vertebrae / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D010146:Pain / Q000378:metabolism / Q000473:pathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000473:pathology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000588:Amines; D000073883:CX3C Chemokine Receptor 1; C516305:CX3CR1 protein, rat; D020746:Calcium Channels, L-Type; D054428:Chemokine CX3CL1; C515540:Cx3cl1 protein, rat; D003509:Cyclohexanecarboxylic Acids; D021122:Protein Subunits; D019707:Receptors, Chemokine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D005620:Freund's Adjuvant