Abstract
BackgroundSpinal 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.ResultsUnilateral 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.ConclusionsHere 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.
Highlights
Spinal glia, microglia and astrocytes, are of the utmost importance in the development and maintenance of chronic pain
We further address whether the anti-hyperalgesic effect of gabapentin in complete Freund's adjuvant (CFA) monoarthritic rats is linked to a reduction of in the activation of spinal glia
A one-way analysis of variance (ANOVA) analysis showed that the density of Iba-1-IR on both sides of the spinal cord was significantly greater in MA rats than that in the controls (Figure 1C)
Summary
Microglia and astrocytes, are of the utmost importance in the development and maintenance of chronic pain. Gabapentin is able to block the persistent sodium current (INaP) [22] and open K+ channels [23], inhibiting the abnormal spontaneous activity and hyperexcitability of sensory neurons, leading to a reduction of pain in rats. A recent report showed that oral gabapentin can significantly reverse diabetes-induced allodynia and suppress microglial activation in the spinal dorsal horn. This evidence suggests that gabapentin may exert its anti-allodynic actions partially through alterations of microglia function [24]. We further address whether the anti-hyperalgesic effect of gabapentin in CFA monoarthritic rats is linked to a reduction of in the activation of spinal glia. The possible mechanisms by which gabapentin modulates the activation of glia would be further defined
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
