A Review on Chronic Pain in Rheumatoid Arthritis: A Focus on Activation of NR2B Subunit of N-Methyl-D-Aspartate Receptors

@#Chronic pain is a debilitating condition that occurs after tissue damage, which substantially affects the patient’s emotional state and physical activity. The chronic pain in rheumatoid arthritis (RA) is the result of various autoimmune-induced inflammatory reactions in the joints. Both types of peripheral and central pain processing can lead to sensitisation. Non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) can result in potent anti-inflammatory effect. However, these drugs are not able to suppress the pain from RA for a prolonged period. For years, researchers have examined the role of the N-methyl-D-aspartic acid receptor 2B (NR2B) subunit of N-methyl-D-aspartate receptors (NMDAR) in chronic and neuropathic pain models. This NMDAR subtype can be found in at the peripheral and central nervous system and it represents an effective therapy for RA pain management. This review focuses on the NR2B subunit of NMDAR and the different pathways leading to its activation. Furthermore, specific attention is given to the possible involvement of NR2B subunit in the peripheral and central pathogenesis of RA.

Effects of Pulsed Radiofrequency on Hyperalgesia and Expression of NR2B Subunit in Spinal Dorsal Horn in Chronic Constriction Injury Rats / 中国康复理论与实践

Objective To observe the behavioral and the histopathology changes and expression of NR2B subunit in spinal dorsal horn in chronic constriction injury (CCI) rats after pulsed radiofrequency (PRF). Methods Forty-eight adult Sprague-Dawley rats were randomly divided into Sham-Sham (SS), Sham-PRF (SP), CCI-Sham (CS) and CCI-PRF (CP) groups. The right sciatic nerves (SNs) of the CS and CP groups were ligated to create the CCI model. For the SS and SP groups, the right SNs were separated without ligation. The CP and SP groups accepted PRF at the ligation site 15 days after modeling, while the electrode was placed in rats in the SS and CS groups without elec-tricity. The hindpaw withdrawal threshold (HWT) was measured before and 3, 7, 11, 15 days after modeling, and 1, 3, 7, 11, 15 days after treatment. The right SNs at ligation sites were assessed with optical microscopic score 15 days after treatment, and the NR2B expression in the L4-6 spinal dorsal horn were determined with Western blotting. Results HWT was significantly shorter in the CS and CP groups than in the SS and SP groups after modeling, and was more in the CP group than in the CS group. Under the optical microscope, the axonal diame-ter and myelin sheath thickness increased in the CP group compared to those in the CS group (P<0.01), the NR2B expression was less in the CP group than in the CS group after treatment (F=10.769, P<0.05). Conclusion PRF may reduce hyperalgesia and repair damaged SNs in CCI-induced neuropathic pain, which may associate with inhibition of the NR2B subunit expression in spinal dorsal horn.

Knockdown of interleukin-10 induces the redistribution of sigma1-receptor and increases the glutamate-dependent NADPH-oxidase activity in mouse brain neurons

BACKGROUND: In the central nervous system, interleukin-10 (IL-10) provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions. This cytokine is primarily produced by glial cells and has beneficial effects on the neuronal viability. However, the mechanisms of IL-10-elicited neuroprotection are not clear. RESULTS: Membrane preparations, isolated from wild-type (Wt) and IL-10 knockout (KO) mice brain were used in this study. It has been shown that compared to wild-type mice, in IL-10 KO mice brain, the amount of immunoglobulin binding protein (BiP) is greatly increased, whereas the content of sigma receptor-1 (SigR1) is not changed significantly. Co-immunoprecipitation experiments have shown that the association of SigR1 with small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1), NR2B subunit of NMDA-receptor (NMDAR) and inositol-3-phosphate receptor (IP3R) is higher in the IL-10 KO mice brain than in the Wt mice brain. Besides, we have found that either glutamate or sigma ligands, separately or together, do not change glutamate-induced NADPH-oxidase (NOX) activity in Wt-type mice brain membrane preparations, whereas in IL-10 KO mice high concentration of glutamate markedly increases the NOX-dependent production of reactive oxygen species (ROS). Glutamate-dependent ROS production was decreased to the normal levels by the action of sigma-agonists. CONCLUSIONS: It has been concluded that IL-10 deprivation, at least in part, can lead to the induction of ER-stress, which causes BiP expression and SigR1 redistribution between components of endoplasmic reticulum (ER) and plasma membrane. Moreover, IL-10 deficiency can change the specific organization of NMDAR, increasing the surface expression of SigR1-sensitive NR2B-containing NMDAR. In these conditions, glutamate-dependent ROS production is greatly increased leading to the initiation of apoptosis. In this circumstances, sigma-ligands could play a preventive role against NMDA receptor-mediated excitotoxicity.

NR2B Receptor Antagonists and Their Application in Ischemic Cerebrovascular Diseases / 国际脑血管病杂志

Neuronal damage is associated with the excessive stimulation of N-Methyl-D- Aspartate (NMDA) receptors by glutamate during cerebral ischemia.Because of non-selective NMDA receptor antagonist can influence all NMDA receptors and produce adverse effects,and its clinical application has been restricted significantly,an increasing attention has been paid to the selective NMDA receptor in recent years.NR2B subunit antagonists are mainly divided into piperidine derivatives,amide derivatives,amidine derivatives,and aminoquinoline derivatives,etc. The representative drugs include ifenprodil and eliprodil.These drugs can selectively act on NMDA receptor NR2B subunit,and they are expected to become safe and effective neuropro- tective agents in clinical practice.