The spinal NR2BR/ERK2 pathway as a target for the central sensitization of collagen-induced arthritis pain

Abstract

ObjectivePain management is a huge challenge in the treatment of rheumatoid arthritis (RA), and central sensitization is reportedly involved in the development of pain. The current study was undertaken to explore the possible role of N-methyl-D-aspartate receptors (NMDARs) in the spinal mechanism of central sensitization in RA using a collagen-induced arthritis (CIA) model.MethodsMechanical hypersensitivity was assessed in C57BL/6 mice, before and after the induction of CIA via administration of chick type II collagen. Analgesic drugs, receptor antagonist, and kinase inhibitor were administrated intrathecally in the spinal cord. Protein expression and phosphorylation changes were detected via immunoblotting.ResultsCIA mice developed significant mechanical hypersensitivity, and spinal administration of the NMDAR antagonist D-2-amino-5-phosphonovaleric acid (D-APV) effectively attenuated peripheral pain hypersensitivity. There was specific enhancement of synaptic NR2B-containing NMDAR (NR2BR) expression in the spinal dorsal horns of the mice. Both the increased total protein expression of NR2B subunit and the enhanced total phosphorylation level of NR2B subunit at 1472 tyrosine promoted the synaptic expression of NMDAR in the mice. Intrathecal injection of tramadol suppressed synaptic NMDAR expression mainly by changing the synaptic phosphorylation state of NR2B subunit at Tyr1472. Extracellular signal-regulated protein kinases 2 (ERK2) activity synchronized with the synaptic expression of NR2BR, which was downregulated by the action of tramadol.ConclusionSpecific enhancement of NR2BR in the spinal dorsal horn may be vital for central sensitization in the CIA model of RA. The NR2BR/ERK2 pathway may be a promising target for pain management in RA patients.

Role of N-Methyl-D-Aspartate Receptor NR2B Subunit in Inflammatory Arthritis-Induced Chronic Pain and Peripheral Sensitized Neuropathic Pain: A Systematic Review

“…The NR2B subunit also induces peripheral sensitization in long-term chronic pain. 76 These findings indicated that NR2B is a novel research target for IA pathogenesis and pain management.…”

N-methyl-d-aspartate receptor subunit 2B on keratinocyte mediates peripheral and central sensitization in chronic post-ischemic pain in male rats

“…However, this nociceptive effect was attributed to NMDA receptors on peripheral nerves rather than on keratinocytes ( Carlton et al, 1995 ; Ma and Hargreaves, 2000 ). NR2B is associated with nociceptive transmission in a series of pain models ( Qu et al, 2009 ; Liao and Xu, 2017 ; Nozaki et al, 2011 ; Xu et al, 2018 ). The expression of NR2B in the forebrain ( Zhuo, 2009 ; Li et al, 2009 ) and spinal cord ( Boyce et al, 1999 ) has been found to enhance central pain potentiation.…”

Nociceptive mechanisms driving pain in a post-traumatic osteoarthritis mouse model

“…Moreover, the intrathecal injection of the ERK1/2 signalling pathway inhibitor PD98059 reduces the pain and the p-ERK1/2 induction in this OA model 66 . In the CIA-induced arthritis model the analgesia achieved by the intrathecal administration of tramadol also show the reduction in the p-ERK1/2 increase 68 . The spinal microglia and astrocytes were shown to play a critical role in development of the pain hypersensitivity, as they can dynamic modulate the activity of spinal neurons 69 , 70 .…”