Contribution of P2X4 receptor in pain associated with rheumatoid arthritis: a review

Abstract

Pain is the most common symptom reported by patients with rheumatoid arthritis (RA) even after the resolution of chronic joint inflammation. It is believed that RA-associated pain is not solely due to inflammation, but could also be attributed to aberrant modifications to the central nervous system. The P2X4 receptor (P2X4R) is an ATP-activated purinergic receptor that plays a significant role in the transmission of information in the nervous system and pain. The involvement of P2X4R during the pathogenesis of chronic inflammatory pain and neuropathic pain is well-established. The attenuation of this receptor alleviates disease pathogenesis and related symptoms, including hyperalgesia and allodynia. Although some studies have revealed the contribution of P2X4R in promoting joint inflammation in RA, how it implicates pain associated with RA at peripheral and central nervous systems is still lacking. In this review, the possible contributions of P2X4R in the nervous system and how it implicates pain transmission and responses were examined.

Keywords: Central pain; Chronic pain; P2X4 receptor; Peripheral pain; Rheumatoid arthritis.

Fig. 1

Structure of the P2X4 receptor. This receptor consists of N- and C-terminals, two transmembrane domains (TM1 and TM2) and a large extracellular domain (adapted from Zhang et al. [8])

Fig. 2

Mechanism of P2X4R at peripheral region involving peripheral nerve lesion and inflammatory cells. Following the injury of a peripheral nerve due to inflammatory reactions in synovial fluid, the released ATP and PGs from the damaged nerve activate P2X4R expressed on the macrophage. Subsequently, the highly Ca²⁺ influx into the macrophage cell may activate p38 MAPK leading to the release of BDNF and PGE₂ into the synovial fluid and surrounding nerves. The high influx of Ca²⁺ also indirectly stimulates P2X7R to allow the production of pro-inflammatory factors from macrophage, which further enhances the BDNF release by monocytes, B- and T-cells. Moreover, the released pro-inflammatory cytokines can further stimulate NLRP1 inflammasome on the macrophage. The synergistic effects between injured peripheral nerves and inflammatory cells lead to the leukocyte infiltration in joints and synovial hyperplasia. The prolonged synovial inflammation may further lead to bone erosion and cartilage destruction (osteoarthritis) and therefore transmit the nociceptive signals to a central level that develop thermal hyperalgesia and mechanical allodynia; the common symptoms of RA-associated chronic pain

Fig. 3

Central mechanisms after P2X4R activation in the spinal cord. The affected neuron secretes adenosine triphosphate (ATP), chemokine ligand 2 (CCL2) and fibronectin that upregulate microglia P2X4 receptor (P2X4R) and promote its trafficking to cell surface prior to peripheral nerve injury due to rheumatoid arthritis (RA). Helper T-cells from peripheral blood vessel may pass through the blood-brain barrier (BBB) and interact with microglia via the released pro-inflammatory cytokines including interferon-ɣ (IFN-ɣ). As a consequence of ATP binding to P2X4R, several pathways are activated including phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinases-protein kinase B (PI3K/Akt) that leads to the release of brain-derived neurotrophic factor (BDNF) and pro-inflammatory mediators (IL-1β, TNF-α, IL-6 and prostaglandins) that contributes to neurogenic inflammation. Secreted BDNF may then bind to tropomyosin receptor kinase B (TrkB) receptors on nociceptive neurons that further downregulate potassium chloride cotransporter (KCC2) resulting in the accumulation of chloride anions (Cl^-) in the neurons. Consequently, the subsequent binding to ɣ-aminobutyric acid A receptor (GABA_A receptor) that is normally inhibitory, shifts to the disinhibition of inhibitory neurons. Meanwhile, the production of cathestatin (CST) via the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) in microglia may further augment the P2X4R activation on the activated microglia. The hyperexcitability resulted from GABA depolarisation together with the release of pro-inflammatory cytokines from microglia and lesioned nerve, as well as N-methyl-d-aspartate receptors (NMDARs) activation, leads to sensitisation of spinal circuits and therefore, chronic pain