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

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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.

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Abbreviations

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor

ASC:

PYD- and CARD-domain containing caspase-1

ASIC:

Acid-sensing channel

ADP:

Adenosine diphosphate

ATP:

Adenosine triphosphate

BDNF:

Brain-derived neurotrophin factor

BDNF-TrKB:

BDNF-tyrosine kinase B

BX430:

1-(2,6-Dibromo-4-isopropyl-phenyl)-3-(3-pyridyl)urea

Ca2+ :

Calcium ion

CCI:

Chronic constriction injury

CCL2:

Chemokine ligand 2

CFA:

Complete Freund’s adjuvant

CNS:

Central nervous system

CORM-2:

Tricarbonyldichlororuthenium (II) dimer

COX-2:

Cyclooxygenase-2

CST:

Catestatin

CXCL25:

ATP-mediated C-X-C motif chemokine-5

DMARDs:

Disease-modifying anti-rheumatic drugs

DRG:

Dorsal root ganglion

ENaC:

Epithelial Na+ channel

EPSPs:

Excitatory postsynaptic potentials

ERK 1/2 :

Extracellular signal-regulated kinase 1/2

GABAA :

ɣ-Aminobutyric acid A receptor

GABAergic:

ɣ-Aminobutyric acidergic

IFN-ɣ:

Interferon-ɣ

IL-6:

Interleukin-6

IL-17:

Interleukin-17

IL-1β:

Interleukin-1β

IRF5:

Interferon regulatory factor-5

KCC2:

Potassium-chloride cotransporter

K+ :

Potassium ion

LTD:

Long-term depression

LTP:

Long-term potentiation

MMP-9:

Matrix metallopeptidase-9

Na+ :

Sodium ion

NLRP1:

Pyrin domain containing 1 of activated NLR family

NMDAR:

N-Methyl-d-aspartate receptor

NP-1815-PX:

(5-[3-(5-Thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1, 2-b][1,4]diazepine-2,4(3H,5H)-dione)

PGs:

Prostaglandins

PNI:

Peripheral nerve injury

PPADs:

Pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid)

P2X4R:

P2X4 receptor

P2X7R:

P2X7 receptor

P13K/Akt:

Phosphatidylinositol 3-kinase-protein kinase B

p38 MAPK:

p38 Mitogen-activated protein kinase

RA:

Rheumatoid arthritis

TGF-β2:

Transforming growth factor-β2

Th1:

T-helper cell 1

TNF-α:

Tumor necrosis factor-α

5-BDBD:

5-(3-Bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one

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Funding

This study was funded by the Ministry of Higher Education, Malaysia and Universiti Sains Malaysia under Fundamental Research Grant Scheme (203.PPSP.6171238) and Short Term Grant (304/PPSP/6315333).

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  1. International Medical School, Management and Science University, 40100, Shah Alam, Selangor, Malaysia

    Nurul Ajilah Mohamed Khir

  2. Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, 16150, Kubang Kerian, Kelantan, Malaysia

    Nurul Ajilah Mohamed Khir, Ain’ Sabreena Mohd Noh, Nazlahshaniza Shafin & Che Aishah Nazariah Ismail

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  1. Nurul Ajilah Mohamed Khir
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  3. Nazlahshaniza Shafin
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Khir NAM and Ismail CAN developed the contents and wrote the manuscript, Noh ASM prepared illustrations and did the search strings and Shafin N proofread and ensured the relevant flow of the manuscript.

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Correspondence to Che Aishah Nazariah Ismail.

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Nurul Ajilah Mohamed Khir declares that she has no conflict of interest. Ain’ Sabreena Mohd Noh declares that she has no conflict of interest. Nazlahshaniza Shafin declares that she has no conflict of interest. Che Aishah Nazariah Ismail declares that she has no conflict of interest.

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Khir, N.A.M., Noh, A.S.M., Shafin, N. et al. Contribution of P2X4 receptor in pain associated with rheumatoid arthritis: a review. Purinergic Signalling 17, 201–213 (2021). https://doi.org/10.1007/s11302-021-09764-z

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