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

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

doi:10.1007/s11302-021-09764-z

Cited by 9 publications

(7 citation statements)

References 102 publications

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“…For example, blocking P2X3 receptors with the selective P2X3 receptor antagonist A-317491 prevented acute muscle hyperalgesia, but had no effect on chronic-muscle pain [18]. Conversely, the activation and upregulation of P2X4 receptors on glial cells (i.e., microglia) are linked to the pathogenesis and development of neuropathic pain and mechanical allodynia, thus representing a pathway promoting the development of chronic pain [20][21][22]. Similarly, P2X7 receptors have been primarily associated with neuropathic and chronic inflammatory pain, showing a selective upregulation in human dorsal root ganglia, glial cells, and immune cells (i.e., monocytes and lymphocytes) [3,23,24].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of ATP release in pain: role of pannexin and connexin channels

Muñoz

Griffith

Contreras

2021

Purinergic Signalling

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Pain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of ATP release in pain: role of pannexin and connexin channels

Muñoz

Griffith

Contreras

2021

Purinergic Signalling

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“…A variety of factors are known to drive spinal microglia reactivity, with purinergic signaling being a key neuron to glia mechanism causally implicated in chronic pain (38,39). Notably, MIA-induced joint injury has been shown to increase P2X7 (20) and P2X4 (40,41) receptor expression and elevate ATP levels within the CSF (20). We found that pharmacologically silencing A-fibres abrogated the increase in ATP two weeks after joint injury.…”

Section: Discussionmentioning

confidence: 76%

Role of Primary Afferents in Arthritis Induced Spinal Microglial Reactivity

et al. 2021

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Increased afferent input resulting from painful injury augments the activity of central nociceptive circuits via both neuron-neuron and neuron-glia interactions. Microglia, resident immune cells of the central nervous system (CNS), play a crucial role in the pathogenesis of chronic pain. This study provides a framework for understanding how peripheral joint injury signals the CNS to engage spinal microglial responses. During the first week of monosodium iodoacetate (MIA)-induced knee joint injury in male rats, inflammatory and neuropathic pain were characterized by increased firing of peripheral joint afferents. This increased peripheral afferent activity was accompanied by increased Iba1 immunoreactivity within the spinal dorsal horn indicating microglial activation. Pharmacological silencing of C and A afferents with co-injections of QX-314 and bupivacaine, capsaicin, or flagellin prevented the development of mechanical allodynia and spinal microglial activity after MIA injection. Elevated levels of ATP in the cerebrospinal fluid (CSF) and increased expression of the ATP transporter vesicular nucleotide transporter (VNUT) in the ipsilateral spinal dorsal horn were also observed after MIA injections. Selective silencing of primary joint afferents subsequently inhibited ATP release into the CSF. Furthermore, increased spinal microglial reactivity, and alleviation of MIA-induced arthralgia with co-administration of QX-314 with bupivacaine were recapitulated in female rats. Our results demonstrate that early peripheral joint injury activates joint nociceptors, which triggers a central spinal microglial response. Elevation of ATP in the CSF, and spinal expression of VNUT suggest ATP signaling may modulate communication between sensory neurons and spinal microglia at 2 weeks of joint degeneration.

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“…In our case, the most accessible oralbased treatment provides low effectiveness, and future studies may use osmotic minipumps or other more effective drug delivery to the renal tissue. Besides the lack of severe side effects of chronic ivermectin and 5-BDBD exposure, our study provides additional insights into the therapeutic potential of these compounds for other applications (Khir et al, 2021;Khoja et al, 2016;Montilla et al, 2020;Ulmann et al, 2013;Varma et al, 2009;Zhang et al, 2020).…”

Section: Discussionmentioning

confidence: 90%

Modulation of P2X ₄ receptor activity by ivermectin and 5‐BDBD has no effect on the development of ARPKD in PCK rats

Nikolaienko

Levchenko

et al. 2022

Physiological Reports

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Autosomal recessive polycystic kidney disease (ARPKD) is an inherited pathology caused mainly by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene, which usually leads to end-stage renal disease. Previous studies suggested that the P2X purinoreceptor 4 (P2X 4 R) may play an important role in the progression of ARPKD. To test this hypothesis, we assessed the chronic effects of ivermectin (P2X 4 R allosteric modulator) and 5-BDBD (P2X 4 R antagonist

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

Cited by 9 publications

References 102 publications

Mechanisms of ATP release in pain: role of pannexin and connexin channels

Mechanisms of ATP release in pain: role of pannexin and connexin channels

Role of Primary Afferents in Arthritis Induced Spinal Microglial Reactivity

Modulation of P2X ₄ receptor activity by ivermectin and 5‐BDBD has no effect on the development of ARPKD in PCK rats

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

Cited by 9 publications

References 102 publications

Mechanisms of ATP release in pain: role of pannexin and connexin channels

Mechanisms of ATP release in pain: role of pannexin and connexin channels

Role of Primary Afferents in Arthritis Induced Spinal Microglial Reactivity

Modulation of P2X 4 receptor activity by ivermectin and 5‐BDBD has no effect on the development of ARPKD in PCK rats

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Product

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Modulation of P2X ₄ receptor activity by ivermectin and 5‐BDBD has no effect on the development of ARPKD in PCK rats