Role of Primary Afferents in Arthritis Induced Spinal Microglial Reactivity.

Charlie H T Kwok,Michael Mousseau,Yuta Kohro,John R Matyas,Tuan Trang,Melissa S O’Brien,Jason J Mcdougall

doi:10.3389/fimmu.2021.626884

Abstract

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.

Highlights

Joint pain is a debilitating and complex feature of arthritis, which affects over 300 million people worldwide [1]
The timecourse of spinal microglial responses to the increased primary afferent activity was evaluated by ionized calcium binding adaptor molecule 1 (Iba1) immunoreactivity at 1, 3, and 7 days after monosodium iodoacetate (MIA) injections (Figure 1D)
Pharmacological silencing of primary afferents after the induction of joint injury by co-administering the membrane impermeable sodium channel blocker, QX-314, with bupivacaine to capture all nociceptive afferents, capsaicin to target C-fibres, or flagellin to target A-fibres [31, 33], rescued pain sensitivity and spinal microglial responses

Summary

Introduction

Joint pain is a debilitating and complex feature of arthritis, which affects over 300 million people worldwide [1]. Arthritis often affects large joints, the knee [7], which is highly innervated by sensory nerves in the synovium, outer meniscus, subchrondral bone and accessory ligaments [8]. These joint afferents comprise of small-diameter myelinated Ad and non-myelinated C fibres, which convey nociceptive information, and large diameter Ab fibres responsible for encoding non-noxious sensory information [9]. Prolonged inflammation can cause neuronal damage and apoptosis [11] Both inflammatory and neuropathic components may be implicated in joint pain [12]

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Results

Conclusion