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.