Inhibiting spinal secretory phospholipase A₂ after painful nerve root injury attenuates established pain and spinal neuronal hyperexcitability by altering spinal glutamatergic signaling

Abstract

Neuropathic injury is accompanied by chronic inflammation contributing to the onset and maintenance of pain after an initial insult. In addition to their roles in promoting immune cell activation, inflammatory mediators like secretory phospholipase A2 (sPLA2) modulate nociceptive and excitatory neuronal signaling during the initiation of pain through hydrolytic activity. Despite having a known role in glial activation and cytokine release, it is unknown if sPLA2 contributes to the maintenance of painful neuropathy and spinal hyperexcitability later after neural injury. Using a well-established model of painful nerve root compression, this study investigated if inhibiting spinal sPLA2 7 days after painful injury modulates the behavioral sensitivity and/or spinal dorsal horn excitability that is typically evident. The effects of sPLA2 inhibition on altered spinal glutamatergic signaling was also probed by measuring spinal intracellular glutamate levels and spinal glutamate transporter (GLAST and GLT1) and receptor (mGluR5, GluR1, and NR1) expression. Spinal sPLA2 inhibition at day 7 abolishes behavioral sensitivity, reduces both evoked and spontaneous neuronal firing in the spinal cord, and restores the distribution of neuronal phenotypes to those of control conditions. Inhibiting spinal sPLA2 also increases intracellular glutamate concentrations and restores spinal expression of GLAST, GLT1, mGluR5, and GluR1 to uninjured expression with no effect on NR1. These findings establish a role for spinal sPLA2 in maintaining pain and central sensitization after neural injury and suggest this may be via exacerbating glutamate excitotoxicity in the spinal cord.

Artesunate Alleviates Paclitaxel-Induced Neuropathic Pain in Mice by Decreasing Metabotropic Glutamate Receptor 5 Activity and Neuroinflammation in Primary Sensory Neurons

“…Nerve injury is accompanied by chronic inflammation, leading to the generation and maintenance of neuropathic pain. Inflammatory mediators such as secreted phospholipase A2 (sPLA2) regulate nociceptive and excitatory neuronal signaling during the development of pain through hydrolytic activity (Kartha et al, 2021). In the chemotherapy pain model, it was demonstrated that the pro-inflammatory mediators in the dorsal root ganglion (DRG) increased, indicating the induction of neuroinflammation in DRG.…”

Itch: from the skin to the brain – peripheral and central neural sensitization in chronic itch

“…The role of PLA2 in maintaining pain and central neural sensitization after neural injury has been demonstrated. Inhibiting spinal PLA2 during painful injury reduced neuronal firing in the spinal cord and elevates intracellular glutamate concentration; thus, suggesting that spinal PLA2 is implicated in spinal mechanisms of neuronal excitability via glutamate signaling, neurotransmitters, or inflammatory cascades ( Quindlen-Hotek et al, 2020 ; Kartha et al, 2021 ). Although the exact mechanism via which PLA2 cause peripheral and central itch sensitization is not well understood, we propose that its ability to stimulate signal transduction and excitation of itch sensory neurons may contribute to peripheral sensitization.…”

Recent progress of nanomedicine in secreted phospholipase A2 as a potential therapeutic target

“…Intrathecal treatment with antisense oligodeoxynucleotide or siRNA targeting sPLA2-III was able to reverse established thermal hyperalgesia. Using a well-established model of pain associated with nerve root compression, Kartha et al 45 investigated how sPLA2 in the spinal cord mediates the process of maintaining pain after nerve injury. The results showed that the level of sPLA2 was upregulated within 4 hours in spinal cord injury, and immediate inhibition could prevent the occurrence of pain and spinal cord hyperexcitability.…”