Spinal P2X7R contributes to streptozotocin-induced mechanical allodynia in mice

Abstract

Painful diabetic neuropathy (PDN) is a diabetes mellitus complication. Unfortunately, the mechanisms underlying PDN are still poorly understood. Adenosine triphosphate (ATP)-gated P2X7 receptor (P2X7R) plays a pivotal role in non-diabetic neuropathic pain, but little is known about its effects on streptozotocin (STZ)-induced peripheral neuropathy. Here, we explored whether spinal cord P2X7R was correlated with the generation of mechanical allodynia (MA) in STZ-induced type 1 diabetic neuropathy in mice. MA was assessed by measuring paw withdrawal thresholds and western blotting. Immunohistochemistry was applied to analyze the protein expression levels and localization of P2X7R. STZ-induced mice expressed increased P2X7R in the dorsal horn of the lumbar spinal cord during MA. Mice injected intrathecally with a selective antagonist of P2X7R and P2X7R knockout (KO) mice both presented attenuated progression of MA. Double-immunofluorescent labeling demonstrated that P2X7R-positive cells were mostly co-expressed with Iba1 (a microglia marker). Our results suggest that P2X7R plays an important role in the development of MA and could be used as a cellular target for treating PDN.

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

“…In addition to mechanical damage to major peripheral nerves also diabetes mellitus (DM) is a frequent cause of neuropathic pain. Streptozocin alone was injected to destroy pancreatic β-cells in order to generate a model of DM type I [ 126 ]; alternatively, after streptozocin injection, animals were fed with a high-sugar and high-fat diet for 4 weeks to generate a model of DM type II [ 127 ]. Streptozocin-treated mice expressed increased P2X7R protein in the dorsal horn of the lumbar spinal cord, and P2X7R-IR was co-localized with the microglial marker Iba1 [ 126 ].…”

“…Streptozocin alone was injected to destroy pancreatic β-cells in order to generate a model of DM type I [ 126 ]; alternatively, after streptozocin injection, animals were fed with a high-sugar and high-fat diet for 4 weeks to generate a model of DM type II [ 127 ]. Streptozocin-treated mice expressed increased P2X7R protein in the dorsal horn of the lumbar spinal cord, and P2X7R-IR was co-localized with the microglial marker Iba1 [ 126 ]. When these mice were injected intrathecally with the P2X7R antagonist A-740003, or when P2X7R −/− mice were rendered diabetic/neuropathic, an attenuated progression of mechanical allodynia was observed.…”

Proteomics Analysis of the Spinal Dorsal Horn in Diabetic Painful Neuropathy Rats With Electroacupuncture Treatment

“…Neuronal ATP receptor P2X7 activation leads to ROS production and subsequent nociceptive pain ( 32 , 33 ). EA can improve neuropathic pain by inhibiting oxidative phosphorylation, reducing ATP production, and suppressing central sensitization in the spinal dorsal horn ( 34 ).…”

The P2X7 Receptor Is Involved in Diabetic Neuropathic Pain Hypersensitivity Mediated by TRPV1 in the Rat Dorsal Root Ganglion

“…Purinergic receptors can be divided into P1 and P2 receptors, and P2 receptors are further divided into ligand-gated ion channel type P2X receptors (including P2X 1−7 ) and G-protein-coupled P2Y receptors (Kuan and Shyu, 2016;Burnstock and Gentile, 2018;Alarcon-Vila et al, 2019). Studies have confirmed that P2X 7 receptors on SGCs are involved in the pathogenesis of NPP and inflammatory pain (Alarcon-Vila et al, 2019;Ni et al, 2020). Our experimental results showed that the MWT and TWL of DNP model rats were significantly reduced compared to those of control rats, indicating that the mechanical and heat hypersensitivity enhanced in DNP model rats.…”

“…The P2X 7 receptor is expressed on satellite glial cells (SGCs) of the dorsal root ganglion (DRG) ( Kobayashi et al, 2013 ), and mechanical and thermal hyperalgesia are related to the activation of SGCs ( Zou et al, 2019 ). Thus, the P2X 7 receptor is involved in the pathogenesis of inflammation and NPP ( Skaper et al, 2010 ; Ni et al, 2020 ).…”