Silencing P2X7R Alleviates Diabetic Neuropathic Pain Involving TRPV1 via PKCε/P38MAPK/NF-κB Signaling Pathway in Rats

Abstract

Transient receptor potential vanillic acid 1 (TRPV1) is an ion channel activated by heat and inflammatory factors involved in the development of various types of pain. The P2X7 receptor is in the P2X family and is associated with pain mediated by satellite glial cells. There might be some connection between the P2X7 receptor and TRPV1 in neuropathic pain in diabetic rats. A type 2 diabetic neuropathic pain rat model was induced using high glucose and high-fat diet for 4 weeks and low-dose streptozocin (35 mg/kg) intraperitoneal injection to destroy islet B cells. Male Sprague Dawley rats were administrated by intrathecal injection of P2X7 shRNA and p38 inhibitor, and we recorded abnormal mechanical and thermal pain and nociceptive hyperalgesia. One week later, the dorsal root ganglia from the L4-L6 segment of the spinal cord were harvested for subsequent experiments. We measured pro-inflammatory cytokines, examined the relationship between TRPV1 on neurons and P2X7 receptor on satellite glial cells by measuring protein and transcription levels of P2X7 receptor and TRPV1, and measured protein expression in the PKCε/P38 MAPK/NF-κB signaling pathway after intrathecal injection. P2X7 shRNA and p38 inhibitor relieved hyperalgesia in diabetic neuropathic pain rats and modulated inflammatory factors in vivo. P2X7 shRNA and P38 inhibitors significantly reduced TRPV1 expression by downregulating the PKCε/P38 MAPK/NF-κB signaling pathway and inflammatory factors in dorsal root ganglia. Intrathecal injection of P2X7 shRNA alleviates nociceptive reactions in rats with diabetic neuropathic pain involving TRPV1 via PKCε/P38 MAPK/NF-κB signaling pathway.

Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions

“…221 PKCε/P38MAPK/NF-κB and NOXS/ROS/NLRP3 were involved in inflammatory of hyperalgesia. 222,223 The chemokine SDF-1 and its receptor CXCR4 could mediate calcium influx and excitability of dorsal root neurons, which lead to neuropathic pain. 104 Additionally, inhibition of T cell infiltration was of positive significance in improv-ing peripheral neuropathic pain in DPN.…”

“…Moreover, activating NLRP3 in the peripheral nerve caused paclitaxel‐induced neuropathic pain 221 . PKCε/P38MAPK/NF‐κB and NOXS/ROS/NLRP3 were involved in inflammatory of hyperalgesia 222,223 . The chemokine SDF‐1 and its receptor CXCR4 could mediate calcium influx and excitability of dorsal root neurons, which lead to neuropathic pain 104 .…”

Pharmacological activation of Sig-1R ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the Akt/GSK-3β/NF-κB pathway

“…Nevertheless, the effects of Sig-1R in the DRG remain elusive in DNP model rats.NF-κB is usually localized in the cytoplasm, but upon activation, phosphorylated NF-κB dimers translocate and accumulate within the nucleus, thereby triggering the release of cytokines and iNOS in microglia to regulate microglia-mediated neuroin ammation(Bhat et al 2002;Jana et al 2002;Nakajima et al 2006). Previous studies have demonstrated a signi cant upregulation in NF-κB levels in DRG tissues of rats with DNP(Chen et al 2022). Furthermore, activation of Sig-1R can also reduce glutamate accumulation and suppress in ammatory signaling pathways, including that of NF-κB(Shen et al.…”

Commentary: P2X7 receptor modulation is a viable therapeutic target for neurogenic pain with concurrent sleep disorders

“…This association can play role in influencing the quality and quantity of sleep in patients with chronic pain, which may be worsened in the context of chronic stress. Another study revealed that rats with diabetic neuropathy had increased expression of the P2X7R and inhibiting the P2X7R in these animals decreased displays of pain (Chen et al, 2022 ). Furthermore, mice models with disruption of P2X7R genes demonstrated significantly less inflammatory and neuropathic hypersensitivity to various pain stimuli compared to their wild-type counterparts (Chessell et al, 2005 ).…”