Protein Tyrosine Phosphatase Receptor Type D Regulates Neuropathic Pain After Nerve Injury via the STING-IFN-I Pathway

Abstract

Neuropathic pain is usually caused by injury or dysfunction of the somatosensory system, and medicine is a common way of treatment. Currently, there are still no satisfactory drugs, like opioids and lidocaine, which carry a high risk of addiction. Protein tyrosine phosphatase receptor type D (PTPRD) is a known therapeutic target in addiction pathways and small molecule inhibitors targeting it, such as 7-butoxy illudalic acid analog (7-BIA), have recently been developed to tackle addition. PTPRD is also upregulated in the dorsal root ganglion (DRG) in a rat model of neuropathic pain, but is not yet clear whether PTPRD contributes to the development of neuropathic pain. Here, we established a chronic constriction injury (CCI) and evaluated PTPRD expression and its association with neuropathic pain. PTPRD expression was found to gradually increase after CCI in DRGs, and its expression was concomitant with the progressive development of hypersensitivity as assessed by both mechanical and thermal stimuli. Both PTPRD knockdown and administration of PTPRD inhibitor 7-BIA alleviated CCI-induced neuropathic pain while upregulating STING and IFN-α in the DRG. Treatment with H-151, a STING inhibitor, abolished the analgesic effects of PTPRD knockdown. Taken together, our study suggests that increased levels of PTPRD in the DRG following CCI are involved in the development of neuropathic pain via the STING-IFN-I pathway. 7-BIA, a small molecule inhibitor of PTPRD with anti-addiction effects, may represent a novel and safe therapeutic strategy for the clinical management of neuropathic pain without the risk of addiction.

What role of the cGAS-STING pathway plays in chronic pain?

“…In addition, STING regulates the type 1 interferon signaling in dorsal root ganglion sensory neurons, which has been disclosed to control nociception in bone cancer pain models (Donnelly et al, 2021 ). Consistently, in chronic constriction injury-induced neuropathic pain, protein tyrosine phosphatase receptor type D (PTPRD) activates STING-type 1 interferon pathway in dorsal root ganglion and displays an analgesic effect (Sun et al, 2022 ). In the light of this, researchers have reviewed that IFN-α and IFN-β may rapidly suppress neuronal activity and synaptic transmission to potent analgesia via nongenomic regulation (Tan et al, 2021 ), while the discrepancy in antinociceptive against pronociceptive effects of type 1 interferons may ascribe to various conditions, and the exact role of STING/type 1 interferons in chronic pain requires further investigation.…”

“…Agonists and inhibitors targeting cGAS-STING have been developed with potentials for the treatment of auto-inflammation, virus infection, and cancers (Ding et al, 2020 ). In chronic-refractory pain, STING-related adjuvant therapy appears to have translational potential, and the latest research has reported that a small molecule drug 7-BIA could alleviate neuropathic pain by upregulating STING and IFN-α in the DRG (Sun et al, 2022 ). There is a possibility of developing new drugs that target the STING signal pathway to treat refractory cancer-induced bone pain or neuropathic pain in patients to avoid systemic effects.…”

Mechanism and effects of STING–IFN-I pathway on nociception: A narrative review

“…In a rat model, deficiency of the STING–IFN-I pathway increased the excitability of nociceptors ( Donnelly et al, 2021 ). In the chronic constriction injury model of rats, knockdown of the D-type protein tyrosine phosphatase receptor increased the expression of STING and IFN-α, which attenuated pain ( Sun et al, 2022 ). STING agonists can relieve neuropathic pain in peripheral neuropathy induced by paclitaxel chemotherapy ( Donnelly et al, 2021 ) and pain induced by nerve injury ( Donnelly et al, 2021 ).…”

“…Moreover, STING agonists can attenuate fracture-induced pain in tumor-free mice ( Wang et al, 2021 ). Notably, after injecting STING agonists in rats, IFN-I levels in serum, DRG tissues, and bone marrow lysates were significantly upregulated 1000-fold in 4 h and maintained for up to 24 h ( Donnelly et al, 2021 ; Wang et al, 2021 ; Sun et al, 2022 ). Therefore, the STING–IFN-I pathway may promote short-term antinociception.…”

“…However, consecutive and repeated administration of STING agonists caused central sensitization and nociception ( Wu et al, 2022 ). Fifth, the STING–IFN-I pathway does not participate in the physiological regulation of pain sensitivity and is only involved in the regulation of pain after nerve injury ( Sun et al, 2022 ; Wu et al, 2022 ). Therefore, observing a positive effect in normal rat models injected with STING agonists or IFN-I is challenging.…”