PGC-1α activation ameliorates cancer-induced bone pain via inhibiting apoptosis of GABAergic interneurons.

Cancer-induced bone pain (CIBP) stands out as one of the most challenging issues in clinical practice due to its intricate and not fully elucidated pathophysiological mechanisms. Existing evidence has pointed toward the significance of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) down-regulation in contributing to pain behaviors in various rodent models of neuropathic pain. In our current study, we aimed to investigate the role of PGC-1α in CIBP. Our results unveiled a reduction in PGC-1α expression within the spinal cord of CIBP rats, particularly in GABAergic interneurons. Notably, intrathecal administration of the PGC-1α activator ZLN005 suppressed the loss of spinal GABAergic interneurons. This suppression was achieved by inhibiting caspase-3-mediated apoptosis, ultimately leading to the alleviation of mechanical allodynia in CIBP rats. Further exploration into the mechanism revealed that PGC-1α activation played a pivotal role in mitigating ATP depletion and reactive oxygen species accumulation linked to mitochondrial dysfunction. This was achieved through the restoration of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. Impressively, the observed effects were prominently reversed upon the application of SR18292, a specific PGC-1α inhibitor. In conclusion, our findings strongly suggest that PGC-1α activation acts as a potent inhibitor of apoptosis in spinal GABAergic interneurons. This inhibition is mediated by the improvement of mitochondrial function, facilitated in part through the enhancement of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. The results of our study shed light on potential therapeutic avenues for addressing CIBP.

Matrix metalloproteinases as attractive therapeutic targets for chronic pain: A narrative review.

Chronic pain constitutes an abnormal pain state that detrimentally affects the quality of life, daily activities, occupational performance, and stability of mood. Despite the prevalence of chronic pain, effective drugs with potent abirritation and minimal side effects remain elusive. Substantial studies have revealed aberrant activation of the matrix metalloproteinases (MMPs) in multiple chronic pain models. Additionally, emerging evidence has demonstrated that the downregulation of MMPs can alleviate chronic pain in diverse animal models, underscoring the unique and crucial role of MMPs in different stages and types of chronic pain. This review delves into the mechanistic insights and roles of MMPs in modulating chronic pain. The aberrant activation of MMPs has been linked to neuropathic pain through mechanisms involving myelin abnormalities in peripheral nerve and spinal dorsal horn (SDH), hyperexcitability of dorsal root ganglion (DRG) neurons, activation of N-methyl-d-aspartate receptors (NMDAR) and Ca2+-dependent signals, glial cell activation, and proinflammatory cytokines release. Different MMPs also contribute significantly to inflammatory pain and cancer pain. Furthermore, we summarized the substantial therapeutic potential of MMP pharmacological inhibitors across different types of chronic pain. Overall, our findings underscore the promising therapeutic prospects of MMPs targeting for managing chronic pain.

Interleukin-17: A Putative Novel Pharmacological Target for Pathological Pain.

Pathological pain imposes a huge burden on the economy and the lives of patients. At present, drugs used for the treatment of pathological pain have only modest efficacy and are also plagued by adverse effects and risk for misuse and abuse. Therefore, understanding the mechanisms of pathological pain is essential for the development of novel analgesics. Several lines of evidence indicate that interleukin-17 (IL-17) is upregulated in rodent models of pathological pain in the periphery and central nervous system. Besides, the administration of IL-17 antibody alleviated pathological pain. Moreover, IL-17 administration led to mechanical allodynia which was alleviated by the IL-17 antibody. In this review, we summarized and discussed the therapeutic potential of targeting IL-17 for pathological pain. The upregulation of IL-17 promoted the development of pathological pain by promoting neuroinflammation, enhancing the excitability of dorsal root ganglion neurons, and promoting the communication of glial cells and neurons in the spinal cord. In general, the existing research shows that IL-17 is an attractive therapeutic target for pathologic pain, but the underlying mechanisms still need to be investigated.

Targeting the JAK2/STAT3 signaling pathway for chronic pain.

Chronic pain is a notable health concern because of its prevalence, persistence, and associated mental stress. Drugs targeting chronic pain with potent abirritation, and minimal side effects remain unidentified. Substantial evidence indicates that the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a distinct and critical role in different stages of chronic pain. Aberrant activation of the JAK2/STAT3 signaling pathway is evident in multiple chronic pain models. Moreover, an increasing number of studies have demonstrated that the downregulation of JAK2/STAT3 can attenuate chronic pain in different animal models. In this review, we investigated the mechanism and role of the JAK2/STAT3 signaling pathway in modulating chronic pain. The aberrant activation of JAK2/STAT3 can trigger chronic pain by interacting with microglia and astrocytes, releasing proinflammatory cytokines, inhibiting anti-inflammatory cytokines, and regulating synaptic plasticity. We also retrospectively reviewed current reports on JAK2/STAT3 pharmacological inhibitors that demonstrated their significant therapeutic potential in different types of chronic pain. In summary, our results provide strong evidence that the JAK2/STAT3 signaling pathway is a promising therapeutic target for chronic pain.

Inhibition of Brd4 alleviates osteoarthritis pain via suppression of neuroinflammation and activation of Nrf2-mediated antioxidant signalling.

BACKGROUND AND PURPOSE: Osteoarthritis (OA) pain remains a major clinical problem. It is urgent to identify novel therapeutic approaches for OA pain states. Bromodomain and extra-terminal (BET) protein inhibitors have robust anti-inflammatory effects in several pain models. However, the underlying mechanisms of these inhibitors in OA pain have not been determined. We, therefore, investigated the effects and the underlying mechanism(s) of BET inhibition on pain-related behaviours in a rat model of OA. EXPERIMENTAL APPROACH: The OA model was established by intra-articular injection of monosodium iodoacetate (MIA) in rat knees. Pain behaviours were assessed in rats by hindlimb weight-bearing asymmetry, mechanical allodynia and thermal hyperalgesia. Possible mechanisms underlying BET inhibition were explored in the MIA-induced OA pain model in the spinal cord and dorsal root ganglia (DRG). KEY RESULTS: Inhibiting bromodomain-containing protein 4 (Brd4) with either JQ1 or MS417, or using AAV2/9-shRNA-Brd4-EGFP-mediated knockdown of Brd4 genes, significantly attenuated MIA-induced pain behaviours. Brd4 inhibition suppressed NF-κB and NF-κB-mediated inflammatory cytokines in both the spinal cord and DRG in rats with MIA-induced OA pain. Brd4 inhibition also attenuated the oxidative stress and promoted nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent antioxidant genes in both the spinal cord and DRG in our odel of MIA-induced OA pain. CONCLUSIONS AND IMPLICATIONS: In conclusion, Brd4 inhibition alleviated MIA-induced OA pain in rats, via suppression of neuroinflammation and activation of Nrf2-mediated antioxidant signalling. Although our model does not perfectly represent how OA develops in humans, inhibition of Brd4 may provide novel insights into possible treatments for OA pain.

Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain.

Nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase (PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.

Targeting α7 nicotinic acetylcholine receptors for chronic pain.

Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

Dimethyl Fumarate Attenuates Pain Behaviors in Osteoarthritis Rats via Induction of Nrf2-Mediated Mitochondrial Biogenesis.

AIMS: Osteoarthritis (OA), a chronic degenerative disease, leads to pain and loss of function. Existing treatments for OA pain have limited efficacy and show significant side effects. Dimethyl fumarate, a robust nuclear factor erythroid 2-related factor 2 (Nrf2) activator, could alleviate pain behaviors in chronic pain. This study aims to investigate the role of dimethyl fumarate in a rat model of OA and its underlying mechanisms. METHODS: We used von Frey filaments to assess the mechanical allodynia. Weight-bearing apparatus was employed to assess the hindlimb weight distribution. Western blot was employed to investigate the protein expressions of mitochondrial biogenesis markers. RT-qPCR was employed to examine the copy number of mitochondrial DNA (mtDNA). RESULTS: Dimethyl fumarate upregulated mechanical paw withdrawal threshold (MIA + Vehicle, 1.6 ± 0.13g [mean ± SEM]; MIA + DMF, 10.5 ± 0.96g; P ＜ 0.0001). Hindlimb weight distribution was alao upregulated by dimethyl fumarate (MIA + Vehicle, 38.17 ± 0.72g; MIA + DMF, 43.59 ± 1.01g; P ＜ 0.01). Besides, activation of Nrf2 remarkably upregulated the protein levels of PGC-1α (MIA + Vehicle, 0.69 ± 0.07; MIA + DMF, 1.08 ± 0.09; P = 0.0037), NRF1 (MIA + Vehicle, 0.69 ± 0.04; MIA + DMF, 1.00 ± 0.11; P = 0.0114), TFAM (MIA + Vehicle, 0.62 ± 0.11; MIA + DMF, 1.02 ± 0.12; P = 0.0147), and the copy number of mtDNA(MIA + Vehicle, 0.52 ± 0.05; MIA + DMF, 3.81 ± 0.21; P ＜ 0.0001) Conclusions: Taken together, these results show that dimethyl fumarate alleviated pain-related behaviors in a rat model of OA through activation of Nrf2-induced mitochondrial biogenesis.

The Emerging Role of Quercetin in the Treatment of Chronic Pain.

Despite much research efforts being devoted to designing alternative pharmacological interventions, chronic pain remains to be an unresolved clinical problem. Quercetin, a compound that belongs to the flavonoids family, is abundantly found in fruits and vegetables. Emerging evidence indicates that quercetin possesses anti-nociceptive effects in different rodent models of chronic pain, including inflammatory pain, neuropathic pain and cancer pain. In this review, we summarize the mechanisms underlying the analgesic effect of quercetin in preclinical studies. These studies showed that quercetin exerts potent analgesic effects against chronic pain via suppressing neuroinflammation and oxidative stress as well as modulation of synaptic plasticity, GABAergic system, and opioidergic system. Considering that the safety of quercetin is well established, it has great potential for clinical use in pain treatment.

Naringenin promoted spinal microglia M2 polarization in rat model of cancer-induced bone pain via regulating AMPK/PGC-1α signaling axis.

Cancer-induced bone pain (CIBP) treatment remains a clinical challenge because the pathophysiological mechanisms are not fully understood. Recently, it was verified that shifting microglial polarization toward the M2 phenotype reveals a potential strategy for CIBP treatment. Naringenin, a natural flavone flavonoid, has been reported to have antioxidant, anti-inflammatory and neuroprotective properties. However, the role of naringenin on regulating microglial polarization in CIBP rats and the molecular mechanisms participating in this process have not been fully clarified. Herein, we investigated the potential effect of naringenin on M1/M2 microglial polarization and further explored the potential mechanisms of this action. Our study demonstrated that intraperitoneal administration of naringenin could upregulate the antioxidative molecule glutathione peroxidase 4 (GPx4) level in the spinal cord, as well as bone cancer-induced mechanical allodynia in rats. Moreover, naringenin treatment also suppressed microglia-mediated neuroinflammation by downregulating the phosphorylation of nuclear factor κB (NF-κB) p65 expression and promoting microglial polarization toward the M2 phenotype in CIBP rats. The promoting effects mediated by naringenin on M1/M2 microglial polarization are dependent on the serine/threonine protein kinase adenosine monophosphate-activated protein kinase (AMPK)/proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling pathway. Inhibition of AMPK activation with the classical AMPK inhibitor Compound C attenuated this effect of naringenin. These results improved the understanding of the anti-inflammatory property of naringenin on microglial polarization, which might provide new alternative avenues for CIBP treatment.

Notch signaling activation contributes to paclitaxel-induced neuropathic pain via activation of A1 astrocytes.

Paclitaxel-induced neuropathic pain (PINP) is a progressive and refractory side effect of chemotherapy with few effective treatments at present. It is well-established that astrocytes activation contributes to the development of PINP. Recent reports showed astrocytes can be divided into A1 and A2 phenotypes. However, whether the transformation of astrocytes participates in PINP and the underlying mechanisms remain unknown. As Notch signaling pathway have shown to be involved in neuropathic pain, we aimed to investigate the relationship between Notch signaling pathway and A1 astrocytes in PINP. Herein we found that both A1 astrocytes and Notch signaling were markedly activated in the spinal cord of PINP rats and the downstream molecules of Notch signaling were colocalized with A1 astrocytes. DAPT (an inhibitor of Notch signaling) not only suppressed the mechanical allodynia of PINP rats, but also inhibited the activation of Notch signaling pathway and A1 astrocytes. Furthermore, Jagged1 (a ligand of Notch1 receptors) dose-dependently induced mechanical hyperalgesia in naïve rats and simultaneously led to Notch signaling activation and A1 astrocytes transformation, all of which were inhibited by DAPT. Taken together, these results demonstrate Notch signaling activation contributes to PINP via A1 astrocytes activation, which provides a promising therapeutic target for PINP.

DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation.

BACKGROUND: Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Microglial activation in the spinal cord plays a critical role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely understood. Here, we investigated the role of Dickkopf (DKK) 3 and its interplay with microglial activation in the spinal cord in neuropathic pain. METHODS: In this study, we investigated the effects of intrathecal injection of recombinant DKK3 (rDKK3) on mechanical allodynia and microglial activation in the spinal cord after spared nerve injury (SNI) in rats by western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that SNI induced a significant decrease in the levels of DKK3, Kremen-1 and Dishevelled-1 (DVL-1) and up-regulated the expression of phosphorylated apoptosis signal-regulating kinase 1 (p-ASK1), phosphorylated c-JUN N-terminal kinase (p-JNK), phosphorylated p38 (p-p38) in the spinal cord. Moreover, our results showed that exogenous intrathecal administration of rDKK3 inhibited expression of p-ASK1, p-JNK, p-p38, promoted the transformation of microglia from M1 type to M2 type, and decreased the production of pro-inflammatory cytokines compared to the rats of SNI + Vehicle. However, these effects were reversed by intrathecal administration of Kremen-1 siRNA or Dishevelled-1 (DVL-1) siRNA. CONCLUSIONS: These results suggest that DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation, at least partly, by the Kremen-1 and DVL-1 pathways.

SIRT1: A promising therapeutic target for chronic pain.

Chronic pain remains an unresolved problem. Current treatments have limited efficacy. Thus, novel therapeutic targets are urgently required for the development of more effective analgesics. An increasing number of studies have proved that sirtuin 1 (SIRT1) agonists can relieve chronic pain. In this review, we summarize recent progress in understanding the roles and mechanisms of SIRT1 in mediating chronic pain associated with peripheral nerve injury, chemotherapy-induced peripheral neuropathy, spinal cord injury, bone cancer, and complete Freund's adjuvant injection. Emerging studies have indicated that SIRT1 activation may exert positive effects on chronic pain relief by regulating inflammation, oxidative stress, and mitochondrial dysfunction. Therefore, SIRT1 agonists may serve as potential therapeutic drugs for chronic pain.

Adipocytokines: Emerging therapeutic targets for pain management.

Although pain has lower mortality rates than cancer, diabetes and stroke, pain is a predominate source of distress and disability. However, the management of pain remains an enormous problem. Many drugs used to pain treatment have more or less side effects. Therefore, the development of novel therapeutic target is critical for the treatment of pain. Notably, studies have shown that adipocytokines have a dual role in pain. Growing shreds of evidence shows that the levels of adipocytokines are upregulated or downregulated in the development of pain. In addition, substantial evidence indicates that regulation of adipocytokines levels in models of pain attenuates or promotes pain behaviors. In this review, we summarized and discussed the effect of adipocytokines in pain. These evidence indicates that adipocytokines attenuate or promote pain behaviors through interacting with their receptors, activating serotonin pathway, interacting with µ-opioid receptor, activating microglia, infiltrating macrophage and so on. Overall, adipocytokines have some potential in treating pain, but the underlying mechanisms remain unclear and need to be further studied.

5-HT1F Receptor Agonist Ameliorates Mechanical Allodynia in Neuropathic Pain via Induction of Mitochondrial Biogenesis and Suppression of Neuroinflammation.

Neuropathic pain is a devastating disease that affects millions of people worldwide. Serotonin (5-hydroxytryptamine, 5-HT) is involved in pain modulation. Several lines of evidence have indicated that 5-HT1F receptor agonists are potent inducers of mitochondrial biogenesis. In this study, we tested the hypothesis that 5-HT1F receptor agonists ameliorate mechanical allodynia in neuropathic pain via the induction of mitochondrial biogenesis and suppression of neuroinflammation. Male Sprague-Dawley rats were used to establish a neuropathic pain model via spared nerve injury (SNI). The paw withdrawal threshold (PWT) was used to evaluate mechanical allodynia. Real-time polymerase chain reaction was used to examine the mitochondrial DNA (mtDNA) copy number. Western blotting and immunofluorescence were used to examine the expression of target proteins. Our results showed that mitochondrial biogenesis was impaired in the spinal cord of rats with SNI. Moreover, activation of PGC-1α, the master regulator of mitochondrial biogenesis, attenuates established mechanical allodynia in rats with neuropathic pain. In addition, the neuronal 5-HT1F receptor is significantly downregulated in the spinal cord of rats with neuropathic pain. Furthermore, the selective 5-HT1F receptor agonist lasmiditan attenuated established mechanical allodynia in rats with neuropathic pain. Finally, lasmiditan (Las) treatment restored mitochondrial biogenesis and suppressed neuroinflammation in the spinal cord of rats with SNI. These results provide the first evidence that lasmiditan ameliorates mechanical allodynia in neuropathic pain by inducing mitochondrial biogenesis and suppressing neuroinflammation in the spinal cord. Inducers of mitochondrial biogenesis may be an encouraging therapeutic option for the management of neuropathic pain.

Galectin-3 in Microglia-Mediated Neuroinflammation: Implications for Central Nervous System Diseases.

Microglial activation is one of the common hallmarks shared by various central nervous system (CNS) diseases. Based on surrounding circumstances, activated microglia play either detrimental or neuroprotective effects. Galectin-3 (Gal-3), a group of ß-galactoside-binding proteins, has been cumulatively revealed to be a crucial biomarker for microglial activation after injuries or diseases. In consideration of the important role of Gal-3 in the regulation of microglial activation, it might be a potential target for the treatment of CNS diseases. Recently, Gal-3 expression has been extensively investigated in numerous pathological processes as a mediator of neuroinflammation, as well as in cell proliferation. However, the underlying mechanisms of Gal-3 involved in microgliamediated neuroinflammation in various CNS diseases remain to be further investigated. Moreover, several clinical studies support that the levels of Gal-3 are increased in the serum or cerebrospinal fluid of patients with CNS diseases. Thus, we summarized the roles and underlying mechanisms of Gal-3 in activated microglia, thus providing a better insight into its complexity expression pattern, and contrasting functions in CNS diseases.

Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation.

BACKGROUND: Our previous study indicated that reactive oxygen species (ROS) are critically involved in chronic pain. Sestrin2 (Sesn2), a novel stress-inducible protein, is evidenced to reduce the generation of ROS. The study examined the role of Sesn2 in osteoarthritis (OA) pain and delineated the underlying molecular mechanisms. METHODS: In the present study, we investigated the impact of Sesn2 on mitochondrial biogenesis in a rat model of OA pain. After adeno-associated viral (AAV)-Sesn2EGFP was injected for 14 days, OA was induced by intra-articular injection of monosodium iodoacetate (MIA). We assessed pain behaviors (weight-bearing asymmetry and paw withdrawal threshold) and explored possible mechanisms in the L4-6 spinal cord. RESULTS: Our results showed that overexpression of Sesn2 in the spinal cord alleviated pain behaviors in OA rats. Moreover, overexpression of Sesn2 increased the activity of AMP-activated protein kinase (AMPK) signaling and significantly restored mitochondrial biogenesis. Besides, Sesn2 overexpression inhibited the activation of astrocytes and microglia, and decreased the production of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the spinal cord of the OA pain rats. These effects were significantly reversed by an AMPK inhibitor. CONCLUSIONS: Collectively, these results suggest that Sesn2 overexpression ameliorates mechanical allodynia and weight-bearing asymmetry in OA rats via activation of AMPK/PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Moreover, Sesn2 overexpression attenuates OA-induced neuroinflammation at least partly by activating AMPK signaling. Sesn2 may become an encouraging therapeutic strategy for OA pain relief and other disorders.

STING/NF-κB/IL-6-Mediated Inflammation in Microglia Contributes to Spared Nerve Injury (SNI)-Induced Pain Initiation.

Innate immune response acts as the first line of host defense against damage and is initiated following the recognition of pathogen-associated molecular patterns (PAMPs). For double-stranded DNA (dsDNA) sensing, interferon gene stimulator (STING) was discovered to be an integral sensor and could mediate the immune and inflammatory response. Selective STING antagonist C-176 was administered and pain behaviors were assessed following spared nerve injury (SNI)-induced neuropathic pain. The level of serum dsDNA following neuropathic pain was assessed using Elisa analysis. STING signaling pathway, microglia activation, and proinflammatory cytokines were assessed by qPCR, western blots, Elisa, and immunofluorescence staining. STING agonist DMXAA was introduced into BV-2 cells to assess the inflammatory response in microglial cells. dsDNA was significantly increased following SNI and STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway was activated in vivo and vitro. Early but not the late intrathecal injection of C-176 attenuated SNI-induced pain hypersensitivity, microglia activation, proinflammatory factors, and phosphorylated JAK2/STAT3 in the spinal cord dorsal horn, and the analgesic effect of C-176 was greatly abolished by recombinant IL-6 following SNI. We provided evidence clarifying dsDNA mediated activation of microglia STING signaling pathway, after which promoting expression of proinflammatory cytokines that are required for hyperalgesia initiation in the spinal cord dorsal horn of SNI model. Further analysis showed that microglial STING/TBK1/NF-κB may contribute to pain initiation via IL-6 signaling. Pharmacological blockade of STING may be a promising target in the treatment of initiation of neuropathic pain.

Wnt signaling: A prospective therapeutic target for chronic pain.

Despite the rapid advance over the past decades to design effective therapeutic pharmacological interventions, chronic pain remains to be an unresolved healthcare concern. Long term use of opioids, the first line analgesics, often causes detrimental side effects. Therefore, a profound understanding of the mechanisms underlying the development and maintenance of chronic pain states is urgently needed for the management of chronic pain. Substantial evidence indicates aberrant activation of Wnt signaling pathways in sciatic nerve, dorsal root ganglia and spinal cord dorsal horn in rodent models of chronic pain. Moreover, growing evidence shows that pharmacological blockage of aberrant activation of Wnt signaling pathways attenuates pain behaviors in animal models of chronic pain. Importantly, both intrathecal injection of Wnt agonists and Wnt ligands to naïve rats lead to the development of mechanical allodynia, which was inhibited by Wnt inhibitors. In this review, we summarized and discussed the therapeutic potential of pharmacological inhibitors of Wnt signaling in chronic pain in preclinical studies. These evidence showed that aberrant activation of Wnt signaling pathways contributed to chronic pain via enhancing neuroinflammation, regulating synaptic plasticity and reducing intraepidermal nerve fiber density. However, these findings raise further questions. Overall, despite the future challenges, these pioneering studies suggest that Wnt signaling is a promising therapeutic target for chronic pain.

Nrf2 Activation Attenuates Chronic Constriction Injury-Induced Neuropathic Pain via Induction of PGC-1α-Mediated Mitochondrial Biogenesis in the Spinal Cord.

BACKGROUND: Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA-408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. METHODS: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB. RESULTS: RTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2-dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that the PGC-1α activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the preinjection of the PGC-1α inhibitor. CONCLUSIONS: Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.