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The functions of the brain and heart, which are the two main supporting organs of human life, are closely linked. Numerous studies have expounded the mechanisms of the brain-heart axis and its related clinical applications. However, the effect of heart disease on brain function, defined as the heart-brain axis, is less studied even though cognitive dysfunction after heart disease is one of its most frequently reported manifestations. Hypoperfusion caused by heart failure appears to be an important risk factor for cognitive decline. Blood perfusion, the immune response, and oxidative stress are the possible main mechanisms of cognitive dysfunction, indicating that the blood-brain barrier, glial cells, and amyloid-β may play active roles in these mechanisms. Clinicians should pay more attention to the cognitive function of patients with heart disease, especially those with heart failure. In addition, further research elucidating the associated mechanisms would help discover new therapeutic targets to intervene in the process of cognitive dysfunction after heart disease. This review discusses cognitive dysfunction in relation to heart disease and its potential mechanisms.

Spinal cord stimulation (SCS) is an emerging, minimally invasive procedure used to treat patients with intractable chronic pain conditions. Although several signaling pathways have been proposed to account for SCS-mediated pain relief, the precise mechanisms remain poorly understood. Recent evidence reveals that injured sensory neuron-derived colony-stimulating factor 1 (CSF1) induces microglial activation in the spinal cord, contributing to the development of neuropathic pain (NP). Here, we tested the hypothesis that SCS relieves pain in a rat model of chronic constriction injury (CCI) by attenuating microglial activation via blocking CSF1 to the spinal cord.Sprague-Dawley rats underwent sciatic nerve ligation to induce CCI and were implanted with an epidural SCS lead. SCS was delivered 6 hours per day for 5 days. Some rats received a once-daily intrathecal injection of CSF1 for 3 days during SCS.Compared with naive rats, CCI rats had a marked decrease in the mechanical withdrawal threshold of the paw, along with increased microglial activation and augmented CSF1 levels in the spinal dorsal horn and dorsal root ganglion, as measured by immunofluorescence or Western blotting. SCS significantly increased the mechanical withdrawal threshold and attenuated microglial activation in the spinal dorsal horn in CCI rats, which were associated with reductions in CSF1 levels in the spinal dorsal horn and dorsal roots but not dorsal root ganglion. Moreover, intrathecal injection of CSF1 completely abolished SCS-induced changes in the mechanical withdrawal threshold and activation of microglia in the spinal dorsal horn in CCI rats.SCS reduces microglial activation in the spinal cord and alleviates chronic NP, at least in part by inhibiting the release of CSF1 from the dorsal root ganglion ipsilateral to nerve injury.

Emerging immune therapy, such as with the anti–programmed cell death–1 (anti–PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1(−/−)) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1(−/−) mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1(−/−) mice. Consistently, these beneficial effects in Pd1(−/−) mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti–PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.

Inflammatory pain is a complex condition that has a major negative impact on post-injury quality of life. Recently, astaxanthin treatment in mice has been shown to relieve the development and maintenance of inflammatory pain through its effective antioxidant and anti-inflammatory activities. However, the specific mechanisms underlying these effects remain unclear. In this study, we aimed to elucidate the mechanism by which astaxanthin alleviated inflammation using complete Freund's adjuvant (CFA)-induced inflammatory pain mice model. Mechanical allodynia and thermal hyperalgesia were observed on day 1 and up to day 14 post-surgery. The expression of p38 mitogen-activated protein kinases (MAPKs) in the left paw and L4-6 DRG were upregulated in the CFA model, and the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme Oxygenase-1 (HO-1) pathways were increased. Astaxanthin relieved mechanical allodynia and thermal hyperalgesia caused by CFA-induced inflammatory pain and inhibited the inflammatory response (e.g., infiltration of inflammatory cells and production of inflammatory factors) in the paw and DRG. Additionally, astaxanthin inhibited p38 MAPK and enhanced Nrf2/HO-1 content in the left paw and DRG; it also reversed the pain caused by p38 MAPK and Nrf2 inhibitors. These findings suggest that AST exerts anti-inflammatory effects and regulates p38 MAPK and Nrf2/HO-1 to alleviate inflammatory pain.

Neuropathic pain is a complex condition that usually lasts a lifetime and has a major negative impact on life after injury. Improving pain management is an important and unmet need. Astaxanthin (AST) is a natural marine medicine with effective antioxidant and anti-inflammatory properties and neuroprotective effects. However, few mechanisms can explain the role of AST in the treatment of neuropathic pain. In the present study, we examined its potential to eliminate spinal nerve ligation (SNL) damage by inhibiting the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor-κB (NF-κB) p65 and the inflammatory response. The results of behavior tests indicated the promising role of AST in analgesic effect in SNL mice. AST decreased the neuronal and non-neuronal activation, the levels of the inflammatory signaling mediators (p-ERK1/2 p-p38 MAPK and NF-κB p65) and inflammatory cytokine expression (interleukin [IL]-1, IL-17, IL-6, and tumor necrosis factor-α [TNF-α]. These results suggest that AST is a promising candidate to reduce nociceptive hypersensitization after SNL.

Although sex dimorphism is increasingly recognized as an important factor in pain, female-specific pain signaling is not well studied. Here we report that administration of IL-23 produces mechanical pain (mechanical allodynia) in female but not male mice, and chemotherapy-induced mechanical pain is selectively impaired in female mice lacking Il23 or Il23r. IL-23-induced pain is promoted by estrogen but suppressed by androgen, suggesting an involvement of sex hormones. IL-23 requires C-fiber nociceptors and TRPV1 to produce pain but does not directly activate nociceptor neurons. Notably, IL-23 requires IL-17A release from macrophages to evoke mechanical pain in females. Low-dose IL-17A directly activates nociceptors and induces mechanical pain only in females. Finally, deletion of estrogen receptor subunit α (ERα) in TRPV1+ nociceptors abolishes IL-23- and IL-17-induced pain in females. These findings demonstrate that the IL-23/IL-17A/TRPV1 axis regulates female-specific mechanical pain via neuro-immune interactions. Our study also reveals sex dimorphism at both immune and neuronal levels.

Agonists of the innate immune regulator stimulator of interferon genes (STING) have shown great efficacy in promoting antitumor immunity in preclinical models, leading to their exploration in cancer immunotherapy trials. Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of metastatic bone cancer, we report that STING agonists confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuated bone cancer-induced pain symptoms and improved locomotor function. Interestingly, STING agonists provided acute pain relief through direct neuronal modulation, as ex vivo incubation of STING agonists reduced excitability of pain-sensing nociceptive neurons from tumor-bearing mice. In addition, STING agonists protected local bone destruction and reduced local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects were dependent on host-intrinsic STING and Ifnar1. Overall, STING activation provides unique advantages in controlling metastatic bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.

Background Voltage-gated sodium channel Nav1.7 has been validated as a perspective target for selective inhibitors with analgesic and anti-itch activity. The objective of this study was to discover new candidate compounds with Nav1.7 inhibitor properties. The authors hypothesized that their approach would yield at least one new compound that inhibits sodium currents in vitro and exerts analgesic and anti-itch effects in mice. Methods In silico structure-based similarity search of 1.5 million compounds followed by docking to the Nav1.7 voltage sensor of Domain 4 and molecular dynamics simulation was performed. Patch clamp experiments in Nav1.7-expressing human embryonic kidney 293 cells and in mouse and human dorsal root ganglion neurons were conducted to test sodium current inhibition. Formalin-induced inflammatory pain model, paclitaxel-induced neuropathic pain model, histamine-induced itch model, and mouse lymphoma model of chronic itch were used to confirm in vivo activity of the selected compound. Results After in silico screening, nine compounds were selected for experimental assessment in vitro. Of those, four compounds inhibited sodium currents in Nav1.7-expressing human embryonic kidney 293 cells by 29% or greater (P < 0.05). Compound 9 (3-(1-benzyl-1H-indol-3-yl)-3-(3-phenoxyphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)propanamide, referred to as DA-0218) reduced sodium current by 80% with a 50% inhibition concentration of 0.74 μM (95% CI, 0.35 to 1.56 μM), but had no effects on Nav1.5-expressing human embryonic kidney 293 cells. In mouse and human dorsal root ganglion neurons, DA-0218 reduced sodium currents by 17% (95% CI, 6 to 28%) and 22% (95% CI, 9 to 35%), respectively. The inhibition was greatly potentiated in paclitaxel-treated mouse neurons. Intraperitoneal and intrathecal administration of the compound reduced formalin-induced phase II inflammatory pain behavior in mice by 76% (95% CI, 48 to 100%) and 80% (95% CI, 68 to 92%), respectively. Intrathecal administration of DA-0218 produced acute reduction in paclitaxel-induced mechanical allodynia, and inhibited histamine-induced acute itch and lymphoma-induced chronic itch. Conclusions This study’s computer-aided drug discovery approach yielded a new Nav1.7 inhibitor that shows analgesic and anti-pruritic activity in mouse models. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Obesity is associated with increased sensitivity to pain, including neuropathic pain, but the precise mechanisms are not fully understood. Recent evidence has revealed that AMP-activated protein kinase (AMPK) in the central nervous system (CNS) regulates the neuropeptide calcitonin gene-related peptide (CGRP), a principal neurotransmitter of the class C nerve fiber, which serves an important role in initiating and maintaining neuropathic pain. AMPK has been demonstrated to be downregulated in the CNS in obesity. The present study hypothesized that obesity may lead to increased sensitivity to neuropathic pain by downregulating AMPK and upregulating CGRP expression levels in the CNS. Sprague-Dawley rats consuming a high-fat diet (HF) for 12 weeks developed obesity; they exhibited significantly decreased levels of phospho (p)-AMPK and increased CGRP expression levels in the spinal cord (SC) and dorsal root ganglion (DRG), respectively, compared with rats consuming a low-fat (LF) diet. HF-fed rats that underwent spared nerve injury (SNI) also exhibited lower p-AMPK and higher CGRP expression levels in the SC and DRG, compared with the corresponding LF-diet rats. The 50% paw withdrawal threshold (PWT; as measured by Von Frey testing) was significantly lower in HF-fed compared with LF-fed rats, with or without SNI. Through intrathecal treatment, the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) or the CGRP antagonist CGRP8-37 decreased CGRP expression levels and increased the 50% PWT; however, the AMPK inhibitor dorsomorphin augmented CGRP expression levels and further reduced the 50% PWT in HF-fed rats, but not LF-fed rats, with or without SNI. The results indicated that blocking the AMPK-CGRP pathway may enhance neuropathic pain in HF-induced obesity, with or without nerve injury. Targeting AMPK in the CNS may be a novel strategy for the prevention and treatment of obesity-associated neuropathic pain.

Earlier studies have demonstrated that essential fatty acid-derived specialized pro-resolving mediators (SPMs) promote the resolution of inflammation and pain. However, the potential analgesic actions of SPMs in chemotherapy-induced peripheral neuropathy (CIPN) are not known. Recent results also showed sex dimorphism in immune cell signaling in neuropathic pain. Here, we evaluated the analgesic actions of D-series resolvins (RvD1, RvD2, RvD3, RvD4, and RvD5) on a CIPN in male and female mice. Paclitaxel (PTX, 2 mg/kg), given on days 0, 2, 4, and 6, produced robust mechanical allodynia in both sexes at 2 weeks. Intrathecal injection of RvD1 and RvD2 (100 ng, i.t.) at 2 weeks reversed PTX-induced mechanical allodynia in both sexes, whereas RvD3 and RvD4 (100 ng, i.t.) had no apparent effects on either sex. Interestingly, RvD5 (100 ng, i.t.) only reduced mechanical allodynia in male mice but not in female mice. Notably, PTX-induced mechanical allodynia was fully developed in Trpv1 or Trpa1 knockout mice, showing no sex differences. Also, intrathecal RvD5 reduced mechanical allodynia in male mice lacking Trpv1 or Trpa1, whereas female mice with Trpv1 or Trpa1 deficiency had no response to RvD5. Finally, RvD5-induced male-specific analgesia was also confirmed in an inflammatory pain condition. Formalin-induced second phase pain (licking and flinching) was reduced by intrathecal RvD5 in male but not female mice. These findings identified RvD5 as the first SPM that shows sex dimorphism in pain regulation. Moreover, these results suggest that specific resolvins may be used to treat CIPN, a rising health concern in cancer survivors.

Summary The immune checkpoint inhibitor programmed cell death protein 1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. Here we report neuronal expression and function of PD-1 in the central nervous system (CNS), including the spinal cord, thalamus, and cerebral cortex. Notably, GABA-induced currents in spinal dorsal horn neurons, thalamic neurons, and cortical neurons are suppressed by the PD-1-neutralizing immunotherapeutic Nivolumab in spinal cord slices, brain slices, and dissociated cortical neurons. Reductions in GABA-mediated currents in CNS neurons were also observed in Pd1−/− mice without changes in GABA receptor expression. Mechanistically, Nivolumab binds spinal cord neurons and elicits ERK phosphorylation to suppress GABA currents. Finally, both GABA-mediated analgesia and anesthesia are impaired by Pd1 deficiency. Our findings reveal PD-1 as a CNS-neuronal inhibitor that regulates GABAergic signaling and GABA-mediated behaviors., Graphical Abstract, Highlights • Pd1 mRNA and PD-1 protein are widely expressed in spinal cord and brain neurons • GABA-induced currents in CNS neurons are suppressed by PD-1 blockade with Nivolumab • Nivolumab binds neuronal PD-1 to induce ERK activation and GABAergic inhibition • GABA-mediated pain inhibition and anesthesia is impaired after Pd1 deficiency, Immunology ; Molecular Biology; Neuroscience