Authorship note: KW and YG share first authorship. RRJ and KW share senior authorship. Conflict of interest: RRJ is a consultant of Boston Scientific and received a research grant from the company. He also serves on the board of directors of Ascletis Pharma. RRJ and KW also filed a patent, Methods and kits for treating pain (16/612,909), in association with Duke University.

No abstract

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 bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce 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 are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.

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.

GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia following challenge by lipopolysaccharide (LPS), Listeria bacteria, and the mouse malaria parasite Plasmodium berghei. Sepsis induced by LPS and Listeria in wild-type mice is protected by artesunate (ARU) and neuroprotectin D1 (NPD1), but the protective actions of these agents are lost in Gpr37−/− mice. Notably, we found that ARU binds to GPR37 in macrophages and promotes phagocytosis and clearance of pathogens. Moreover, ablation of macrophages potentiated infection, sepsis, and their sequelae, whereas adoptive transfer of NPD1- or ARU-primed macrophages reduced infection, sepsis, and pain-like behaviors. Our findings reveal physiological actions of ARU in host cells by activating macrophages and suggest that GPR37 agonists may help to treat sepsis, bacterial infections, and malaria.

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 P d1 −/− 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.

The current crises in opioid abuse and chronic pain call for the development of nonopioid and nonpharmacological therapeutics for pain relief. Neuromodulation-based approaches, such as spinal cord stimulation, dorsal root ganglion simulation, and nerve stimulation including vagus nerve stimulation, have shown efficacy in achieving pain control in preclinical and clinical studies. However, the mechanisms by which neuromodulation alleviates pain are not fully understood. Accumulating evidence suggests that neuromodulation regulates inflammation and neuroinflammation-a localized inflammation in peripheral nerves, dorsal root ganglia/trigeminal ganglia, and spinal cord/brain-through neuro-immune interactions. Specialized proresolving mediators (SPMs) such as resolvins, protectins, maresins, and lipoxins are lipid molecules produced during the resolution phase of inflammation and exhibit multiple beneficial effects in resolving inflammation in various animal models. Recent studies suggest that SPMs inhibit inflammatory pain, postoperative pain, neuropathic pain, and cancer pain in rodent models via immune, glial, and neuronal modulations. It is noteworthy that sham surgery is sufficient to elevate resolvin levels and may serve as a model of resolution. Interestingly, it has been shown that the vagus nerve produces SPMs and vagus nerve stimulation (VNS) induces SPM production in vitro. In this review, we discuss how neuromodulation such as VNS controls pain via immunomodulation and neuro-immune interactions and highlight possible involvement of SPMs. In particular, we demonstrate that VNS via auricular electroacupuncture effectively attenuates chemotherapy-induced neuropathic pain. Furthermore, auricular stimulation is able to increase resolvin levels in mice. Thus, we propose that neuromodulation may control pain and inflammation/neuroinflammatioin via SPMs. Finally, we discuss key questions that remain unanswered in our understanding of how neuromodulation-based therapies provide short-term and long-term pain relief.

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.