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Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte ‘gliopathy’. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal–glial and glial–glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.

Acute pain is protective and a cardinal feature of inflammation. Chronic pain after arthritis, nerve injury, cancer, and chemotherapy is associated with chronic neuroinflammation, a local inflammation in the peripheral or central nervous system. Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. We review how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain. Recent studies also suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections. We also discuss new therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.

Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. In the central nervous system (CNS), two major glial cell types predominate: astrocytes and microglia. Injuries or pathological conditions which evoke pain are concurrently associated with the presence of a reactive microglia or astrocyte state, which is characterized by a variety of changes in the morphological, molecular, and functional properties of these cells. In this review, we highlight the changes that reactive microglia and astrocytes undergo following painful injuries and insults and discuss the critical and interactive role these two cell types play in the initiation and maintenance of chronic pain. Additionally, we focus on several crucial mechanisms by which microglia and astrocytes contribute to chronic pain and provide commentary on the therapeutic promise of targeting these pathways. In particular, we discuss how the inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal- and glial regulations. Moreover, we highlight several potentially-druggable hemichannels and proteases produced by reactive microglia and astrocytes in pain states and discuss how these pathways regulate distinct phases during pain pathogenesis. We also review two emerging areas in chronic pain research: 1) sexually dimorphic glial cell signaling and 2) the role of oligodendrocytes. Finally, we highlight important considerations for potential pain therapeutics targeting glial cell mediators as well as questions that remain in our conceptual understanding of glial cell activation in pain states.

Inflammation is known to cause pain, and pain is of one of the cardinal signs of inflammation. Mounting evidence suggests that acute inflammation also resolves pain through specialized pro-resolving mediators (SPMs) and macrophage signaling. GPR37 is expressed by neurons and oligodendrocytes in the brain and has been implicated in multiple disorders, such as demyelination, Parkinson’s disease, stroke, and cancer. Recent studies have demonstrated that GPR37 is expressed by macrophages and confers protection against infection by bacteria and parasites. Furthermore, GPR37 promotes the resolution of inflammatory pain and infection-induced pain, as the duration of pain after tissue injury and infection is prolonged in mice lacking Gpr37. Mechanistically, activation of GPR37 enhances macrophage phagocytosis, and Gpr37-deficient macrophages exhibit dysregulations of pro-inflammatory and anti-inflammatory cytokines, switching from M2- to M1-like phenotypes. We also discuss novel ligands of GPR37, including neuroprotectin D1 (NPD1), a SPM derived from docosahexaenoic acid (DHA), and bone-derived hormone osteocalcin (OCN), which can suppress oligodendrocyte differentiation and myelination. NPD1 stimulates macrophage phagocytosis via GPR37 and exhibits potent analgesic actions in various animal models of inflammatory and neuropathic pain. Targeting GPR37 may lead to novel therapeutics for treating inflammation, infection, pain, and neurological diseases.

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. There is an unmet clinical need to develop therapies to alleviate metastatic bone pain, frequently observed in patients with advanced cancers. Here, using mouse models of bone cancer pain, the authors show that STING agonists not only suppress bone cancer tumor burden, but also attenuate bone pain and reduce cancer-induced bone destruction.

Effective control of pain management has the potential to significantly decrease the need for prescription opioids following a surgical procedure. While extended release products for pain management are available commercially, the implementation of a device that safely and reliably provides extended analgesia and is sufficiently flexible to facilitate a diverse array of release profiles would serve to advance patient comfort, quality of care and compliance following surgical procedures. Herein, we review current polymeric systems that could be utilized in new, controlled post-operative pain management devices and highlight where opportunities for improvement exist. Pain management is an extremely important topic both medically and socio-economically. Here the authors offer an overview of the use of degrading polymeric materials for delivery of pharmaceutical agents for pain management and offer a perspective of the future directions of the field.

Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte-based mechanism of neural pathology. Astrocyte morphogenesis depends on interactions between astrocytic neuroligins and neuronal neurexins. Neuroligins adjust their astrocytes It has long been known that astrocytes maintain an intimate relationship with neurons and can influence synapses with their complex morphology and close physical interactions. However, the molecular means by which the astrocyte initiates and maintains the required morphology to participate in synaptic regulation are not well known. Here, Cagla Eroglu and colleagues report that neuroligins—a family of cell adhesion molecules—expressed by astrocytes can bind to neurexins expressed on neurons to regulate astrocyte morphogenesis and modulate synaptic density and function.

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.

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. GPR37 is expressed in macrophages, and has been implicated in resolution of inflammatory pain. Here the authors show that GPR37 can modulate sepsis in several animal models.

Current treatments for chronic pain, such as inflammatory pain, neuropathic pain, and cancer pain are insufficient and cause severe side effects. Mounting evidence suggests that neuroinflammation in the peripheral and central nervous system (PNS and CNS) plays a pivotal role in the genesis and maintenance of chronic pain. Characteristic features of neuroinflammation in chronic pain conditions include infiltration of immune cells into the PNS [e.g., the sciatic nerve and dorsal root ganglion (DRG)], activation of glial cells such as microglia and astrocytes in the CNS (spinal cord and brain), and production and secretion of pro-inflammatory cytokines and chemokines [TNF, interleukin (IL)-1β, IL-6, CCL2, and CXCL1]. Recent studies suggest that bone marrow stem cells or bone marrow stromal cells (BMSCs) produce powerful analgesic effects in animal models of inflammatory pain, neuropathic pain, and cancer pain. We recently demonstrated that intrathecal injection of BMSCs resulted in a long-term relief of neuropathic pain for several weeks after peripheral nerve injury. Strikingly, this analgesic effect is mediated by the anti-inflammatory cytokine transforming growth factor beta secreted from BMSCs. Additionally, BMSCs exhibit potent modulation of neuroinflammation, by inhibiting monocyte infiltration, glial activation, and cytokine/chemokine production in the DRG and spinal cord. Thus, BMSCs control chronic pain by regulation of neuroinflammation in the PNS and CNS paracrine signaling. In this review, we discuss the similar results from different laboratories of remarkable anti-nociceptive efficacy of BMSCs in animal and clinical studies. We also discuss the mechanisms by which BMSCs control neuroinflammation and chronic pain and how these cells specifically migrate to damaged tissues.