STING recognition of viral dsDNA by nociceptors mediates pain in mice.

Pain is often one of the initial indicators of a viral infection, yet our understanding of how viruses induce pain is limited. Immune cells typically recognize viral nucleic acids, which activate viral receptors and signaling, leading to immunity. Interestingly, these viral receptors and signals are also present in nociceptors and are associated with pain. Here, we investigate the response of nociceptors to nucleic acids during viral infections, specifically focusing on the role of the viral signal, Stimulator of Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers pain responses through STING expression in nociceptors. In addition, STING agonists alone can elicit pain responses. Notably, these responses involve the direct activation of STING in nociceptors through TRPV1. We also provided a proof-of-concept showing that STING and TRPV1 significantly contribute to the mechanical hypersensitivity induced by HSV-1 infection. These findings suggest that STING could be a potential therapeutic target for relieving pain during viral infections.

Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice.

Microglia, resident immune cells in the central nervous system, play a role in neuroinflammation and the development of neuropathic pain. We found that the stimulator of interferon genes (STING) is predominantly expressed in spinal microglia and upregulated after peripheral nerve injury. However, mechanical allodynia, as a marker of neuropathic pain following peripheral nerve injury, did not require microglial STING expression. In contrast, STING activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated neuropathic pain in male mice, but not female mice. STING activation in female mice leads to increase in proinflammatory cytokines that may counteract the analgesic effect of ADU-S100. Microglial STING expression and type I interferon-ß (IFN-ß) signaling were required for the analgesic effects of STING agonists in male mice. Mechanistically, downstream activation of TANK-binding kinase 1 (TBK1) and the production of IFN-ß, may partly account for the analgesic effect observed. These findings suggest that STING activation in spinal microglia could be a potential therapeutic intervention for neuropathic pain, particularly in males.

Single-cell analysis of dorsal root ganglia reveals metalloproteinase signaling in satellite glial cells and pain.

Satellite glial cells (SGCs) are among the most abundant non-neuronal cells in dorsal root ganglia (DRGs) and closely envelop sensory neurons that detect painful stimuli. However, little is still known about their homeostatic activities and their contribution to pain. Using single-cell RNA sequencing (scRNA-seq), we were able to obtain a unique transcriptional profile for SGCs. We found enriched expression of the tissue inhibitor metalloproteinase 3 (TIMP3) and other metalloproteinases in SGCs. Small interfering RNA and neutralizing antibody experiments revealed that TIMP3 modulates somatosensory stimuli. TIMP3 expression decreased after paclitaxel treatment, and its rescue by delivery of a recombinant TIMP3 protein reversed and prevented paclitaxel-induced pain. We also established that paclitaxel directly impacts metalloproteinase signaling in cultured SGCs, which may be used to identify potential new treatments for pain. Therefore, our results reveal a metalloproteinase signaling pathway in SGCs for proper processing of somatosensory stimuli and potential discovery of novel pain treatments.

Targeting Nociceptive Neurons and Transient Receptor Potential Channels for the Treatment of Migraine.

Migraine is a neurovascular disorder that affects approximately 12% of the global population. While its exact causes are still being studied, researchers believe that nociceptive neurons in the trigeminal ganglia play a key role in the pain signals of migraine. These nociceptive neurons innervate the intracranial meninges and convey pain signals from the meninges to the thalamus. Targeting nociceptive neurons is considered promising due to their accessibility and distinct molecular profile, which includes the expression of several transient receptor potential (TRP) channels. These channels have been linked to various pain conditions, including migraine. This review discusses the role and mechanisms of nociceptive neurons in migraine, the challenges of current anti-migraine drugs, and the evidence for well-studied and emerging TRP channels, particularly TRPC4, as novel targets for migraine prevention and treatment.

Functional Expression of Piezo1 in Dorsal Root Ganglion (DRG) Neurons.

Piezo channels are mechanosensitive ion channels. Piezo1 is primarily expressed in nonsensory tissues, whereas Piezo2 is predominantly found in sensory tissues, including dorsal root ganglion (DRG) neurons. However, a recent study demonstrated the intracellular calcium response to Yoda1, a selective Piezo1 agonist, in trigeminal ganglion (TG) neurons. Herein, we investigate the expression of Piezo1 mRNA and protein in mouse and human DRG neurons and the activation of Piezo1 via calcium influx by Yoda1. Yoda1 induces inward currents mainly in small- (< 25 µm) and medium-sized (25-35 µm) mouse DRG neurons. The Yoda1-induced Ca2+ response is inhibited by cationic channel blocker, ruthenium red and cationic mechanosensitive channel blocker, GsMTx4. To confirm the specific inhibition of Piezo1, we performed an adeno-associated virus serotype 2/5 (AAV2/5)-mediated delivery of short hairpin RNA (shRNA) into mouse DRG neurons. AAV2/5 transfection downregulates piezo1 mRNA expression and reduces Ca2+ response by Yoda1. Piezo1 also shows physiological functions with transient receptor potential vanilloid 1 (TRPV1) in the same DRG neurons and is regulated by the activation of TRPV1 in mouse DRG sensory neurons. Overall, we found that Piezo1 has physiological functions in DRG neurons and that TRPV1 activation inhibits an inward current induced by Yoda1.

Role of Resolvins in Inflammatory and Neuropathic Pain.

Chronic pain is an unpleasant experience associated with actual or potential tissue damage. Inflammatory pain alerts the body to inflammation and promotes healing; however, unresolved inflammation can lead to chronic pain. Conversely, neuropathic pain, due to somatosensory damage, can be a disease in itself. However, inflammation plays a considerable role in the progression of both types of pain. Resolvins, derived from omega-3 fatty acids, actively suppress pro-inflammatory mediators and aid in the resolution of inflammation. Resolvins alleviate various inflammatory and neuropathic pain models by reducing hypersensitivity and regulating inflammatory cytokines and glial activation in the spinal cord and dorsal root ganglia. Thus, resolvins are a promising alternative for pain management with the potential to reduce the side effects associated with conventional medications. Continued research is crucial to unlock the therapeutic potential of resolvins and integrate them into effective clinical pain management strategies. This review aimed to evaluate the literature surrounding the resolvins in inflammatory and neuropathic pain.

Resolvins: Potent Pain Inhibiting Lipid Mediators via Transient Receptor Potential Regulation.

Chronic pain is a serious condition that occurs in the peripheral nervous system (PNS) and the central nervous system (CNS). It is caused by inflammation or nerve damage that induces the release of inflammatory mediators from immune cells and/or protein kinase activation in neuronal cells. Both nervous systems are closely linked; therefore, inflammation or nerve damage in the PNS can affect the CNS (central sensitization). In this process, nociceptive transient receptor potential (TRP) channel activation and expression are increased. As a result, nociceptive neurons are activated, and pain signals to the brain are amplified and prolonged. In other words, suppressing the onset of pain signals in the PNS can suppress pain signals to the CNS. Resolvins, endogenous lipid mediators generated during the resolution phase of acute inflammation, inhibit nociceptive TRP ion channels and alleviate chronic pain. This paper summarizes the effect of resolvins in chronic pain control and discusses future scientific perspectives. Further study on the effect of resolvins on neuropathic pain will expand the scope of pain research.