The peripheral nervous system comprises an infinity of neural networks that act in the communication between the central nervous system and the most diverse tissues of the body. Along with the extension of the primary sensory neurons (axons and cell bodies), a population of resident macrophages has been described. These newly called sensory neuron–associated macrophages (sNAMs) seem to play an essential role in physiological and pathophysiological processes, including infection, autoimmunity, nerve degeneration/regeneration, and chronic neuropathic pain. After different types of peripheral nerve injury, there is an increase in the number and activation of sNAMs in the sciatic nerve and sensory ganglia. The activation of sNAMs and their participation in neuropathic pain development depends on the stimulation of pattern recognition receptors such as Toll-like receptors and Nod-like receptors, chemokines/cytokines, and microRNAs. On activation, sNAMs trigger the production of critical inflammatory mediators such as proinflammatory cytokines (eg, TNF and IL-1β) and reactive oxygen species that can act in the amplification of primary sensory neurons sensitization. On the other hand, there is evidence that sNAMs can produce antinociceptive mediators (eg, IL-10) that counteract neuropathic pain development. This review will present the cellular and molecular mechanisms behind the participation of sNAMs in peripheral nerve injury–induced neuropathic pain development. Understanding how sNAMs are activated and responding to nerve injury can help set novel targets for the control of neuropathic pain.

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase–expressing astrocytes into the pronociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase–derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate receptor. In conclusion, these data revealed a role for DCs driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.

Introduction: ZIKV is a highly neurotropic virus that can cause the death of infected neuroprogenitor cells through mitochondrial damage and intrinsic apoptotic signaling. In this context, the role of reactive oxygen species (ROS) in neuronal cell death caused by ZIKV still remains elusive. Objective: We aimed at evaluating the role of these cellular components in the death of human undifferentiated neuroblastoma cell line infected with ZIKV. Results: ZIKV infection resulted in the extensive death of SH-SY5Y cells with the upregulation of several genes involved in survival and apoptotic responses as well as the colocalization of mitochondrial staining with ZIKV Envelope (E) protein. Notably, levels of intracellular reactive oxygen species (ROS) were not altered during ZIKV infection in undifferentiated SH-SY5Y cells, and consistent with these results, the treatment of infected cells with the widely studied ROS scavenger N-acetylcysteine (NAC) did not prevent cell death in these cells. Conclusion: Altogether, our results suggest that excessive ROS production is not the main trigger of SH-SY5Y cells death in ZIKV infection.