The pleiotropic cytokine interleukin-6 (IL-6) is emerging as a molecule with both beneficial and destructive potentials. It can exert opposing actions triggering either neuron survival after injury or causing neurodegeneration and cell death in neurodegenerative or neuropathic disorders. Importantly, neurons respond differently to IL-6 and this critically depends on their environment and whether they are located in the peripheral or the central nervous system. In addition to its hub regulator role in inflammation, IL-6 is recently emerging as an important regulator of neuron function in health and disease, offering exciting possibilities for more mechanistic insight into the pathogenesis of mental, neurodegenerative and pain disorders and for developing novel therapies for diseases with neuroimmune and neurogenic pathogenic components.

Chronic pain patients frequently develop and suffer from mental comorbidities such as depressive mood, impaired cognition, and other significant constraints of daily life, which can only insufficiently be overcome by medication. The emotional and cognitive components of pain are processed by the medial prefrontal cortex, which comprises the anterior cingulate cortex, the prelimbic, and the infralimbic cortex. All three subregions are significantly affected by chronic pain: magnetic resonance imaging has revealed gray matter loss in all these areas in chronic pain conditions. While the anterior cingulate cortex appears hyperactive, prelimbic, and infralimbic regions show reduced activity. The medial prefrontal cortex receives ascending, nociceptive input, but also exerts important top-down control of pain sensation: its projections are the main cortical input of the periaqueductal gray, which is part of the descending inhibitory pain control system at the spinal level. A multitude of neurotransmitter systems contributes to the fine-tuning of the local circuitry, of which cholinergic and GABAergic signaling are particularly emerging as relevant components of affective pain processing within the prefrontal cortex. Accordingly, factors such as distraction, positive mood, and anticipation of pain relief such as placebo can ameliorate pain by affecting mPFC function, making this cortical area a promising target region for medical as well as psychosocial interventions for pain therapy.

Numerous experimental studies demonstrate that the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases) Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42) are important regulators in somatosensory neurons, where they elicit changes in the cellular cytoskeleton and are involved in diverse biological processes during development, differentiation, survival and regeneration. This review summarizes the status of research regarding the expression and the role of the Rho GTPases in peripheral sensory neurons and how these small proteins are involved in development and outgrowth of sensory neurons, as well as in neuronal regeneration after injury, inflammation and pain perception. In sensory neurons, Rho GTPases are activated by various extracellular signals through membrane receptors and elicit their action through a wide range of downstream effectors, such as Rho-associated protein kinase (ROCK), phosphoinositide 3-kinase (PI3K) or mixed-lineage kinase (MLK). While RhoA is implicated in the assembly of stress fibres and focal adhesions and inhibits neuronal outgrowth through growth cone collapse, Rac1 and Cdc42 promote neuronal development, differentiation and neuroregeneration. The functions of Rho GTPases are critically important in the peripheral somatosensory system; however, their signalling interconnections and partially antagonistic actions are not yet fully understood.

Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain in general, and members of the non-coding RNA (ncRNA) family, specifically the short, 22 nucleotide microRNAs (miRNAs) and the long non-coding RNAs (lncRNAs) act as master switches orchestrating both immune as well as neuronal processes. Several chronic disorders reveal unique ncRNA expression signatures, which recently generated big hopes for new perspectives for the development of diagnostic applications. lncRNAs may offer perspectives as candidates indicative of neuropathic pain in liquid biopsies. Numerous studies have provided novel mechanistic insight into the role of miRNAs in the molecular sequelae involved in the pathogenesis of neuropathic pain along the entire pain pathway. Specific processes within neurons, immune cells, and glia as the cellular components of the neuropathic pain triad and the communication paths between them are controlled by specific miRNAs. Therefore, nucleotide sequences mimicking or antagonizing miRNA actions can provide novel therapeutic strategies for pain treatment, provided their human homologues serve the same or similar functions. Increasing evidence also sheds light on the function of lncRNAs, which converge so far mainly on purinergic signalling pathways both in neurons and glia, and possibly even other ncRNA species that have not been explored so far.

Neurofibromatosis type‐1 (NF‐1) is caused by mutations in the tumor suppressor gene NF1; its protein product neurofibromin is a RasGTPase‐activating protein, a property that has yet to explain aneuploidy, most often observed in astrocytes in NF‐1. Here, we provide a mechanistic model for the regulated nuclear import of neurofibromin during the cell cycle and for a role in chromosome congression. Specifically, we demonstrate that neurofibromin, phosphorylated on Ser2808, a residue adjacent to a nuclear localization signal in the C‐terminal domain (CTD), by Protein Kinase C‐epsilon (PKC‐ε), accumulates in a Ran‐dependent manner and through binding to lamin in the nucleus at G2 in glioblastoma cells. Furthermore, we identify CTD as a tubulin‐binding domain and show that a phosphomimetic substitution of its Ser2808 results in a predominantly nuclear localization. Confocal analysis shows that endogenous neurofibromin localizes on the centrosomes at interphase, as well as on the mitotic spindle, through direct associations with tubulins, in glioblastoma cells and primary astrocytes. More importantly, analysis of mitotic phenotypes after siRNA‐mediated depletion shows that acute loss of this tumor suppressor protein leads to aberrant chromosome congression at the metaphase plate. Therefore, neurofibromin protein abundance and nuclear import are mechanistically linked to an error‐free chromosome congression. image Concerned with neurofibromin's, a tumor suppressor, mechanism of action, we demonstrate in astrocytic cells that its synthesis, phosphorylation by Protein Kinase C‐ε on Ser2808 (a residue adjacent to a nuclear localization sequence), and nuclear import are cell cycle‐dependent, being maximal at G2. During mitosis, neurofibromin is an integral part of the spindle, while its depletion leads to aberrant chromosome congression, possibly explaining the development of chromosomal instability in Neurofibromatosis type‐1.Read the Editorial Highlight for this article on page 11.Cover Image for this issue: doi: 10.1111/jnc.13300.