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Purpose of Review Chronic pain is a distressing condition that is ineffectively treated at present. In order to develop novel, more efficacious analgesics for chronic pain, a better understanding of the underlying mechanisms is required. Despite chronic pain initially being considered as a neurocentric process, the role of communication between immune cells and neurons has been shown to be essential to the modulation of chronic pain. In the spinal cord, chemokine-mediated communication between microglia and neurons has been shown to play a crucial mechanistic role in preclinical chronic pain. Recent Findings Here, we present convincing evidence specifically for the role of the neuronal chemokine, fractalkine and its receptor CX3CR1, which is expressed by microglia, in mediating neuronal/microglia crosstalk in the spinal cord in the context of preclinical pain behaviour. Summary In light of the compelling preclinical evidence and emerging clinical evidence, we consider the promising therapeutic potential of manipulating this signalling partnership for the treatment of chronic pain.

Highlights • Vincristine (VCR) induced nociception can be dose-limiting. • VCR increases permeability of the blood-spinal cord barrier. • Increased permeability results in infiltration of monocytes into the spinal cord. • Infiltrating monocytes express the pronociceptive enzyme Cathepsin S (CatS). • A centrally-penetrant CatS antagonist reduces VCR-induced nociception., Chemotherapy-induced neuropathic pain is a dose-limiting side effect of many cancer therapies due to their propensity to accumulate in peripheral nerves, which is facilitated by the permeability of the blood-nerve barrier. Preclinically, the chemotherapy agent vincristine (VCR) activates endothelial cells in the murine peripheral nervous system and in doing so allows the infiltration of monocytes into nerve tissue where they orchestrate the development of VCR-induced nociceptive hypersensitivity. In this study we demonstrate that VCR also activates endothelial cells in the murine central nervous system, increases paracellular permeability and decreases trans endothelial resistance. In in vivo imaging studies in mice, VCR administration results in trafficking of inflammatory monocytes through the endothelium. Indeed, VCR treatment affects the integrity of the blood-spinal cord-barrier as indicated by Evans Blue extravasation, disrupts tight junction coupling and is accompanied by the presence of monocytes in the spinal cord. Such inflammatory monocytes (Iba-1+ CCR2+ Ly6C+ TMEM119- cells) that infiltrate the spinal cord also express the pro-nociceptive cysteine protease Cathepsin S. Systemic treatment with a CNS-penetrant, but not a peripherally-restricted, inhibitor of Cathepsin S prevents the development of VCR-induced hypersensitivity, suggesting that infiltrating monocytes play a functional role in sensitising spinal cord nociceptive neurons. Our findings guide us towards a better understanding of central mechanisms of pain associated with VCR treatment and thus pave the way for the development of innovative antinociceptive strategies.

There is a continual need to develop new therapies for neuropsychiatric disorders such as Schizophrenia, and identifying the underlying molecular processes remains challenging. Chadha et al. recently discovered a potential role for mTOR kinase activity disruption in Schizophrenia and further uncover the precise pathomechanism. Their study sheds further light on the role of mTOR in Schizophrenia and could inform the development of future therapeutic strategies for the condition.

Sepsis-associated encephalopathy, as well as increasing mortality, has been associated with long-lasting depressive behaviour, which is thought to be caused by infection-induced neuroinflammation in the brain. Saito et al. have recently demonstrated in a mouse model of sepsis that infiltrated regulatory T cells in the cerebral cortex mediate the resolution of neuroinflammation and alleviate anxious/depressive behaviour. Their study paves the way for further research that investigates the role of T cells in the underlying mechanisms mediating recovery of sepsis-associated depression.

Here, we discuss evidence for changes in blood–spinal cord barrier permeability and consider the possibility of associated neuroimmune communication changes in models of chronic pain., Advancing our understanding of the underlying mechanisms of chronic pain is instrumental to the identification of new potential therapeutic targets. Neuroimmune communication throughout the pain pathway is of crucial mechanistic importance and has been a major focus of preclinical chronic pain research over the last 2 decades. In the spinal cord, not only do dorsal horn neurons partake in mechanistically important bidirectional communication with resident immune cells such as microglia, but in some cases, they can also partake in bidirectional crosstalk with immune cells, such as monocytes/macrophages, which have infiltrated into the spinal cord from the circulation. The infiltration of immune cells into the spinal cord can be partly regulated by changes in permeability of the blood–spinal cord barrier (BSCB). Here, we discuss evidence for and against a mechanistic role for BSCB disruption and associated changes in neuroimmune crosstalk in preclinical chronic pain. We also consider recent evidence for its potential involvement in the vincristine model of chemotherapy-induced painful neuropathy. We conclude that current knowledge warrants further investigation to establish whether preventing BSCB disruption, or targeting the changes associated with this disruption, could be used for the development of novel approaches to treating chronic pain.

Chronic pain is a distressing yet poorly-treated condition that can arise as a result of diseases and injuries to the nervous system. The development of more efficacious therapies for chronic pain is essential and requires advances in our understanding of its underlying mechanisms. Clinical and preclinical evidence has demonstrated that immune responses play a crucial role in chronic pain. The lysosomal cysteine protease cathepsin S (CatS) plays a key role in such immune response. Here we discuss the preclinical evidence for the mechanistic importance of extracellular CatS in chronic pain focussing on studies utilising drugs and other pharmacological tools that target CatS activity. We also consider the use of CatS inhibitors as potential novel antihyperalgesics, highlighting that the route and timing of delivery would need to be tailored to the initial cause of pain in order to ensure the most effective use of such drugs., Highlights • Cathepsin S plays a key extracellular role in the underlying mechanisms of chronic pain • Pharmacological tools provide crucial evidence for this role and the therapeutic potential of targeting Cathepsin S • The route of delivery and timing of cathepsin S inhibitor administration should be tailored to specific causes of chronic pain

Supplemental Digital Content is Available in the Text. In inflammatory arthritis, we show an imbalance of proresolving bioactive lipid mediators in dorsal root ganglia, under persistent nociceptive states, and antinociceptive effects of maresin-1 administration., Rheumatoid arthritis-associated pain is poorly managed, often persisting when joint inflammation is pharmacologically controlled. Comparably, in the mouse K/BxN serum-transfer model of inflammatory arthritis, hind paw nociceptive hypersensitivity occurs with ankle joint swelling (5 days after immunisation) persisting after swelling has resolved (25 days after immunisation). In this study, lipid mediator (LM) profiling of lumbar dorsal root ganglia (DRG), the site of sensory neuron cell bodies innervating the ankle joints, 5 days and 25 days after serum transfer demonstrated a shift in specialised proresolving LM profiles. Persistent nociception without joint swelling was associated with low concentrations of the specialised proresolving LM Maresin 1 (MaR1) and high macrophage numbers in DRG. MaR1 application to cultured DRG neurons inhibited both capsaicin-induced increase of intracellular calcium ions and release of calcitonin gene-related peptide in a dose-dependent manner. Furthermore, in peritoneal macrophages challenged with lipopolysaccharide, MaR1 reduced proinflammatory cytokine expression. Systemic MaR1 administration caused sustained reversal of nociceptive hypersensitivity and reduced inflammatory macrophage numbers in DRG. Unlike gabapentin, which was used as positive control, systemic MaR1 did not display acute antihyperalgesic action. Therefore, these data suggest that MaR1 effects observed after K/BxN serum transfer relate to modulation of macrophage recruitment, more likely than to direct actions on sensory neurons. Our study highlights that, in DRG, aberrant proresolution mechanisms play a key role in arthritis joint pain dissociated from joint swelling, opening novel approaches for rheumatoid arthritis pain treatment.

The accumulation of amyloid β (Aβ) in the brain is an established feature of Alzheimer’s disease, however mechanisms that regulate Aβ accumulation are not fully understood. In a recent study, Wang et al show that Aβ accumulation in neurons is tightly regulated by cholesterol production in astrocytes. This finding paves the way for future work that will establish whether the selective removal of Aβ by targeting this mechanism has therapeutic potential.

The progressive loss of CD4 + T cells has been recognised as being central to HIV-1 pathogenesis, however a precise understanding of the underlying mechanisms and, consequently, improved therapies have yet to be achieved. Zhang et al. have recently shown in HIV-1 patients that the NLRP3 inflammasome pathway, which plays a key role in innate immunity, is a crucial mediator of the loss of CD4 + T cells. This advance could inform the development of innovative anti-HIV-1 therapies.

Despite being a life-restricting condition, chronic pain remains poorly treated. A better understanding of the underlying mechanisms of chronic pain and thence development of innovative targets is therefore essential. Recently we have started to elucidate the importance of the role of microRNAs (miRs) in preclinical chronic pain. miRs are small, non-coding RNAs that regulate genes including those involved in nociceptive signalling. MiRs can exert their effects both intracellularly and extracellularly, the latter of which requires that they are released either as naked species or packaged in exosomes. Here we discuss changes in miR expression that occur in the dorsal root ganglia in murine models of chronic pain. We consider the downstream targets of changes in miR expression, including voltage-gated ion channels, as well as discuss extracellular consequences such as changes in macrophage phenotype that constitute of means by which neuron-immune cell crosstalk occurs. Such miR-mediated intracellular communication could provide a novel target for the treatment of chronic pain, which would be most effective if tailored to the specific cause of pain. Indeed, we conclude by reviewing evidence for the involvement of miRs in clinical cases of chronic pain, supporting the notion that tailored, miR-targeted therapies could prove to be an effective new strategy for the treatment of chronic pain clinically.

Background A dose-limiting side effect of chemotherapeutic agents such as vincristine (VCR) is neuropathic pain, which is poorly managed at present. Chemokine-mediated immune cell/neuron communication in preclinical VCR-induced pain forms an intriguing basis for the development of analgesics. In a murine VCR model, CX3CR1 receptor-mediated signalling in monocytes/macrophages in the sciatic nerve orchestrates the development of mechanical hypersensitivity (allodynia). CX3CR1-deficient mice however still develop allodynia, albeit delayed; thus, additional underlying mechanisms emerge as VCR accumulates. Whilst both patrolling and inflammatory monocytes express CX3CR1, only inflammatory monocytes express CCR2 receptors. We therefore assessed the role of CCR2 in monocytes in later stages of VCR-induced allodynia. Methods Mechanically evoked hypersensitivity was assessed in VCR-treated CCR2- or CX3CR1-deficient mice. In CX3CR1-deficient mice, the CCR2 antagonist, RS-102895, was also administered. Immunohistochemistry and Western blot analysis were employed to determine monocyte/macrophage infiltration into the sciatic nerve as well as neuronal activation in lumbar DRG, whilst flow cytometry was used to characterise monocytes in CX3CR1-deficient mice. In addition, THP-1 cells were used to assess CX3CR1-CCR2 receptor interactions in vitro, with Western blot analysis and ELISA being used to assess expression of CCR2 and proinflammatory cytokines. Results We show that CCR2 signalling plays a mechanistic role in allodynia that develops in CX3CR1-deficient mice with increasing VCR exposure. Indeed, the CCR2 antagonist, RS-102895, proves ineffective in mice possessing functional CX3CR1 receptors but reduces VCR-induced allodynia in CX3CR1-deficient mice, in which CCR2+ monocytes are elevated by VCR. We suggest that a novel interaction between CX3CR1 and CCR2 receptors in monocytes accounts for the therapeutic effect of RS-102895 in CX3CR1-deficient mice. Indeed, we observe that CCR2, along with its ligand, CCL2, is elevated in the sciatic nerve in CX3CR1-deficient mice, whilst in THP-1 cells (human monocytes), downregulating CX3CR1 upregulates CCR2 expression via p38 MAP kinase signalling. We also show that the CX3CR1-CCR2 interaction in vitro regulates the release of pronociceptive cytokines TNF-α and IL1β. Conclusions Our data suggests that CCL2/CCR2 signalling plays a crucial role in VCR-induced allodynia in CX3CR1-deficient mice, which arises as a result of an interaction between CX3CR1 and CCR2 in monocytes. Electronic supplementary material The online version of this article (10.1186/s12974-018-1116-6) contains supplementary material, which is available to authorized users.

In cancer treatments a dose-limiting side-effect of chemotherapeutic agents is the development of neuropathic pain, which is poorly managed by clinically available drugs at present. Chemotherapy-induced painful neuropathy (CIPN) is a major cause of premature cessation of treatment and so a greater understanding of the underlying mechanisms and the development of novel, more effective therapies, is greatly needed. In some cases, only a weak correlation between chemotherapy-induced pain and neuronal damage is observed both clinically and preclinically. As such, a critical role for non-neuronal cells, such as immune cells, and their communication with neurons in CIPN has recently been appreciated. In this mini-review, we will discuss preclinical evidence for the role of monocytes/macrophages in the periphery in CIPN, with a focus on that which is associated with the chemotherapeutic agents vincristine and paclitaxel. In addition we will discuss the potential mechanisms that regulate monocyte/macrophage-neuron crosstalk in this context. Informed by preclinical data, we will also consider the value of monocytes/macrophages as therapeutic targets for the treatment of CIPN clinically. Approaches that manipulate the signaling pathways discussed in this review show both promise and potential pitfalls. Nonetheless, they are emerging as innovative therapeutic targets with CX3CL1/R1-regulation of monocyte/macrophage-neuron communication currently emerging as a promising front-runner.

Following peripheral axon injury, dysregulation of non-coding microRNAs (miRs) occurs in dorsal root ganglia (DRG) sensory neurons. Here we show that DRG neuron cell bodies release extracellular vesicles, including exosomes containing miRs, upon activity. We demonstrate that miR-21-5p is released in the exosomal fraction of cultured DRG following capsaicin activation of TRPV1 receptors. Pure sensory neuron-derived exosomes released by capsaicin are readily phagocytosed by macrophages in which an increase in miR-21-5p expression promotes a pro-inflammatory phenotype. After nerve injury in mice, miR-21-5p is upregulated in DRG neurons and both intrathecal delivery of a miR-21-5p antagomir and conditional deletion of miR-21 in sensory neurons reduce neuropathic hypersensitivity as well as the extent of inflammatory macrophage recruitment in the DRG. We suggest that upregulation and release of miR-21 contribute to sensory neuron–macrophage communication after damage to the peripheral nerve., Exosomes are known to contain microRNAs (miRs). Here the authors show that dorsal root ganglion neurons release exosomes containing miR-21-5p, which contributes to inflammatory cell recruitment following peripheral nerve injury.

A core structural and functional motif of the vertebrate central nervous system is discrete clusters of neurons or ‘nuclei’. Yet the developmental mechanisms underlying this fundamental mode of organisation are largely unknown. We have previously shown that the assembly of motor neurons into nuclei depends on cadherin-mediated adhesion. Here, we demonstrate that the emergence of mature topography among motor nuclei involves a novel interplay between spontaneous activity, cadherin expression and gap junction communication. We report that nuclei display spontaneous calcium transients, and that changes in the activity patterns coincide with the course of nucleogenesis. We also find that these activity patterns are disrupted by manipulating cadherin or gap junction expression. Furthermore, inhibition of activity disrupts nucleogenesis, suggesting that activity feeds back to maintain integrity among motor neurons within a nucleus. Our study suggests that a network of interactions between cadherins, gap junctions and spontaneous activity governs neuron assembly, presaging circuit formation.

Interactions between the ventral premotor (PMv) and the primary motor cortex (M1) are crucial for transforming an object's geometrical properties, such as its size and shape, into a motor command suitable for grasp of the object. Recently, we showed that PMv interacts with M1 in a specific fashion, depending on the hand posture. However, the functional connectivity between PMv and M1 during the preparation of an actual grasp is still unknown. To address this issue, PMv–M1 interactions were tested while subjects were preparing to grasp different visible objects requiring either a precision grip or a whole hand grasp. A conditioning–test transcranial magnetic stimulation (TMS) paradigm was used: a test stimulus was applied over M1 either in isolation or after a conditioning stimulus delivered, at different delays, over the ipsilateral PMv. Motor evoked potentials (MEPs) were recorded in the first dorsal interosseus and abductor digiti minimi muscles, which show highly differentiated activity according to grasp. While subjects prepared to grasp, delivering a conditioning PMv pulse 6 or 8 msec before a test pulse over M1 strikingly facilitated MEPs in the specific muscles that were used in the upcoming grasp. This degree of facilitation correlated with the amount of muscle activity used later in the trial to grasp the objects. The present results demonstrate that, during grasp preparation, the PMv–M1 interactions are muscle-specific. PMv appears to process the object geometrical properties relevant for the upcoming grasp, and transmits this information to M1, which in turn generates a motor command appropriate for the grasp. We also reveal that the grasp-specific facilitation resulting from PMv–M1 interactions is differently related to the upcoming grasp muscle activity than is that from paired-pulse stimulation over M1, suggesting that these two TMS paradigms assess the excitability of cortico-cortical pathways devoted to the control of grasp at two different levels.