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.
HighlightsVincristine (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.
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.
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 CX 3 CR1, 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.
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.
It doesn't take much to disrupt our sleep. Whilst we are aware of environmental factors that can disturb our circadian rhythms, the precise mechanisms that control molecular time cues have remained elusive. Beesley and co-workers demonstrate that diseases associated with cytoplasmic crowding affect the sleep-wake cycle. They also pinpoint a precise time-limiting step in the trafficking of the pacemaker protein PERIOD.
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.
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