Inflammation and neuroinflammation are critical mechanisms in the generation of neuropathic pain that is experienced in several chronic diseases. The aberrant inflammation that triggers this pathophysiologic process can be tracked down to an exacerbated immune response, which establishes a vicious cycle and continuously recruits inflammatory cells by inducing chronic tissue damage. Recently, impairment of the cellular and molecular machinery orchestrated by specialized pro-resolving mediators (SPMs)—i.e., endogenous lipids termed resolvins, protectins, maresins, and lipoxins that confine the inflammatory cascades in space and time during the “resolution of inflammation”–has emerged as a crucial event in the derangement of the inflammatory homeostasis and the onset of chronic inflammation and pain. Indeed, a deviant inflammatory response that is not adequately controlled by the resolution network leads to the overproduction of pro-inflammatory eicosanoids that, opposite to SPMs, lead to neuropathic pain. Interestingly, in the last two decades convincing evidence has demonstrated that SPMs antagonize the in vivo activity of pro-inflammatory eicosanoids and, overall, exert potent anti-hyperalgesic effects in a number of pain-associated paradigms of disease, such as arthritis and chemotherapy-induced peripheral neuropathy, as well as in many experimental models of pain like mechanical allodynia, chemical pain, heat hypersensitivity and phase 1 and 2 inflammatory pain. Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected. Here, we aim at presenting a state-of-the-art view of SPMs, their metabolism and signalling, in the context of cellular and molecular pathways associated to neuropathic pain.
Since the first Apollo mission in 1969, microgravity has been linked to many alterations of astronauts’ physiology, among which immunosuppression, altered inflammation and bone loss represent relevant examples. In the past 40 years, extensive investigations have been conducted in order to characterize the molecular mechanisms driving the alterations caused by prolonged weightlessness on human health. However, almost all studies eluded the role played by bioactive lipids, a vastly heterogeneous class of endogenous molecules, which, under normal conditions, control immune and bone homeostasis. This is somewhat surprising, because it is widely accepted that pathological derangement of the production or signalling of these endogenous compounds leads to the onset and/or progression of numerous diseases. In particular, eicosanoids and endocannabinoids are known to play a role in immune responses and bone remodelling. Both classes represent the only lipids as yet investigated in Space, and are increasingly recognised as promising therapeutic candidates to combat different human disorders. This review summarizes evidence gathered in the past two decades on the changes in these two pivotal lipid signalling systems, through both simulated and authentic weightlessness (i.e., on board the International Space Station and in parabolic flights).
In the context of Space Medicine, the aim of "SERiSM" (Role of the Endocannabinoid System in Reprogramming human pluripotent Stem cells under Microgravity) project, selected by the Italian Space Agency, was to study the involvement of the endocannabinoid system (ECS) in the osteogenic differentiation under real microgravity. An innovative and easily accessible stem cell model derived from human blood (human blood-derived stem cells, hBDSCs) was used to this purpose. This model is autologous and possesses a remarkable proliferative and differentiative capacity underground gravity conditions, with high therapeutic potential for bone degenerative diseases. ECS is a fine network of proteins that interact to regulate the endogenous levels of lipid mediators, collectively termed endocannabinoids (eCBs), which in turn are involved in cell communication and in the mechanisms governing the switch between cell life and death. In the frame of the VITA mission, led by European Space Agency (ESA) astronaut Paolo Nespoli, we analyzed the differentiation process also under microgravity condition and evaluated the expression of ECS proteins through immunoassay methods. Our results demonstrate that some elements of the ECS are modulated during the differentiation process and in microgravity, supporting the idea that increased levels of anandamide are indeed need to stimulate type-1 cannabinoid receptor. In conclusion, microgravity could drive endocannabinoid signalling in the former stages of hBDSCs differentiation.
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