Pain
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The rich diversity of lipids and the specific signalling pathways they recruit provides tremendous scope for modulation of biological functions. Lysophosphatidylinositol (LPI) is emerging as a key modulator of cell proliferation, migration, and function, and holds important pathophysiological implications due to its high levels in diseased tissues, such as in cancer. ⋯ Using pharmacological and conditional genetic tools in mice, we delineated receptor-mediated from non-receptor-mediated effects of LPI and we observed that GPR55, which functions as an LPI receptor when heterologously expressed in mammalian cells, only partially mediates LPI-induced actions in the context of pain sensitization in vivo; we demonstrate that, in vivo, LPI functions by activating Gα(13) as well as Gα(q/11) arms of G-protein signalling in sensory neurons. This study thus reports a novel pathophysiological function for LPI and elucidates underlying molecular mechanisms.
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The molecular/genetic era has seen the discovery of a staggering number of molecules implicated in pain mechanisms [18,35,61,69,96,133,150,202,224]. This has stimulated pharmaceutical and biotechnology companies to invest billions of dollars to develop drugs that enhance or inhibit the function of many these molecules. Unfortunately this effort has provided a remarkably small return on this investment. ⋯ To paraphrase a recent editorial in Science magazine [223], although we live in the Golden age of Genetics, the fundamental unit of biology is still arguably the cell, and the cell is the critical structural and functional setting in which the function of pain-related molecules must be understood. This review summarizes our current understanding of the nociceptor as a cell-biological unit that responds to a variety of extracellular inputs with a complex and highly organized interaction of signaling molecules. We also discuss the insights that this approach is providing into peripheral mechanisms of chronic pain and sex dependence in pain.
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After 4 millennia of more or less documented history of cannabis use, the identification of cannabinoids, and of Δ(9)-tetrahydrocannabinol in particular, occurred only during the early 1960s, and the cloning of cannabinoid CB1 and CB2 receptors, as well as the discovery of endocannabinoids and their metabolic enzymes, in the 1990s. Despite this initial relatively slow progress of cannabinoid research, the turn of the century marked an incredible acceleration in discoveries on the "endocannabinoid signaling system," its role in physiological and pathological conditions, and pain in particular, its pharmacological targeting with selective agonists, antagonists, and inhibitors of metabolism, and its previously unsuspected complexity. ⋯ In fact, these molecules, as compared to "magic bullets," seem to offer the advantage of modulating the "endocannabinoidome" in a safer and more therapeutically efficacious way. This approach has provided so far promising preclinical results potentially useful for the future efficacious and safe treatment of chronic pain and inflammation.
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Cut points that classify pain intensity into mild, moderate, and severe levels are widely used in pain research and clinical practice. At present, there are no agreed-upon cut points for the visual analog scale (VAS) in pediatric samples. We applied a method based on Serlin and colleagues' procedure (Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. ⋯ We found a set of cut points that can be used both parental ratings of their children's pain and self-reports for adolescents. Adopting these cut points greatly enhances the comparability of trials. We call for more systematic assessment of diagnostic procedures in pain research.
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There has been a tension between the needs of regulators and industry to demonstrate that interventions are effective and safe, and the needs of professionals to understand how well interventions will work for their patients, and patients to understand what might work for them as individuals. The custom has been to focus on statistical outcomes based on average results, but in-depth analysis based on outcomes obtained by individual patients demonstrates that few are average. ⋯ This changes how benefit and risk are seen; nonresponders should stop treatments that don't work and not, therefore, be exposed to risks, while responders have very large benefits to offset against rare but potentially serious harm. This alternative view, patient-centred and practice-orientated, has major implications for clinical practice, how and why we do clinical trials and how they are designed, how health economic evaluations are done, for decisions made by regulatory and other bodies, and for the theory and practice of evidence-based medicine.