Pain
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Activation of glial cells and neuro-glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. ⋯ Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of "gliopathy," that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions.
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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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Observational Study
Longitudinal Relationships between Anxiety, Depression, and Pain: Results from a Two Year Cohort Study of Lower Extremity Trauma Patients.
Previous studies have shown that pain, depression, and anxiety are common after trauma. A longitudinal relationship between depression, anxiety, and chronic pain has been hypothesized. Severe lower extremity trauma patients (n = 545) were followed at 3, 6, 12, and 24 months after injury using a visual analog "present pain intensity" scale and the depression and anxiety scales of the Brief Symptom Inventory. ⋯ The results suggest that in the early phase after trauma, pain predicts anxiety and depression, but the magnitude of these relationships are smaller than the longitudinal relationship from anxiety to pain over this period. In the late (or chronic) phase after injury, the longitudinal relationship from anxiety on pain nearly doubles and is the only significant relationship. Despite missing data and a single item measure of pain intensity, these results provide evidence that negative mood, specifically anxiety, has an important role in the persistence of acute pain.