Neuroscience
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The noradrenergic system is crucial for several activities in the body, including the modulation of pain. As the major producer of noradrenaline (NA) in the central nervous system (CNS), the Locus Coeruleus (LC) is a nucleus that has been studied in several pain conditions, mostly due to its strategic location. ⋯ The main goal of this review is to bring together the data available regarding the noradrenergic system in relation to pain, particularly focusing on the ascending and descending LC projections in different conditions. How such findings influence our understanding of these conditions is also discussed.
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We have witnessed an accelerated growth of photonics technologies in recent years to enable not only monitoring the activity of specific neurons, while animals are performing certain types of behavior, but also testing whether specific cells, circuits, and regions are sufficient or necessary for initiating, maintaining, or altering this or that behavior. Compared to other sensory systems, however, such as the visual or olfactory system, photonics applications in pain research are only beginning to emerge. One reason pain studies have lagged behind is that many of the techniques originally developed cannot be directly implemented to study key relay sites within pain pathways, such as the skin, dorsal root ganglia, spinal cord, and brainstem. ⋯ We review a number of strategies to circumvent these challenges, by delivering light into, and collecting it from the different key sites to unravel how nociceptive signals are encoded at each level of the neuraxis. We conclude with an outlook on novel imaging modalities for label-free chemical detection and opportunities for multimodal interrogation in vivo. While many challenges remain, these advances offer unprecedented opportunities to bridge cellular approaches with context-relevant behavioral testing, an essential step toward improving translation of basic research findings into clinical applications.
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Fibromyalgia is the current term for chronic widespread musculoskeletal pain for which no alternative cause can be identified. The underlying mechanisms, in both human and animal studies, for the continued pain in individuals with fibromyalgia will be explored in this review. There is a substantial amount of support for alterations of central nervous system nociceptive processing in people with fibromyalgia, and that psychological factors such as stress can enhance the pain experience. ⋯ We will explore the data and neurobiology related to the role of the CNS in nociceptive processing, followed by a short review of studies examining potential peripheral nervous system changes and cytokine involvement. We will not only explore the data from human subjects with fibromyalgia but will relate this to findings from animal models of fibromyalgia. We conclude that fibromyalgia and related disorders are heterogenous conditions with a complicated pathobiology with patients falling along a continuum with one end a purely peripherally driven painful condition and the other end of the continuum is when pain is purely centrally driven.
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The main focus for the development of adenosine targets as analgesics to date has been A1Rs due to its antinociceptive profile in various preclinical pain models. The usefulness of systemic A1R agonists may be limited by other effects (cardiovascular, motor), but enhanced selectivity for pain might occur with partial agonists, potent and highly selective agonists, or allosteric modulators. A2AR agonists exhibit some peripheral pronociceptive effects, but also act on immune cells to suppress inflammation and on spinal glia to suppress pain signaling and may be useful for inflammatory and neuropathic pain. ⋯ Endogenous adenosine contributes to antinociception by several pharmacological agents, herbal remedies, acupuncture, transcutaneous electrical nerve stimulation, exercise, joint mobilization, and water immersion via spinal and/or peripheral effects, such that this system appears to constitute a major pain regulatory system. Finally, caffeine inhibits A1-, A2A- and A3Rs with similar potency, and dietary caffeine intake will need attention in trials of: (a) agonists and/or modulators acting at these receptors, (b) some pharmacological and herbal analgesics, and (c) manipulations that enhance endogenous adenosine levels, all of which are inhibited by caffeine and/or A1R antagonists in preclinical studies. All adenosine receptors have effects on spinal glial cells in regulating nociception, and gender differences in the involvement of such cells in chronic neuropathic pain indicate gender may also need attention in preclinical and human trials evaluating the efficacy of adenosine-based analgesics.
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Opioids produce strong analgesia but their use is limited by a paradoxical hypersensitivity named opioid-induced hyperalgesia (OIH) that may be associated to analgesic tolerance. In the last decades, a significant number of preclinical studies have investigated the factors that modulate OIH development as well as the cellular and molecular mechanisms underlying OIH. Several factors have been shown to influence OIH including the genetic background and sex differences of experimental animals as well as the opioid regimen. ⋯ Neurons and glial cells exert synergistic effects, which contribute to OIH. The molecular actors identified include the Toll-like receptor 4 and the anti-opioid systems as well as some other excitatory molecules, receptors, channels, chemokines, pro-inflammatory cytokines or lipids. This review summarizes the intracellular and intercellular pathways involved in OIH and highlights some mechanisms that may be challenged to limit OIH in the future.