Pain
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The formalin test still surprises with its biphasic pain-related behavior resulting from a quiescent interphase that does not occur with other algogenic compounds and remains unexplained. The first phase has been attributed to TRPA1-mediated excitation of nociceptors, the second phase to their inflammatory and/or spinal sensitization. We show that the second and interphase require higher formaldehyde concentrations to emerge, and that from 12 mM on calcium influx is induced in TRPA1-deficient sensory neurons as well as in native HEK293T cells. ⋯ The parameters gained were entered into a computational model to predict the activation pattern of primary afferents. The model supports a peripherally generated biphasic response, the time course matching the behavioral results. In conclusion, the interphase is a result of hyperpolarization and transient inactivation by formaldehyde of the surviving neurons; their recovery and the centrifugal spread of formalin in the skin induce a second phase of nociceptive activity before the formalin concentration falls below threshold.
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Inflammatory and degenerative diseases of the joint are major causes of chronic pain. Long-lasting pain symptoms are thought to result from a central sensitization of nociceptive circuits. These processes include activation of microglia and spinal disinhibition. ⋯ In the spinal cord, EFX analgesia was accompanied by a reduction in microglial activation and in the levels of proinflammatory mediators. Using electrophysiological tools, we found that EFX treatment not only amplified spinal GABAergic inhibition, but also prevented prostaglandin E2-induced glycinergic disinhibition and restored a "normal" spinal pain processing. Because EFX is already distributed in several countries under the trade name of Stresam for its anxiolytic actions in humans, new clinical trials are now required to further extend its therapeutic indications as pain killer.