Pain
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The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. ⋯ To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.
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Comparative Study
Fast non-genomic effects of progesterone-derived neurosteroids on nociceptive thresholds and pain symptoms.
Fast Inhibitory controls mediated by glycine (GlyRs) and GABAA receptors (GABAARs) play an important role to prevent the apparition of pathological pain symptoms of allodynia and hyperalgesia. The use of positive allosteric modulators of these receptors, specifically expressed in the spinal cord, may represent an interesting strategy to limit or block pain expression. In this study, we have used stereoisomers of progesterone metabolites, acting only via non-genomic effects, in order to evaluate the contribution of GlyRs and GABAARs for the reduction of mechanical and thermal heat hypernociception. ⋯ We clearly show that 3alpha5beta neurosteroid exerts an antinociceptive effect via a positive allosteric modulation of GABAARs but, at the same time, is pronociceptive by reducing GlyR function. This illustrates the importance of the inhibitory amino acid receptor channels and their allosteric modulators in spinal pain processing. Moreover, our results indicate that neurosteroids, which are synthesized in the dorsal horn of the spinal cord and have limited side effects, may be of significant interest in order to treat pathological pain symptoms.
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The synaptic vesicle protein synapsin II is specifically expressed in synaptic terminals of primary afferent nociceptive neurons and regulates transmitter release in the spinal cord dorsal horn. Here, we assessed its role in nerve injury-evoked molecular and behavioral adaptations in models of peripheral neuropathic pain using mice genetically lacking synapsin II. Deficiency of synapsin II resulted in reduced mechanical and cold allodynia in two models of peripheral neuropathic pain. ⋯ In addition, the expression of the vesicular glutamate transporters, VGLUT1 and VGLUT2, was strongly reduced in synapsin II knockout mice in the spinal cord. Conversely, synapsin II knockout mice showed a stronger and longer-lasting increase of GABA in lamina II of the dorsal horn after nerve injury than wild type mice. These results suggest that synapsin II is involved in the regulation of glutamate and GABA release in the spinal cord after nerve injury, and that a imbalance between glutamatergic and GABAergic synaptic transmission contributes to the manifestation of neuropathic pain.
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Randomized Controlled Trial Comparative Study
Effects of morphine on the experimental illusion of pain produced by a thermal grill.
We compared the effects of systemic morphine on normal (heat and cold) pain and paradoxical burning pain evoked by the simultaneous application of innocuous warm and cold stimuli to the skin. Twelve healthy volunteers participated in a randomised, double-blind, cross-over study to compare the effects of intravenous administration of morphine (0.025 or 0.1mg/kg) or placebo (saline). Stimuli were applied to the palm of the right hand with a thermode ("thermal grill") composed of six bars, whose temperatures were controlled by Peltier elements. ⋯ No differences were observed for non-painful thermal sensations. The paradoxical burning pain evoked by a thermal grill can be modified pharmacologically by analgesics and share some mechanisms with normal pain. This unique experimental "illusion of pain" may represent a new model to test analgesics in healthy volunteers.
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Comparative Study
The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation.
Long-term potentiation (LTP) of nociceptive synaptic transmission induced by high-frequency electrical stimulation (HFS) predominantly modulates natural somatosensory perceptions mediated by Adelta- and Abeta-fibers in humans at the site of conditioning stimulation. The relative contribution of homo- and heterosynaptic mechanisms underlying those perceptual changes remained unclear. We therefore compared changes of the somatosensory profile between a conditioned skin site (homotopic zone) and an area adjacent to conditioning HFS (heterotopic zone). ⋯ Moreover, a small decrease of thresholds to blunt pressure was found at both zones (p<0.05). Pain summation (windup ratio), mechanical detection threshold as well as vibration detection threshold remained unchanged. Because none of the changes in sensory parameters was unique for the site of conditioning stimulation, these data suggest that heterosynaptic interactions are the predominant mechanism of LTP in nociceptive pathways.