Handbook of experimental pharmacology
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The pseudounipolar sensory neurons of the dorsal root ganglia (DRG) give rise to peripheral branches that convert thermal, mechanical, and chemical stimuli into electrical signals that are transmitted via central branches to the spinal cord. These neurons express unique combinations of tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na(+) channels that contribute to the resting membrane potential, action potential threshold, and regulate neuronal firing frequency. The small-diameter neurons (<25 μm) isolated from the DRG represent the cell bodies of C-fiber nociceptors that express both TTX-S and TTX-R Na(+) currents. ⋯ Post-translational regulation of Na(+) channels by protein kinases (PKA, PKC, MAPK) alter the expression and function of the channels. Injury-induced changes in these signaling pathways have been linked to sensory neuron hyperexcitability and pain. This review examines the signaling pathways and regulatory mechanisms that modulate the voltage-gated Na(+) channels of sensory neurons.
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Handb Exp Pharmacol · Jan 2014
ReviewClinical and ethical implications of placebo effects: enhancing patients' benefits from pain treatment.
Expectancy and learning are the core psychological mechanisms of placebo analgesia. They interact with further psychological processes such as emotions and motivations (e.g., anxiety, desire for relief), somatic focus, or cognitions (e.g., attitudes toward the treatment). The development of placebo responsiveness and the actual placebo response in a person is the result of the complex interaction between factors traced back to the individual learning history related to analgesic drugs or treatments and factors of the current context referring to the analgesic or placebo treatment. ⋯ It joins aspects of the learning history (preexisting experiences and preexisting expectations) of a patient with aspects of the current context (current expectation as a result of external and internal situation in which a pain medication/treatment/placebo is taken, e.g., current information about pain medication, current specific context/cues, desire for pain relief, certainty about upcoming pain relief, current expectation about pain reducing course, current selective attention, increased pain experience, or decreased pain experience). In order to exploit placebo efficacy for an analgesic treatment it is worthwhile to assess in which direction each of these factors exerts its influence in order to maximize placebo effects for a specific patient. By applying placebo mechanisms in this differentiated way, the efficacy of pain treatment can be deliberately boosted.
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Handb Exp Pharmacol · Jan 2014
ReviewLearned placebo responses in neuroendocrine and immune functions.
The phenomenon of learned placebo responses in neuroendocrine and immune functions is a fascinating example of communication between the brain and both the endocrine and peripheral immune systems. In this chapter, we will give a short overview of afferent and efferent communication pathways, as well as the central mechanisms, which steer the behavioral conditioned immune response. Subsequently, we will focus on data that provides evidence for learned immune responses in experimental animals and learned neuroendocrine and immune placebo responses in humans. ⋯ Together, these findings not only provide an excellent basis to increase our understanding of human biology but may also have far reaching clinical implications. They pave the way for the ultimate aim of employing associative learning protocols as supportive treatment strategies in pharmacological regimens. As a result, medication levels may be reduced, as well as their unwanted side effects, providing a maximized therapeutic outcome to the benefit of the patient.
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In this chapter we present and discuss recent studies on the mechanisms underlying placebo and nocebo effects in physical performance, showing how expectations and both pharmacological and nonpharmacological preconditioning procedures can be very effective in inducing placebo responses, with important implications for sport competitions. Furthermore, we place these findings within the biological model of central governor of fatigue, whose main goal is to protect our body from damage. A crucial aspect of this emerging field of placebo studies is related to the limit beyond which these procedures can be called doping in all respects.
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Handb Exp Pharmacol · Jan 2014
ReviewProbing gating mechanisms of sodium channels using pore blockers.
Several classes of small molecules and peptides bind at the central pore of voltage-gated sodium channels either from the extracellular or intracellular side of the membrane and block ion conduction through the pore. Biophysical studies that shed light on the chemical nature, accessibility, and kinetics of binding of these naturally occurring and synthetic compounds reveal a wealth of information about how these channels gate. Here, we discuss insights into the structural underpinnings of gating of the channel pore and its coupling to the voltage sensors obtained from pore blockers including site 1 neurotoxins and local anesthetics.