Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale
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Transient receptor potential receptors (TRP) on primary afferent neurons respond to noxious and/or thermal stimuli. TRPV1 receptors can be activated by noxious heat, acid, capsaicin and resiniferatoxin, leading to burning pain or itch mediated by discharges in C polymodal and Adelta mechano-heat nociceptors and in central neurons, including spinothalamic tract (STT) cells. Central nociceptive transmission involves both non-NMDA and NMDA receptors, and inhibitory interneurons as well as projection neurons contribute to the neural interactions. ⋯ Central sensitization depends on activation of several protein kinases and other enzymes, such as nitric oxide synthase. This process is regulated by protein phosphatases. Central sensitization can be regarded as a spinal cord form of long-term potentiation.
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Bradykinin is an endogenous nonapeptide known to induce pain and hyperalgesia to heat and mechanical stimulation. Correspondingly, it excites nociceptors in various tissues and sensitizes them to heat, whereas sensitizing effect on the mechanical response of nociceptors is not well established. ⋯ In addition, TRPA1 and other ion channels appear to contribute to excitation caused by bradykinin. Finally, prostaglandins sensitize bradykinin-induced excitation in normal tissues by restoring desensitized responses due to the inhibition of protein kinase A.
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Microneurography is a method for recording single unit action potentials with microelectrodes from the nerves of awake cooperating humans. Although this method is now in use since almost 40 years, its potency has been strengthened by the recent technical developments. A great progress was the discovery that different functional groups of nociceptors are characterized by a distinctly different post-excitatory slowing of their conduction velocities. ⋯ It has been shown that different types of neuropathies are characterized by different patterns of abnormal nociceptor functions. Although some of them are characterized by abnormal spontaneous activity in C-nociceptors, others show mainly signs of denervation. Microneurography is, therefore, a tool for translational studies on human nociceptor functions by linking direct animal studies on experimental neuropathies with human diseases.
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The capsaicin receptor TRPV1 is a polymodal sensory transducer molecule in the pain pathway. TRPV1 integrates noxious heat, tissue acidosis and chemical stimuli which are all known to cause pain. Studies on TRPV1-deficient mice suggest that TRPV1 is essential for acid sensing by nociceptors and for thermal hyperalgesia in inflammation of the skin, but not for transducing noxious heat. ⋯ On the contrary, the proton and heat-induced discharge responses of the single fibres were not influenced. Additionally, we found that the dye concentration dependently increases the excitability of the neurons resulting in ongoing activity and burstlike discharge. These differential results are discussed in the light of recent findings from transgenic mouse models, and they point once more to major (pharmacological) differences between cellular models of nociception, including spinal ganglion neuron and transfected cell lines, and the real native nerve endings.
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Morphologically, muscle nociceptors are free nerve endings connected to the CNS by thin myelinated (group III) or unmyelinated (group IV) afferent fibers. Not all of these endings are nociceptive; approximately 40% have a low mechanical threshold and likely fulfill non-nociceptive functions. Two chemical stimuli are particularly relevant as causes of muscle pain. ⋯ However, stimulants such as ATP, NGF, and solutions of low pH were found to be less effective in inflamed muscle. A possible explanation for this surprising finding is that in inflamed muscle the concentrations of ATP and NGF and H+ are increased. Therefore, experimental administration of these agents is a less effective stimulus.