Pain
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It is increasingly recognized that pain-induced plasticity may not only provoke sensory gain (hyperalgesia), but also sensory decline, i.e. hypoesthesia and hypoalgesia. We investigated perceptual changes by conditioning electrical stimulation of peptidergic C-nociceptors differing in stimulation frequencies and duty cycles at the left forearm. Four noxious electrical stimulation paradigms (Stim1: 0.5 Hz, continuously; Stim2: 20 Hz, continuously; Stim3: 1s 20 Hz train, 1s break; Stim4: 1s 20 Hz train, 2s break) were applied. ⋯ In summary, we describe here that depending on the applied frequencies and duty cycles, either sensory gain (i.e. hyperalgesia) or sensory decline (i.e. hypoesthesia and hypoalgesia) can be induced. Sensory decline was found to be centrally mediated. Underlying mechanisms may include differential recruitment of inhibitory and facilitating gain control systems leading to homo- and heterosynaptic inhibition or facilitation at the level of the spinal cord or interference of noxious input with tactile processing in the cortex.
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Comparative Study
Retigabine, the specific KCNQ channel opener, blocks ectopic discharges in axotomized sensory fibres.
The M-current has been proposed as a potential target for analgesia under neuropathic pain conditions. M-currents and/or their molecular correlates, KCNQ proteins, have been demonstrated in key elements of the nociceptive system including spinal and dorsal root ganglion neurons. Here we demonstrate that retigabine, a selective KCNQ channel opener, applied at neuromatose endings modulates the excitability of axotomized fibres inhibiting ectopic discharges. ⋯ Application of XE-991 (10 microM), a KCNQ channel blocker, had no effect on responses to stimulation of the neuroma but blocked the effects of retigabine indicating a specific involvement of KCNQ channels. In contrast to the strong effects on ectopic discharges, retigabine did not change responses to stimulation recorded from intact receptors. Results indicate that KCNQ channel opening at axotomized endings may constitute a novel and selective mechanism for modulation of some neuropathic pain symptoms.