L Bernal1, J A Lopez-Garcia1, C Roza1. 1. Dpto. Biología de Sistemas, Edificio de Medicina Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
Abstract
BACKGROUND: Spontaneous pain is the most devastating positive symptom in neuropathic pain patients. Recent data show a direct relationship between spontaneous discharges in C-fibres and spontaneous pain in neuropathic patients. Unfortunately, to date there is a lack of experimental animal models for drug testing. METHODS: We recorded afferent fibres from a new experimental model in vitro. The preparation contains a neuroma formed in a peripheral branch of the saphenous nerve together with the undamaged branches, which maintain intact terminals in a skin flap. RESULTS: Fibres with stable rates of ectopic spontaneous discharges were found among axotomized (5 A- and 18 C-fibres, mean discharge 0.48 ± 0.08 Hz) and 'putative intact' fibres (12 C-fibres, mean discharge 0.28 ± 0.08 Hz). A proportion (~9%) of axotomized fibres had mechanical receptive fields in the skin far beyond the site of injury. Collision experiments demonstrated that action potentials evoked from neuroma and skin travelled by the same fibre, indicating functional cross-talk between neuromatose and putative intact fibres. Retigabine, the specific Kv7 channel opener, depressed spontaneous discharges by 70% in 15/18 units tested. In contrast, responses to mechanical stimulation of the skin were unaltered by retigabine. CONCLUSIONS: Partial damage to a peripheral nerve may increase the incidence of spontaneous activity in C-fibres. Retigabine reduced spontaneous activity but not stimulus-evoked activity, suggesting an important role for ion channels in the control of spontaneous pain and demonstrating the utility of the model for the testing of compounds in clinically relevant variables. WHAT DOES THIS STUDY ADD?: Our in vitro experimental model of peripheral neuropathy allows for pharmacological characterization of spontaneously active fibres. Using this model, we show that retigabine inhibits aberrant spontaneous discharges without altering physiological responses in primary afferents.
BACKGROUND: Spontaneous pain is the most devastating positive symptom in neuropathic painpatients. Recent data show a direct relationship between spontaneous discharges in C-fibres and spontaneous pain in neuropathicpatients. Unfortunately, to date there is a lack of experimental animal models for drug testing. METHODS: We recorded afferent fibres from a new experimental model in vitro. The preparation contains a neuroma formed in a peripheral branch of the saphenous nerve together with the undamaged branches, which maintain intact terminals in a skin flap. RESULTS: Fibres with stable rates of ectopic spontaneous discharges were found among axotomized (5 A- and 18 C-fibres, mean discharge 0.48 ± 0.08 Hz) and 'putative intact' fibres (12 C-fibres, mean discharge 0.28 ± 0.08 Hz). A proportion (~9%) of axotomized fibres had mechanical receptive fields in the skin far beyond the site of injury. Collision experiments demonstrated that action potentials evoked from neuroma and skin travelled by the same fibre, indicating functional cross-talk between neuromatose and putative intact fibres. Retigabine, the specific Kv7 channel opener, depressed spontaneous discharges by 70% in 15/18 units tested. In contrast, responses to mechanical stimulation of the skin were unaltered by retigabine. CONCLUSIONS: Partial damage to a peripheral nerve may increase the incidence of spontaneous activity in C-fibres. Retigabine reduced spontaneous activity but not stimulus-evoked activity, suggesting an important role for ion channels in the control of spontaneous pain and demonstrating the utility of the model for the testing of compounds in clinically relevant variables. WHAT DOES THIS STUDY ADD?: Our in vitro experimental model of peripheral neuropathy allows for pharmacological characterization of spontaneously active fibres. Using this model, we show that retigabine inhibits aberrant spontaneous discharges without altering physiological responses in primary afferents.
Authors: Zizhen Wu; Lin Li; Fuhua Xie; Junhui Du; Yan Zuo; Jeffrey A Frost; Susan M Carlton; Edgar T Walters; Qing Yang Journal: J Neurotrauma Date: 2017-02-27 Impact factor: 5.269
Authors: Robert Y North; Max A Odem; Yan Li; Claudio Esteves Tatsui; Ryan M Cassidy; Patrick M Dougherty; Edgar T Walters Journal: J Pain Date: 2022-03-12 Impact factor: 5.383
Authors: Omer Barkai; Robert H Goldstein; Yaki Caspi; Ben Katz; Shaya Lev; Alexander M Binshtok Journal: Front Mol Neurosci Date: 2017-06-13 Impact factor: 5.639
Authors: Carolina Roza; José A Campos-Sandoval; María C Gómez-García; Ana Peñalver; Javier Márquez Journal: Front Mol Neurosci Date: 2019-05-28 Impact factor: 5.639
Authors: Max A Odem; Alexis G Bavencoffe; Ryan M Cassidy; Elia R Lopez; Jinbin Tian; Carmen W Dessauer; Edgar T Walters Journal: Pain Date: 2018-11 Impact factor: 7.926