Ionic Channels and Neuropathic Pain: Phisiopatology and Applications CATERINA AURILIO, * VINCENZO POTA, MARIA CATERINA PACE, MARIA BEATRICE PASSAVANTI, AND MANLIO BARBARISI Department of Anaesthesiology Surgical and Emergency Science, Second University of Studies of Naples, Naples, Italy Neuropathic pain is defined by the International Association for Pain research as a pain associated to a primary lesion or a dysfunction of the central or peripheral system. Over the past few years the causes of the neuropathic pain were not known and there were not good treatments for it, now we have a better knowledge of the physiopathological aspects and there is a wider diffusion of the research for target aimed therapies. The physiologic genesis of nervous messages occurs exclusively in skin sensorial endings or in nerve tissues as a consequence of an adequate sensorial stimulus and depends on the quick variations of the electric potential difference at the endings of ionic membranes. These variations of even 500 V a second are possible because of the presence of ionic channels. In neuropathic pain impulses can be originated even from ectopic sites. Ectopic discharges originated in a peripheral neuropathic system have an important role in the early stage of neuropathic pain development in two different ways. First they give an excess of spontaneous and evoked electric impulses to the central nervous system, causing a primitive neuropathic pain signal; then the ectopic activity develops and maintains the central sensitisation process. All this amplifies the afferent signals deriving from residual efferents that go on innerving cutaneous areas damaged and partly disnerved, causing tactile allodynie. Sodium channels are the greatest responsible for electrogenesis, that is the basis of the action potential generation and its propagation. Action potential begins after a depolarization such that it could cause a membrane transitory modification, turning prevalently permeable to Naþ more than to Kþ as during a release phase. Neuropathy generates a local accumulation of sodium channels, with a consequent increase of density. This remodel seems to be the basis of neuro hyperexecitably. Calcium channels have also an important role in cell working. Intracellular calcium increase contributes to depolarization processes, through kinase and determines the phosphorylation of membrane proteins that can make powerful the efficacy of the channels themselves. In the future new diagnostic opportunities of physiopathologist mechanism leading to neuropathic pain will allow treatments aimed at specific molecular changes of ionic channels. J. Cell. Physiol. 215: 8–14, 2008. ß 2008 Wiley-Liss, Inc. Neuropathic pain is defined by the International Association for Pain research as a pain associated to a primary lesion or a dysfunction of the central or peripheral system. Over the past few years the causes of the neuropathic pain were not known and there were not good treatments for it, now we have a better knowledge of the physiopathological aspects and there is a wider diffusion of the research for target aimed therapies. The physiologic genesis of nervous messages occurs exclusively in skin sensorial endings or in nerve tissues as a consequence of an adequate sensorial stimulus and depends on the quick variations of the electric potential difference at the endings of ionic membranes. These variations of even 500 V a second are possible because of the presence of ionic channels. These ionic channels have three important properties. They let ions pass; they recognize and select different ionic species; they open and close at specific signals that can be of electric, mechanic and chemical nature (Fig. 1a–c). Only in the past 15 years we have known for certain that ionic channels are made up of protein molecules and are not holes made in the membrane lipidic matrix. The main stimuli that can open or close the admission to different ionic channels are three:  Voltage: voltage dependent channels  Neurotransmitters: channels depending on neurotransmit- ters  Stretching and pressure: channels depending on mechanic stimuli In neuropathic pain impulses can be originated even from ectopic sites. Ectopic discharges, originated in a peripheral neuropathic system have an important role in the early stage of neuropathic pain development in two different ways. First they give an excess of spontaneous and evoked electric impulses to the central nervous system, causing a primitive neuropathic pain signal; then the ectopic activity develops and maintains the central sensitization process. All this amplifies the afferent signals deriving from residual efferents that go on innerving cutaneous areas damaged and partly disnerved, causing tactile allodynie. Furthermore it amplifies the spontaneous ectopic input increasing spontaneous disaesthesia and pain. This hyperexcitability of afferent damaged neurons is not due to a synaptic mechanism (Fig. 1d). Instead the hyperexcitability is due to an electrogenic increase inherent neuronal membranes. Ionic channels have a fundamental role in causing membrane hyperexcitability, especially sodium ones. The distinction between membrane hyperexcitability and synaptic action is important even as regards the most suitable drugs in neuropathies. The endogenous systemic opium activate descending inhibitory tracts, causing a synaptic inhibitory action at spinal level, and the NMDA antagonist (Ketamine) activate some forms of spinal amplification of signal dependent activity, blocking the synaptic effect of exciter amino acids as glutamate. Drugs blocking calcium channels have an *Correspondence to: Caterina Aurilio, Department of Anaesthesiology Surgical and Emergency Science, Second University of Studies of Naples, Naples, Italy. E-mail: caterina.aurilio@unina2.it Received 24 April 2007; Accepted 3 August 2007 DOI: 10.1002/jcp.21280 REVIEW ARTICLE 8 Journal of Journal of Cellular Physiology Cellular Physiology ß 2008 WILEY-LISS, INC.