Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis. In the absence of any regulation, excessive acidification of the cytosol would have the tendency to produce cellular damage. Mammalian Na+/H+ exchangers (NHEs) are electroneutral Na+-dependent proteins that exchange extracellular Na+ for intracellular H+. To date, there are 9 identified NHE isoforms where NHE1 is the most ubiquitous member, known as the housekeeping exchanger. NHE1 seems to have a protective role in the ischemia-reperfusion injury and other inflammatory diseases. In nociception, NHE1 is found in neurons along nociceptive pathways, and its pharmacological inhibition increases nociceptive behavior in acute pain models at peripheral and central levels. Electrophysiological studies also show that NHE modulates electrical activity of primary nociceptive terminals. However, its role in neuropathic pain still remains controversial. In humans, NHE1 may be responsible for inflammatory bowel diseases since its expression is reduced in Crohn’s disease and ulcerative colitis. The purpose of this work is to provide a review of the evidence about participation of NHE1 in the nociceptive processing. 1. Introduction Intracellular pH (pHi) is a fundamental parameter to cell function that requires tight homeostasis [1]. In the absence of any regulation, the cytosol would have the tendency to become acidified due to the continuous buildup of metabolic acid (H+) equivalents [2, 3]. Cells have developed means to raise cytosolic pH, guarding against dangerous acidification. Regulation of pHi comprises several processes such as cytosolic H+ buffering, H+ sequestration into cellular organelles, and transmembrane movement of acid equivalents [1, 3, 4]. Cells regulate rapid and localized pH swings by their intrinsic pH buffering capacity which is provided by several intracellular weak acids and bases. Moreover, cells regulate pH through the bicarbonate ( ) buffer system which combines with excess H+ ions to form carbonic acid [5]. Then, carbonic acid is transformed to carbon dioxide (CO2) by the enzyme carbonic anhydrase [5]. The total buffer capacity includes both components [1, 2, 4]. Although effective this buffering system has limited capacity to counteract continuous generation of H+ equivalents by metabolism, ongoing transport of ions that alter the pH (H+ and ), or the presence of diseases that contribute to extracellular acidification (inflammation, hypoxia, or ischemia). The mechanism of regulation of pHi carried out by transporters requires energy as H+ is
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