Role of NHE1 in Nociception

Abstract

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.

Functional NHE1 expression is critical to blood brain barrier integrity and sumatriptan blood to brain uptake

“…Our results correspond well with the former data published showing that blockade of peripheral, as well as spinal, NHE1 by administration of selective and non-selective inhibitors, such as zoniporide, amiloride, and 5-(N,N-dimethyl)-amiloride increased pain behavior in capsaicin, serotonin, and formalin tests [73][74][75][76]. In line with these experiments, electrophysiological studies showed that the blockade of NHE1 can modulate electrical activity of primary nociceptive terminals [47].…”

“…The reduction of NHE1 functional expression seems to be beneficial to conserve paracellular BBB integrity, however, the data showing facial sensitivity induced by a single, systemic dose of zoniporide raises question about the overall positive effect of NHE1 blockade in migraine/secondary headache patients. The role of NHE1 in nociception has been recently discovered, suggesting a protective role of NHE1 in acute and chronic inflammatory pain [47]. Our results correspond well with the former data published showing that blockade of peripheral, as well as spinal, NHE1 by administration of selective and non-selective inhibitors, such as zoniporide, amiloride, and 5-(N,N-dimethyl)-amiloride increased pain behavior in capsaicin, serotonin, and formalin tests [73][74][75][76].…”

“…A recent review paper discussed the role of NHE1 in nociception, drawing attention its possible protective role in pain models [47]. These studies and our observation that pretreatment with zoniporide did not fully prevent the induction of the KCl-mediated periorbital allodynia led to evaluation of the effect of zoniporide administration in the absence of sumatriptan after cortical aCSF or KCl injections; rats were treated with zoniporide (1 mg/kg, IP) at 10 min before cortical KCl or aCSF injection (Fig 5D).…”

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

“…NHE1 is the most extensively studied of the four isoforms. It has been implicated in pain 35 , several diseases, e.g. myocardial hypertrophy 36 and cancer.…”

Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification

“…However, other scenarios could explain the amiloride effect on gene expression. Zhou et al pointed to the role of NHE1, the most ubiquitous member of the mammalian Na + /H + exchanger family [ 21 , 38 ], as a signaling protein involved in gene expression regulation [ 39 ]. In the brain of a spontaneous NHE1 null mutant mouse strain, several genes were significantly up- or downregulated.…”