Interaction of NHE1 and TRPA1 Activity in DRG Neurons Isolated from Adult Rats and its Role in Inflammatory Nociception

• Published in: Neuroscience 2021-06, Vol.465, p.154-165
• Main Authors: Martínez-Rojas, Vladimir A., Salinas-Abarca, Ana B., Gómez-Víquez, Norma L., Granados-Soto, Vinicio, Mercado, Francisco, Murbartián, Janet
• Format: Article
• Language: English
• Subjects: Animals; Ganglia, Spinal; inflammatory pain; intracellular acidification; intracellular calcium; Neurons; NHE1; Nociception; Rats; Sodium-Hydrogen Exchanger 1; Transient Receptor Potential Channels; TRPA1; TRPA1 Cation Channel
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2021.04.025

•Zoniporide reduced pHi and increased intracellular calcium concentration in small DRG neurons sensitive to AITC.•A-967079 prevented zoniporide-induced increased intracellular calcium in small DRG neurons.•Zoniporide reduced TRPA1 channel desensitization induced by AITC in DRG neurons.•Zoniporide increased CFA-induced mechanical hypersensitivity, and this effect is prevented by a TRPA1 blocker.•CFA up-regulated TRPA1 and down-regulated NHE1 protein expression in DRG. Transient receptor potential ankyrin 1 (TRPA1) channel is expressed in a subset of nociceptive neurons. This channel integrates several nociceptive signals. Particularly, it is modulated by intracellular pH (pHi). Na+/H+ exchanger 1 (NHE1) contributes to the maintenance of pHi in nociceptors. However, it is currently unknown whether the interaction between TRPA1 and NHE1 contributes to the nociceptive processing. Thus, the purpose of this study was to assess the functional interaction between NHE1 and TRPA1 in small dorsal root ganglion (DRG) neurons from primary culture obtained from adult rats. Moreover, we also evaluated their possible interaction in acute and inflammatory pain. Zoniporide (selective NHE1 inhibitor) reduced pHi and increased intracellular calcium in a concentration-dependent fashion in DRG neurons. Zoniporide and allyl isothiocyanate (AITC, TRPA1 agonist) increased calcium transients in the same DRG neuron, whereas that A-967079 (TRPA1 antagonist) prevented the effect of zoniporide in DRG neurons. Repeated AITC induced TRPA1 desensitization and this effect was prevented by zoniporide. Both NHE1 and TRPA1 were localized at the membrane surface of DRG neurons in culture. Local peripheral zoniporide enhanced AITC-induced pronociception and this effect was prevented by A-967079. Likewise, zoniporide potentiated Complete Freund’s Adjuvant (CFA)-induced hypersensitivity, effect which was prevented by A-967079 in vivo. CFA paw injection increased TRPA1 and decresed NHE1 protein expression in DRG. These results suggest a functional interaction between NHE1 and TRPA1 in DRG neurons in vitro. Moreover, data suggest that this interaction participates in acute and inflamatory pain conditions in vivo.