Tissue acidification causes sustained activation of primary nociceptors, which causes
pain. In mammals,
acid-sensing ion channels (ASICs) are the primary
acid sensors; however, Na+/H+ exchangers (NHEs) and TRPV1 receptors also contribute to tissue acidification sensing. ASICs, NHEs, and TRPV1 receptors are found to be expressed in nociceptive nerve fibers.
ASIC inhibitors reduce peripheral
acid-induced
hyperalgesia and suppress inflammatory
pain. Also, it was shown that pharmacological inhibition of NHE1 promotes nociceptive behavior in
acute pain models, whereas inhibition of TRPV1 receptors gives relief. The murine skin-nerve preparation was used in this study to assess the activation of native polymodal nociceptors by mild acidification (pH 6.1). We have found that
diminazene, a well-known antagonist of ASICs did not suppress pH-induced activation of CMH-fibers at concentrations as high as 25 μM. Moreover, at 100 μM, it induces the potentiation of the fibers' response to acidic pH. At the same time, this concentration virtually completely inhibited ASIC currents in mouse dorsal root ganglia (DRG) neurons (IC50 = 17.0 ± 4.5 μM). Non-selective ASICs and NHEs inhibitor
EIPA (5-(N-ethyl-N-isopropyl)amiloride)
at 10 μM, as well as selective NHE1 inhibitor
zoniporide at 0.5 μM induced qualitatively the same effects as 100 μM of
diminazene. Our results indicate that excitation of afferent nerve terminals induced by mild acidification occurs mainly due to the NHE1, rather than
acid-sensing ion channels. At high concentrations,
diminazene acts as a weak blocker of the NHE. It lacks chemical similarity with
amiloride,
EIPA, and
zoniporide, so it may represent a novel structural motif for the development of NHE antagonists. However, the effect of
diminazene on the
acid-induced excitation of primary nociceptors remains enigmatic and requires additional investigations.