The role of large-conductance, calcium-activated potassium channels in a rat model of trigeminal neuropathic pain.

Background: Trigeminal neuralgia is a disorder of paroxysmal and severely disabling facial pain and continues to be a real therapeutic challenge. At present there are few effective drugs. Here the aim of this study was to investigate the role of BKCa channels in trigeminal neuropathic pain.Methods: Rats were divided into two groups: a sham and a chronic constriction injury of infraorbital branch of trigeminalnerve (ION-CCI) group. Nociceptive behavior testing, immunohistochemistry, RT-PCR, Western blotting and whole-cellpatch clamp recording were used.Results: Relative to the sham group, rats with ION-CCI consistently displayed lower mechanical pain thresholds in thevibrissal pad region from day 6 to 42 after ION-CCI operation. ION-CCI induced a significant down-regulation of BKCachannels both in mRNA and protein levels in the ipsilateral trigeminal ganglion (TG), a lower threshold intensity of actionpotential, and decreased total BKCa currents in cultured TG neurons. TG target injection of NS1619 (20–100 mg), anopener of BKCa channels, dose-dependently increased the mechanical pain threshold, which was blocked by the BKCachannel inhibitor iberiotoxin (IbTX, 20 mg). NS1619 (10 mM) significantly increased the mean threshold intensities ofaction potentials in ION-CCI rats, while failing to affect those in the sham rats.The levels of phosphorylated extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinases (JNK) in TG were significantly increased after ION-CCI operation. The ERK1/2 antagonist U0126, p38 antagonist SB203580 and JNK antagonist SP600125 significantly reversed the facial mechanical allodynia in ION-CCI rats. However, the ERK1/2 antagonist U0126, p38 antagonist SB203580 but not JNK antagonist SP600125 significantly increased BKCa currents in ION-CCI TG neurons.Conclusions: Our results indicate the important involvement of mainly ERK and p38 MAPK pathways in modulating BKCa channels in ION-CCI TG neurons. BKCa channels represent a new therapeutic target for the clinical treatment of trigeminal neuropathic pain. [ABSTRACT FROM AUTHOR]