Tapentadol inhibits calcitonin gene-related peptide release from rat brainstem in vitro

• We studied the effects of tapentadol on CGRP release from isolated rat brainstem.
• Tapentadol did not modify CGRP release in basal condition.
• Tapentadol inhibited both K+- and capsaicin-evoked CGRP release.
• The effects of tapentadol were compared to those morphine and reboxetine.
• Tapentadol fully mimicked the effects of reboxetine in this paradigm.

We have previously developed an in vitro model of rat brainstem explants. The latter release sizable amounts of calcitonin gene-related peptide (CGRP); basal release can be stimulated by such secretagogues as high KCl concentrations, veratridine or capsaicine. In this paradigm we investigated the activity of the analgesic agent tapentadol; the effects of tapentadol were compared to those of a classical opioid receptor agonist, morphine, and the selective noradrenaline reuptake inhibitor reboxetine. Morphine inhibited basal CGRP release, with statistical significance from 1 nM onward and maximal (−44%) inhibition at 100 μM. Morphine also inhibited K+-stimulated peptide release, with a significant effect from 1 μM and maximal (−39%) decrease at 100 μM, but failed to inhibit release stimulated by 10 μM capsaicin. At variance, reboxetine had no effect on baseline CGRP outflow, but was able to inhibit both K+-stimulated [significant inhibition from 1 μM onward and maximal (−37%) decrease at 100 μM], and capsaicin-stimulated release [significant effect from 1 μM and maximal (−31%) decrease at 100 μM]. Likewise, tapentadol had no effect on baseline CGRP release up to 100 μM, but decreased secretion stimulated by 56 mM KCl or capsaicin, with significant effects from 0.1 and 1 μM respectively; maximal inhibition over 56 mM KCl and capsaicin stimuli was −29% and −31%, respectively. Naloxone antagonized the effect of morphine, but not those of reboxetine and tapentadol, on K+-stimulated CGRP secretion. In conclusion the present study provides consistent pharmacological evidence that tapentadol acts as a noradrenaline reuptake inhibitor agent in this experimental model.