Role of the histamine system in nefopam-induced antinociception in mice

Abstract

The present study explored the role of the histaminergic system in nefopam analgesia based on the structural relationship between nefopam and diphenhydramine. In vitro binding assays revealed that nefopam possesses moderate affinity for histamine H 1 and H 2 receptor subtypes, with IC 50 of 0.8 and 6.9 μM, respectively, but no affinity for histamine H 3 receptor subtype until 100 μM. Subcutaneous nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1–30 mg/kg) and formalin (1–10 mg/kg) tests in the mouse. Pretreatment with the histamine-depleting agent α-fluoromethylhistidine (α-FMH, 50 mg/kg), the histamine H 1 receptor antagonist pyrilamine (3 or 10 mg/kg), or the histamine H 2 receptor antagonists cimetidine (100 mg/kg) and zolantidine (10 or 30 mg/kg) did not significantly modify nefopam antinociception in both tests. The histamine H 3 receptor agonist R(−)α-methylhistamine (RAMH, 10 mg/kg) did not significantly modify the nefopam analgesic activity in the writhing test. At 25 mg/kg, RAMH inhibited nefopam antinociception at 3 mg/kg, but not at 10 mg/kg in the formalin test. However, pretreatment with the histamine H 3 receptor antagonist thioperamide (25 mg/kg) inhibited nefopam antinociception in the writhing test, but not in the formalin test. In conclusion, nefopam analgesic activity is not mediated by histamine H 1 or H 2 receptors, but can be slightly modulated by histamine H 3 receptors in mouse pain tests.