Role of catecholamines and serotonin receptor subtypes in nefopam-induced antinociception

The non-opiate analgesic nefopam has been shown to inhibit monoamines uptake, but little is known about receptor subtypes effectively involved in its analgesic effect. In vitro binding assays yielded the following measures of affinity (IC50): serotonergic 5-HT2C (1.4 μM), 5-HT2A (5.1 μM), 5-HT3 (22.3 μM), 5-HT1B (41.7 μM), 5-HT1A (64.9 μM), adrenergic α1 (15.0 μM) and dopaminergic D1 (100 μM). Subcutaneous nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1–30 mg kg−1) and formalin (1–10 mg kg−1) tests in the mouse. Pretreatments with adrenergic α1 (prazosin) and α2 (yohimbine), and serotonergic 5-HT1B (GR127935) receptor antagonists significantly increased the nefopam ED50 in the writhing test. The serotonergic 5-HT2C (RS102221) and the dopaminergic D2 (sulpiride) receptor antagonists inhibited nefopam antinociception in the formalin test. However, in both tests, nefopam analgesic activity was not modified by the following receptor antagonists: dopaminergic D1 (SCH23390), serotonergic 5-HT1A (NAN-190, WAY100635), 5-HT2A (R96544, ketanserin), 5-HT3 (tropisetron), and 5-HT4 (SDZ205557). In conclusion, nefopam analgesic activity could be modulated by the adrenergic α1 and α2 receptors, the dopaminergic D2 receptors, and the serotonergic 5-HT1B and 5-HT2C receptor subtypes.