The involvement of opioidergic and noradrenergic mechanisms in nefopam antinociception

Nefopam is a clinically effective analgesic agent used to control mild to moderate pain, whose mechanism of action is unknown. We have investigated the antinociceptive activity of nefopam in the mouse abdominal constriction assay and tail immersion test (48°C). Nefopam was found to possess a high degree of potency against acetic acid-induced visceral nociception (ED50 2.5 mg kg−1). In the presence of the opioid receptor antagonists, naloxone or naltrindole, the resulting nefopam dose–response relationships were shifted to the right. Naloxone or naltrindole had no effect upon aspirin (ED50 32.1 mg kg−1) or clonidine (ED50 0.061 mg kg−1) induced antinociception. Acetorphan (10 mg kg−1; s.c.), an inhibitor of neutral endopeptidase (EC 3.4.24.11) was able to potentiate nefopam's antinociceptive activity (ED50 1.5 mg kg−1). The α2-adrenoceptor antagonist, 2-[2-(2-methoxy-1,4-benzodioxanyl)]imidazoline hydrochloride (RX821002; 1 mg kg−1; s.c.), shifted the dose–response curves for clonidine (ED50 7.1 mg kg−1) and nefopam (ED50 5.3 mg kg−1) to the right in this assay. Additionally, centrally administered RX821002 (1 μg/5 μl/animal; i.c.v.) reduced both clonidine (ED50 7.2 mg kg−1) and nefopam's (ED50 15.5 mg kg−1) efficacy in the abdominal constriction assay. Nefopam (3 and 7.5 mg kg−1; s.c.) produced significant antinociceptive effect in the thermal assay. Aspirin and RX821002 were devoid of any significant activity in the tail immersion test. Nefopam was shown to possess RX821002-reversible antinociceptive activity in both the tail immersion test and the abdominal constriction assay. These data suggest the involvement of an opioidergic and noradrenergic component to nefopam's antinociceptive activity in the mouse abdominal constriction assay and tail immersion test. However, the present results are unable to determine if the opioidergic component of nefopam antinociception is through a direct and/or indirect activation of opioid receptors