N-(4-Methoxy-2-nitrophenyl)hexadecanamide, a palmitoylethanolamide analogue, reduces formalin-induced nociception.

AIMS To investigate the local antinociceptive effect as well as the possible mechanisms of action of a novel analogue of palmitoylethanolamide (PEA) N-(4-methoxy-2-nitrophenyl)hexadecanamide (HD) in the rat formalin test. MAIN METHODS The formalin test was used to assess the antinociceptive activity of HD in vivo. The hydrolysis of anandamide catalyzed by fatty acid amide hydrolase (FAAH) was used to determine the action of HD on FAAH activity in vitro. KEY FINDINGS Local peripheral ipisilateral, but not contralateral, administration of HD (10-100μg/paw) produced a dose-dependent antinociceptive effect in rats. The CB(1) and CB(2) receptor antagonists AM281 (0.3-30μg/paw) and SR144528 (0.3-30μg/paw), respectively, reduced the antinociceptive effect of HD (100μg/paw). In addition, methiothepin (0.03-0.3μg/paw) and naloxone (5-50μg/paw) significantly reduced HD-induced antinociception (100μg/paw). In vitro, HD reduced only to a minor extent the hydrolysis of anandamide catalyzed by FAAH. SIGNIFICANCE HD local administration produces antinociception that probably results from an indirect activation of peripheral CB(1) and CB(2) cannabinoid receptors. Data suggest that 5-HT(1) and opioid receptors also participate in the antinociceptive effect of this compound. HD may have potential as analgesic drug.