Background N-docosahexaenoyl ethanolamine (DHEA; also known as synaptamide) binds to both the cannabinoid-1 and 2 (CB1 and CB2) cannabinoid receptors and has anti-inflammatory properties in vitro. However, the in vivo effects of DHEA remain unknown. Therefore, this study was designed to understand the effects of DHEA in models of pain and inflammation in mice. Methods The intraplantar formaldehyde assay, hot water tail withdrawal assay and hotplate model were used to assess the antinociceptive properties of DHEA in mice. The mechanism of action was studied by antagonising the cannabinoid receptors, transient receptor potential vanilloid 1 (TRPV1) ion channel, peroxisome proliferator-activated receptors (PPARs) and G-protein receptor 55 (GPR55). Results N-docosahexaenoyl ethanolamine (2-10 mg/kg) reduced the levels of nociceptive and inflammatory pain-related behaviour over 60 min in the intraplantar formaldehyde assay via both intraperitoneal and local intraplantar administration. The area under the curve analysis showed the overall antinociceptive effects of DHEA (10 mg/kg) were not modulated by pre-treatment with antagonists for the cannabinoid receptors, TRPV1ion channel, PPAR alpha, PPAR gamma or GPR55. However, the time-course analysis showed that within the early inflammatory phase, antagonism of the CB2 receptor, PPAR alpha and PPAR gamma led to a partial reversal of the antinociceptive effects of DHEA. In the hot water tail withdrawal and hotplate models of thermal nociception, DHEA (2-10 mg/kg) did not have any antinociceptive effects. Conclusions N-docosahexaenoyl ethanolamine reduced the level of formaldehyde-induced nociceptive and inflammatory pain-related behaviour; however, was not active in thermal nociceptive models. This study highlights the potential of DHEA for the treatment of acute inflammatory pain. Significance This study shows that both intraperitoneal and intraplantar administration of DHEA reduces the level of formaldehyde-induced nociceptive and inflammatory pain.
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