Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: A role for endogenous fatty-acid ethanolamides?

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit fatty-acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of anandamide, an endocannabinoid. It has been suggested that the mechanisms of action of NSAIDs could be due to inhibition of cyclooxygenase (COX) and also to an increase in endocannabinoid concentrations. In a previous study we have demonstrated that the local analgesic interaction between anandamide and ibuprofen (a non-specific COX inhibitor) was synergistic for the acute and inflammatory phases of the formalin test. To test this hypothesis further, we repeated similar experiments with rofecoxib (a selective COX-2 inhibitor) and also measured the local concentrations of anandamide, and of two fatty-acid amides, oleoylethanolamide and palmitoylethanolamide. We established the ED 50 for anandamide (34.52 pmol ± 17.26) and rofecoxib (381.72 pmol ± 190.86) and showed that the analgesic effect of the combination was synergistic. We also found that paw tissue levels of anandamide, oleoylethanolamide and palmitoylethanolamide were significantly higher when anandamide was combined with NSAIDs and that this effect was greater with rofecoxib. In conclusion, local injection of anandamide or rofecoxib was antinociceptive in a test of acute and inflammatory pain and the combination of anandamide with rofecoxib was synergistic. Finally, locally injected anandamide with either NSAID (ibuprofen or rofecoxib) generates higher amount of fatty-acid ethanolamides. The exact comprehension of the mechanisms involved needs further investigation.

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

“…The PPAR-α receptor agonist GW7647 and anandamide were found to produce synergistic antinociception in this same study. In addition combination of anandamide and the COX-2 inhibitor, rofecoxib, synergistically decrease pain in the formalin model and to increase levels of AEA, OEA, and PEA in the formalin treated paw (Guindon et al, 2006). These findings suggest that the antiedema effects of FAAH inhibition may be mediated by multiple mechanisms and that the results from these combination studies should be extended to investigate their effects on inflammation.…”

Effects of centrally administered endocannabinoids and opioids on orofacial pain perception in rats

“…Allosteric modulators of CB 1 receptors may therefore be a useful strategy for amplifying effects of ECs only at sites where they are produced and released on demand (Laprairie et al, 2017). Nonetheless, multifunctional compounds targeting the ECS allied to inhibition of COX2 (Grim et al, 2014), antagonism of TRPV1 (Maione et al, 2006; or in combination with opioids (Wilson-Poe et al, 2013) or non-steroidal anti-inflammatory drugs (Guindon et al, 2006) have great potential to produce a superior therapeutic profile with minimized unwanted cannabimimetic side effects. A novel therapeutic approach in many pathological states can be the possible modulation of EC activity through the regulation of their synthesis or degradation.…”

Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-α receptor agonist GW7647

“…These drugs produce, however, a variety of psychotropic side effects that severely limit their therapeutic utility (Piomelli, 2005). Alternative cannabinoid-based therapeutic strategies are being explored, therefore, which include activating peripheral cannabinoid receptors with brain impermeant receptor agonists, prolonging the half-life time of endocannabinoids by inhibiting their degradation (Bari et al, 2006;Piomelli et al, 2006) or using low-dose combinations of cannabinoid receptor agonists in conjunction with other analgesic agents to produce synergistic reductions in pain (Calignano et al, 2001;Cichewicz, 2004;Guindon et al, 2006). An example of the combination approach is when anandamide is administered together with the naturally occurring analgesic and antiinflammatory factor palmitoylethanolamide (PEA) (Calignano et al, 1998;Jaggar et al, 1998;Mazzari et al, 1996) -the two agents exert a synergistic antinociceptive effect in mice without eliciting overt psychotropic responses (Calignano et al, 2001).…”