Fatty acid amide hydrolase (FAAH) inhibitor reduces persistent inflammatory pain in mice depending on μ- and δ-opioid receptors activity: Involvement of heme oxygenase-1.

The endocannabinoid system modulates chronic pain, and its actions in the nervous system may involve interactions with other systems. We aimed to investigate the effect of activating the endocannabinoid system by inhibiting fatty acid amide hydrolase (FAAH) on persistent inflammatory pain, as well as its interactions with heme oxygenase 1 (HO-1) and μ-opioid receptors (MOR) and δ-opioid receptors (DOR). Male BALB/c mice submitted to persistent inflammatory pain through intra-plantar injection of CFA were treated with a FAAH inhibitor (PF3845) or an HO-1 inducer (CoPP), combined with an HO-1 inhibitor (SnPP), a MOR antagonist (CTAP), or a DOR antagonist (naltrindole). PF3845 and CoPP reduced nociception and pain aversion, and this effect was blocked by SnPP, CTAP, and Naltrindole. PF3845 decreased FAAH and increased HO-1 levels in the amygdala and prevented microglial expression increase in the basolateral amygdala. This study highlights FAAH inhibition as a relevant mechanism for modulating persistent pain, potentially involving MOR, DOR, and HO-1 activity. Supraspinal circuits, including amygdala nuclei, may be relevant to the development and reduction of pain aversion by FAAH inhibitors and require further investigation to determine causal relationships.