FIGURE 4 TRPV1-mediated anti-inflammatory and immunomodulatory effects
It has been suggested that the central analgesic effect of acetaminophen is mediated by activation of TRPV1 (Mallet et al., 2010). Higher co-expression of TRPV1 and FAAH support this proposition. A preclinical finding confirmed that the antinociceptive effect of acetaminophen is lacking in TRPV1 and FAAH knockout mice. Supporting to this finding, pharmacological suppression of TRPV1 also abolish the antinociceptive effect of acetaminophen (Mallet et al., 2010). As well, the analgesic effect of AM404 is mediated through activation of TRPV1 (Stueber et al., 2018). It has been reported that oral administration of acetaminophen in mice did not affect brain PGE2 level and COX activity, but activates neuronal TRPV1 (Mallet et al., 2010). Furthermore, acetaminophen promotes the activation of supraspinal TRPV1 (Ohashi & Kohno, 2020). Moreover, higher expression of FAAH in the dorsal ganglion and spinal cord, increases biosynthesis of AM404 which activate spinal TRPV1 (Nazıroğlu et al., 2019). In addition, acetaminophen metabolite NAPQI but not acetaminophen activates TRPV1 irreversibly in HEK293 cells (Eberhardt et al., 2017). It has been shown that acetaminophen metabolites including pBQ and NAPQI which are generated by cytochrome P450-dependent acetaminophen metabolism also activate neuronal TRPV1 (Holme et al., 1984). As well, NAPQI has potent agonist effect on ankyrin 1 receptor (Gentry et al., 2015). Remarkably, both acetaminophen and its metabolites stimulate TRPV1 in the inhibitory pain pathway leading to analgesic effects at supraspinal level (Irinmwinuwa et al., 2022). In addition, TRPV4 which is highly expressed in the CNS is involved in the activation of dorsal root ganglion, neuronal hyperexcitability, hyperalgesia and the development of neuropathic pain (Qu et al., 2016). It has been shown that acetaminophen induces analgesic effect by inhibiting TRPV4 which mediate pro-inflammatory and oxidative stress effects, and involved in mechanosensations (Nakagawa et al., 2020). These findings indicated that acetaminophen and its metabolites induce analgesic effects at spinal and supraspinal level via activation of TRPV1 and inhibition of TRPV4.
ACETAMINOPHEN AND ENDOCANNABINOID PATHWAY
Endocannabinoid system is consist of endocannabinoid receptors, ligands and associated enzymes that maintain energy homeostasis, preserve cognitive function and pain control (Al-Kuraishy et al., 2023) (Figure 5).