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).