FIGURE 6 Endocannabinoid pathway
Of note, endocannabinoids are rapidly synthesized on demand, and act in
paracrine and autocrine fashions (Boczek & Zylinska, 2021). It has been
shown that the analgesic effect of acetaminophen is mediated through
modulation of endocannabinoid system (Topuz et al., 2020). In addition,
AM404 activates supraspinal CB1R with subsequent reinforcement of
descending serotonergic inhibitory pathway (Elmer, 2021). Of note, AM404
inhibits reuptake of AEA increasing the central activity of
endocannabinoid system (Scienza-Martin et al., 2022). Both acetaminophen
and AM404 inhibit FAAH leading to increasing of AEA level (Mallet et
al., 2023). However, FAAH is necessary for conversion of acetaminophen
to AM404 which has a potent TRPV1 agonist effect (Barrière et al.,
2013). Acetaminophen has been reported to exerts anxiolytic effects by
activating CB1R (Mageed et al., 2022), however CB1R antagonists does not
block the analgesic effects of acetaminophen since this drug acting on
multiple pathway in the CNS. A preclinical study confirmed that CB2R
antagonist did not affect the analgesic effect of acetaminophen
(Mallettet al., 2008) suggesting that acetaminophen effect is mediated
by CB1R but not by CB2R. Furthermore, acetaminophen inhibits reuptake of
anandamide or AEA leading to mild anxiolytic effect. Inhibition of FAAH
which involved in the metabolism of acetaminophen to AM404 in the CNS
attenuates the analgesic effect of acetaminophen (Zaitone et al., 2012)
signifying that AM404 is mainly involved in the anxiolytic effect of
acetaminophen.
It has been shown that acetaminophen has a neuroprotective effect
against brain ischemic-reperfusion injury by activating CB1R in rat
model (Mageed et al., 2022). Notably, endocannabinoid system is
implicated in the pathophysiology of autism spectrum disorder as
peripheral and central dysregulated CBRs and enzymes are found in
patients with autism spectrum disorder. Therefore, acetaminophen through
interaction with endocannabinoid system may induce the development of
autism spectrum disorder (Schultz et al., 2021). Thus, prolong use of
acetaminophen may increase risk of autism spectrum disorder. Moreover,
an in vitro study demonstrated that acetaminophen and its metabolites
exert toxic effects on developing mouse cortical neurons by inducing
neuronal apoptosis through activating CB1R (Schultz et al., 2012).
Therefore, acetaminophen use in children as antipyretic and analgesic
with traumatic brain injury may increase risk of cognitive impairment.
Of interest, acute acetaminophen intoxication not only induces acute
liver failure but also causes acute neurotoxicity by inducing brain
oxidative stress and injury of dopaminergic neurons (Vigo et al., 2019).
Therefore, endocannabinoid system is regarded a critical pathway for the
analgesic and antinociceptive effects of acetaminophen. However,
endocannabinoid system may mediate the neurotoxic and neurodetrimental
effect of acetaminophen. Through this pathway acetaminophen has as a
double-sward effect could be beneficial or detrimental.
ACETAMINOPHEN AND NEUROTRANSMITTERS
It has been illustrated that prolong use of acetaminophen may affect
brain neurotransmitters as confirmed by different studies. A preclinical
study showed that use of acetaminophen for 8 weeks leads to behavioral
and learning changes in rats by alternating many neurotransmitters in
prefrontal cortex (Blecharz-Klin et al., 2013). In addition,
augmentation of dopaminergic neurotransmission by L-DOPA and
bromocriptine potentiate the analgesic effect of acetaminophen in
experimental studies (Bhagyashree et al., 2017). Furthermore, AM404
improves dopaminergic neurotransmission by increasing of anandamide and
reducing of nitric oxide (NO) (Oz et al., 2010). Furthermore, endogenous
opioid receptors can mediate the spinal and supraspinal analgesic effect
of acetaminophen [105]. Backup to notion, administration of opioid
receptor antagonist naltrindol abolish the analgesic effect of
acetaminophen in an animal model study (Raffa et al., 2004). However, a
pilot study showed that opioid receptor antagonist naloxone did not
abolish the analgesic effect of acetaminophen in normal healthy
volunteers (Pickering et al., 2013) suggesting that opioid system is not
involved in the central antinociceptive effect of acetaminophen. Though,
opioid system is upregulated during fever by the effect of IL-6, and
opioid system also contributes in fever and thermoregulation (Benamar et
al., 2002). Thus, low basal activity of opioid system in healthy state
may explain the negative association between acetaminophen and opioid
system. Furthermore, AM404 has a neuroprotective effect by inhibiting
NMDA-induced neurotoxicity, and glutamate release (Saliba et al., 2019).
Therefore, acetaminophen analgesic effect could be mediated through
inhibition of glutamatergic neurotransmission.
These findings suggest that acetaminophen analgesic effect may be
mediated through modulation of different neurotransmitters such as
dopaminergic and glutamatergic neurotransmissions.
Taken together, the analgesic effects of acetaminophen and its
metabolites are mediated by various pathways including inhibition of COX
pathway, activation of descending inhibitory pathway and endocannabinoid
pathway (Figure 7 ).