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 ).