8 CONCLUSION
Acetaminophen is a non-narcotic analgesic used as an analgesic and antipyretic, despite it act on COX it not regarded as a NSAID. Acetaminophen is used for mild to moderate pain; its efficacy is low compared to other NSAIDs as it has no any anti-inflammatory effect. In spite of its famous use and safely, however; the precise mechanism of acetaminophen still mysterious. Findings from preclinical studies suggest that the main mechanism of acetaminophen is related to the inhibition of COX-3 which is a variant of COX-1 expressed in the brain. Though, the substantial analgesic and antinociceptive effects of acetaminophen cannot explain only by COX pathway. Further findings from preclinical and clinical studies confirmed that acetaminophen and its metabolites can modulate different signaling pain pathways other than COX pathway. Acetaminophen acts either directly by inhibition of COX-2 enzyme, or indirectly through its metabolite AM404 which activate CB1R, CB2R, and TRPV1. In addition, acetaminophen improves brain serotonin by reducing of serotonin metabolism, increasing its release or through inhibition of serotonin reuptake. However, the exact mechanism of acetaminophen effect on brain serotonin is not fully elucidated. Therefore, the analgesic effect of acetaminophen at spinal and supraspinal levels may be mediated by activation serotonin release or direct activation of serotonin receptors. Moreover, acetaminophen has ability to inhibit NO synthase in the spinal cord that involved in pain transmission. It has been suggested that the central analgesic effect of acetaminophen is mediated by activation of TRPV1 at spinal and supraspinal level with inhibition of TRPV4. Interestingly, the endocannabinoid system is regarded as a critical pathway for the analgesic and antinociceptive effects of acetaminophen. However, endocannabinoid system may mediate the neurotoxic and neurodetrimental effects of acetaminophen. Through this pathway acetaminophen has as a double-sward effect could be beneficial or detrimental. Finally, 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. Despite of these findings the central analgesic effect of acetaminophen still vague, therefore preclinical and clinical studies are warranted in this regard.