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.