Acetaminophen: Ancient drug with a novel analgesic mechanism of action

Paracetamol is used worldwide for its analgesic and antipyretic actions. Its spectrum of activity similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors,but with a lesser anti-inflammatory effect, its metabolism is complex, and its analgesic mechanisms have not been completely understood. It was previously explained to produce analgesia by inhibiting the enzyme cyclooxygenase (COX) which is incorrect, however recent findings revealed that acetaminophen is metabolized to p-aminophenol, which crosses the blood-brain barrier and get metabolized by fatty acid amide hydrolase (FAAH) to yield N-acylphenolamine (AM404). AM404 acts on a number of receptors viz; the transient receptor potential vanilloid-1 (TRPV1) and cannabinoid 1 (CB1) receptors in the midbrain and medulla which are mediators of pain modulation. Moreover it has also been reported to act via Cav3.2 calcium channel. Evidence also show that acetaminophen analgesic action of acetaminophen could be due to its interaction with endogenous neurotransmitter systems, opioid, serotonergic systems and nitric oxide system. additionally, it is also been unraveled that paracetamol may exert novel mechanisms of action, likely relevant for their analgesic action, by modulating protein kinase C epsilon (PKCε) and substance P (SP) in the peripheral sensory neurons. This review is geared towards explaining and updating with experimental proof the analgesic novel mechanism of action of Acetaminophen since it has no ant-inflammory effect