pain-pateint
03-11-2009, 04:13 AM
Friends --
Recently, I came across the abstract below which sets forth the proposition that acetaminophen (Tylenol) is actually a cannabinoid related compound, perhaps explaining its analgesic and anti-pyretic activities. I am no chemist, but I am intrigued by this, so I invite comment from those on this list with much more experience in psycho-pharmacology than this writer.
Thanks,
Mike Segesta
***********************
Paracetamol: new vistas of an old drug.
*Bertolini A, Ferrari A, Ottani A, et al.
Division of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, Modena, Italy. bertolini.alfio@unimore.it
Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.
PMID: 17227290 [PubMed - indexed for MEDLINE]
Recently, I came across the abstract below which sets forth the proposition that acetaminophen (Tylenol) is actually a cannabinoid related compound, perhaps explaining its analgesic and anti-pyretic activities. I am no chemist, but I am intrigued by this, so I invite comment from those on this list with much more experience in psycho-pharmacology than this writer.
Thanks,
Mike Segesta
***********************
Paracetamol: new vistas of an old drug.
*Bertolini A, Ferrari A, Ottani A, et al.
Division of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, Modena, Italy. bertolini.alfio@unimore.it
Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.
PMID: 17227290 [PubMed - indexed for MEDLINE]