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Nonopiate Analgesics and Adjuvants
Published in Gary W. Jay, Practical Guide to Chronic Pain Syndromes, 2016
Acetaminophen, or N-acetyl-para-amino-phenol (APAP) appears to work centrally; its MOA appears far more complex than initially thought. Oral APAP has efficacy in the prevention of the development of hyperalgesia induced via direct activation of algetic spinal receptors (9). It is able to penetrate into the brain enabling both antipyresis and analgesic properties (10). The MOA of APAP appears to involve several systems: The eicosanoid system: APAP inhibits the COX enzyme and interferes with the conversion of arachidonic acid to prostaglandins (11, 12); COX-3 may be at least one site of APAP action (13).The serotonergic system: Up to fivefold increase in serotonin levels in multiple areas of the central nervous system (CNS) has been detected after APAP treatment (14). APAP analgesia is inhibited by tropisetron, an antiemetic and serotonin (5-HT) type 3 antagonist (15).The cannabinoid system: In the human CNS, paracetamol is metabolized to P-aminophenol which, via fatty acid amide hydrolase is transformed into N-arachidonoyl-phenolamine (AM404) (16). AM404 is a ligand at selective cannabinoid subtype 1 (CB1) receptors, as well as an agonist of transient receptor potential vanilloid type 1 receptors (TRPV1) and an inhibitor of fatty acid amide hydrolase, which would inhibit the reuptake and metabolism of anandamide, an endocannabinoid with analgesic properties (14, 16-19). The cannabinoids as well as endocannabinoids induce antinociceptive effects that are secondary mainly to CB1 receptors (20, 21).The opioid system: Cannabinoid-induced antinociception does appear to be associated with the release of opioid peptides into the brain (22). Opioid mu receptors, like the CB1 receptors found on many of the same neurons, are both associated with G proteins. The APAP metabolite AM404 may activate, at least in part, both the opioid and cannabinoid systems. The secondary interaction between CB1 and opiate receptors may then modulate other neurotransmitters including 5-HT, gamma-aminobutyric acid, both antinociceptive, as well as glutamate (21, 23, 24).
Nonopiate Analgesics and Adjuvants
Published in Gary W. Jay, Clinician’s Guide to Chronic Headache and Facial Pain, 2016
Acetaminophen, or N-acetyl-para-amino-phenol (APAP) appears to work centrally; its MOA appears far more complex than initially thought. Oral APAP has efficacy in the prevention of the development of hyperalgesia induced via direct activation of algetic spinal receptors (9). It is able to penetrate into the brain enabling both antipyresis and analgesic properties (10). The MOA of APAP appears to involve several systems: The eicosanoid system: APAP inhibits the COX enzyme and interferes with the conversion of arachidonic acid to prostaglandins (11, 12); COX-3 may be at least one site of APAP action (13).The serotonergic system: Up to fivefold increase in serotonin levels in multiple areas of the central nervous system (CNS) has been detected after APAP treatment (14). APAP analgesia is inhibited by tropisetron, an antiemetic and serotonin (5-HT) type 3 antagonist (15).The cannabinoid system: In the human CNS, paracetamol is metabolized to P-aminophenol which, via fatty acid amide hydrolase is transformed into N-arachidonoyl-phenolamine (AM404) (16). AM404 is a ligand at selective cannabinoid subtype 1 (CB1) receptors, as well as an agonist of transient receptor potential vanilloid type 1 receptors (TRPV1) and an inhibitor of fatty acid amide hydrolase, which would inhibit the reuptake and metabolism of anandamide, an endocannabinoid with analgesic properties (14, 16-19). The cannabinoids as well as endocannabinoids induce antinociceptive effects that are secondary mainly to CB1 receptors (20, 21).The opioid system: Cannabinoid-induced antinociception does appear to be associated with the release of opioid peptides into the brain (22). Opioid mu receptors, like the CB1 receptors found on many of the same neurons, are both associated with G proteins. The APAP metabolite AM404 may activate, at least in part, both the opioid and cannabinoid systems. The secondary interaction between CB1 and opiate receptors may then modulate other neurotransmitters including 5-HT, gamma-aminobutyric acid, both antinociceptive, as well as glutamate (21, 23, 24).
Treating osteoarthritis pain: mechanisms of action of acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, and nerve growth factor antibodies
Published in Postgraduate Medicine, 2021
Yvonne D’Arcy, Patrick Mantyh, Tony Yaksh, Sean Donevan, Jerry Hall, Mojgan Sadrarhami, Lars Viktrup
Loss of cannabinoid receptor CB1 activity attenuates acetaminophen- or N-arachidonoylphenolamine (AM404; a acetaminophen metabolite formed in the CNS)-mediated analgesia in rodents, implicating the endocannabinoid system in acetaminophen MOA [74,75]. The lipid neurotransmitter anandamide is the primary endogenous agonist of the CB1 receptor, and AM404 may promote indirect activation of CB1 receptors by blocking anandamide reuptake and, possibly, metabolism [76,77]. Though CB1 receptors are highly expressed in many structures of the CNS (and to some extent in the peripheral nervous system), the RVM is believed to be an important site of acetaminophen action. It is possible that AM404 promotes activation of CB1 receptors (by inhibiting anandamide reuptake and/or degradation) on terminals of tonically active, gamma-aminobutyric acid (GABA)-releasing neurons projecting to the RVM from upstream structures (e.g. the PAG). The resulting decrease in GABA release from these neurons would promote activity of anti-nociceptive serotonergic fibers projecting from the RVM to the dorsal horn of the spinal cord and produce analgesia (i.e. activate descending inhibitory pathways).
Novel therapeutic and drug development strategies for tobacco use disorder: endocannabinoid modulation
Published in Expert Opinion on Drug Discovery, 2020
Increasing our understanding of the impact of anandamide reuptake inhibitors should also be a research focus given that they attenuate reinstatement of nicotine seeking and may also reduce nicotine self-administration, and some withdrawal signs. To date, the majority of research examining the effects of anandamide modulation has come from studies using FAAH inhibitors. Given the scarcity of studies with the reuptake inhibitors, it has been difficult to draw firm conclusions regarding their impact. An important consideration regarding anandamide reuptake inhibition relates to the potential for abuse. Squirrel monkeys self-administer the anandamide reuptake inhibitor AM404 [173] suggesting reuptake inhibitors may have some risk for abuse. In contrast, the FAAH inhibitor URB597 was not self-administered in squirrel monkeys [174] while the newer FAAH inhibitor URB694 was self-administered at a moderate rate [78]. Whether self-administration of AM404 represents a specific property of this compound or a more general drug class effect requires further research. Careful assessment of abuse risk will be required for both FAAH inhibitors and anandamide reuptake inhibitors going forward.
Provider-directed analgesia for dental pain
Published in Expert Review of Clinical Pharmacology, 2023
Several other analgesic mechanisms of action for acetaminophen have been postulated, including acting upon serotonergic and cannabinoid signaling pathways [29,58,59]. This may explain why some patients who consume acetaminophen experience a greater well-being effect compared to placebo [60]. In the body, acetaminophen is eventually metabolized to N-arachidinoyl-phenolamine (AM404), which is structurally similar to capsaicin [26,61]. AM404 is an agonist at cannabinoid receptors (CB1 and CB2) [26], and inhibits the anandamide membrane transporter (AMT) in the brain, thereby increasing levels of endogenous cannabinoids [62]. In addition, AM404 activates the capsaicin (vanilloid) subtype 1 receptors (TRPV1) that are involved in pain mechanisms [61].