The Contribution of Serotonergic Receptors and Nitric Oxide Systems in the Analgesic Effect of Acetaminophen: An Overview of the Last Decade

Abstract

Yeşim HAMURTEKİN, Ammar NOUILATI, Cansu DEMİRBATIR, Emre HAMURTEKİN* Asetaminofen yaygın kullanılan analjezik ve antipiretik bir ajandır. Reçetesiz verilebilen formülasyonlarının da mevcudiyeti sık kullanımını artırmıştır. Günümüze kadar asetaminofenin analjezik etki mekanizmasını inceleyen bir çok çalışma bulunmaktadır. Santral sinir sisteminde siklooksijenaz yolağını inhibe etmesinin yanında, opioiderjik, kannabinoiderjik, dopaminerjik, kolinerjik ve nitrerjik sistemler kadar, bulbospinal serotonerjik yolaklar gibi analjezik etkili inen inhibitör yolakların da asetaminofenin analjezik etkisinde katkısı olan olası mekanizmalar olduğu önerilmiştir. Bu derlemede santral serotonerjik sistem ve santral sinir sistemindeki serotonerjik reseptör alt tiplerinin parasetamolün analjezik etkisine katkısını ortaya koyan verileri bir araya getirmeyi amaçladık. Bunu yaparken, esas olarak son on yılda yapılmış çalışmalara odaklandık ve önceki verilerle son eklenenler arasında bir bağlantı kurmaya çalıştık. Serotonerjik sistemin katkısına ek olarak, aynı zamanda son on yıldaki yeni bulgularla asetaminofenin ağrı kesici etkisinde nitrik oksidin rolünü de derledik. Anahtar kelimeler: Asetaminofen, serotonin, ağrı, nitrik oksit Acetaminophen is a widely used analgesic and antipyretic agent. It is also available in over the counter formulations, which has increased its wide use. There have been many studies to date that have aimed to evaluate the mechanism of the analgesic action of acetaminophen. Additional to the inhibition of the cyclooxygenase pathway in the central nervous system, the involvement of opioidergic, cannabinoidergic, dopaminergic, cholinergic, and nitrergic systems as well as the contribution of descending pain inhibitory systems like the bulbospinal serotonergic pathway has been proposed as possible mechanisms of the analgesic action of acetaminophen. In this review, we aimed to collect the data from studies revealing the contribution of the central serotonergic system and the role of central nervous system-located serotonergic receptor subtypes in the analgesic effect of acetaminophen. While doing this, we mainly focused on the research that has been performed in the last ten years and tried to link the previous data with the lately added results. In addition to serotonergic system involvement, we also reviewed the role of nitric oxide in the analgesic action of acetaminophen, especially with the new findings reported over the last decade.

Medication-overuse headache overlapping with serotonin syndrome

“…Most of the time such drugs cause mild-to-moderate SS 19 21. Several painkillers such as aspirin, acetaminophen, tramadol and rofecoxib are known to increase serotonin levels in the brain 22–25. Tramadol is one of the most commonly prescribed drugs associated with SS 26.…”

An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact

“…[60][61][62][63][64][65][66][67][68][69][70][71] Nonetheless, the evidence was not conclusive regarding the contribution of serotonergic receptors to the paracetamol action. As an example, the involvement of 5-HT3 receptors has been discussed in humans, 62,70,[72][73][74] and experimental work in rodents with 5-HT3 receptor antisense oligonucleotides showed that they were not involved in the analgesic effect of paracetamol, while a tropisetron-sensitive receptor was. 74 However, investigations showed that p-aminophenol analgesic action was mediated by the bulbospinal serotonergic system, 18 which may suggest an involvement of this serotonergic system in the AM404 antinociceptive activity, as recently suggested.…”

“…As an example, the involvement of 5-HT3 receptors has been discussed in humans, 62,70,[72][73][74] and experimental work in rodents with 5-HT3 receptor antisense oligonucleotides showed that they were not involved in the analgesic effect of paracetamol, while a tropisetron-sensitive receptor was. 74 However, investigations showed that p-aminophenol analgesic action was mediated by the bulbospinal serotonergic system, 18 which may suggest an involvement of this serotonergic system in the AM404 antinociceptive activity, as recently suggested. 63 Finally, if bulbospinal serotoninergic pathways seem to be involved in the analgesic effect of paracetamol or its metabolites, the exact nature of the spinal tropisetron-sensitive receptor involved in this effect remains to be elucidated.…”

Current and Emerging Approaches for Pain Management in Hemophilic Arthropathy

“…Paracetamol exerts a moderate analgesic effect by inhibiting the same cyclooxygenase (COX1) targeted by NSAIDs and aspirin [ 9 ]. At the central level, paracetamol also acts by increasing serotonin release [ 58 ]. Paracetamol blocks COX for its peroxidase catalytic activity rather than at the COX catalytic site.…”