Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT7 receptors

Doğrul, Ahmet; Seyrek, Melik; Akgül, Emin Özgür; Çaycı, Tuncer; Kahraman, Serdar; Bolay, Hayrünnisa

doi:10.1016/j.ejphar.2011.12.016

Cited by 74 publications

(57 citation statements)

References 48 publications

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“…They demonstrated that the analgesic effect of paracetamol was reduced after lesion of the serotonergic bulbospinal pathway by 5,6-dihydroxytryptamine or total depletion of the central serotonin (5-HT) synthesis by p-chlorophenylalanine. These results were confirmed by another team using 5,7-dihydroxytryptamine [39]. Studies showing that paracetamol did not bind serotonin receptors [38,40] prompted investigation of the mobilization of the serotonin neurotransmitter.…”

Section: Involvement Of the Serotonergic Systemsupporting

confidence: 64%

“…Later studies showed that the spinal role of 5-HT 1A , 5-HT 2A , 5-HT 2C and 5-HT 7 receptor subtypes of serotonin receptors was involved in the action of paracetamol [39,[42][43][44][45][46][47][48]. However, investigations of the involvement of 5-HT 3 receptors yielded conflicting results in both animals [36,42,43,47,49,50] and humans [51][52][53][54].…”

Section: Involvement Of the Serotonergic Systemmentioning

confidence: 99%

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Paracetamol: Update on its Analgesic Mechanism of Action

Mallet¹,

Eschalier²,

Daulhac³

2017

Pain Relief - From Analgesics to Alternative Therapies

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Paracetamol is the most widely used over-the-counter medication in the world. The mechanism of action of its analgesic effect was often considered as based on the mobilization of the cyclooxygenases and more recently on serotonergic pathways. A new metabolic pathway involving the generation of an active metabolite, AM404 (N-(4-Hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide), in the brain by the fatty acid amide hydrolase (FAAH) enzyme, was recently identified. This chapter describes experimental data that have shown the involvement of this metabolic pathway in the analgesic action of paracetamol and its relationship with the cyclooxygenase and serotonergic systems. It also explains how new targets and systems, such as the cannabinoid and vanilloid systems and the calcium channel receptor Cav3.2, play a role in the action of paracetamol. Finally, it suggests how research on the mechanism of the clinically relevant effects of this long-established analgesic could lead to new therapeutic pain strategies.

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Section: Involvement Of the Serotonergic Systemsupporting

confidence: 64%

Section: Involvement Of the Serotonergic Systemmentioning

confidence: 99%

Paracetamol: Update on its Analgesic Mechanism of Action

Mallet¹,

Eschalier²,

Daulhac³

2017

Pain Relief - From Analgesics to Alternative Therapies

View full text Add to dashboard Cite

show abstract

“…drugs in 20% DMSO/ saline. Receptor antagonist dosages were selected on the basis of previous studies in mice (Dogrul et al, 2012;Sawynok and Reid, 2012;Liu et al, 2013aLiu et al, , 2013b.…”

Section: Drugs and Drug Administration Methodsmentioning

confidence: 99%

Spinal and peripheral adenosine A1 receptors contribute to antinociception by tramadol in the formalin test in mice

Sawynok

Reid

Liu

2013

European Journal of Pharmacology

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“…Regarding the potential target sites, it has been indicated that the synergism of nefopam and acetaminophen may occurs in connection with the descending serotonergic (5-HT) pathways and spinal serotonin 5-HT receptors. It has been reported that the potential effect of acetaminophen is indirectly/directly related to 5-HT 3 receptors at spinal sites (50,51) and descending serotonergic pathways (52). Similarly, the action of nefopam have been indicated to involve serotonergic pathways and 5-HT receptors (49,53).…”

Section: Discussionmentioning

confidence: 99%

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Zhuang

et al. 2017

biom rep

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Abstract. Nefopam, an analgesic drug, effectively elicits antinociception in the majority of noxious and thermal models in rodents. Acetaminophen is among the most commonly used analgesic and antipyretic drugs worldwide, either on prescription or over the counter. The present study aimed to investigate the analgesic activity of nefopam combined with acetaminophen, which was expected to maximize the potency of analgesia and decrease the dose of nefopam required. Three series of experiments, namely acetic acid-induced writhing tests in mice, hot plate tests in mice and tail flick tests in rats, were used to evaluate the analgesic effect. Initially, an optimum proportion of the two drugs, 3.5 mg/kg nefopam (N) + 60 mg/kg acetaminophen (A), was determined by orthogonal array design based on writhing response number. Subsequently, combinations of N and A (1.75 N + 30 A, 3.5 N + 60 A and 7.0 N + 120 A mg/kg) were determined to elicit antinociception in the writhing test (P<0.01 vs. normal saline control) in a dose-dependent manner. In the hot plate test, hot plate latencies up to 60 min after drug treatment were observed. The combination of 7.0 N + 120 A mg/kg exerted a greater cumulative antinociceptive effect throughout the observation period, with an area under the curve value of 1,156.95±199.30 area units (AU), compared with that achieved by 7.0 N mg/kg alone (632.12±62.38 AU). Furthermore, both monotherapy and compound therapy exhibited antinociception dose-dependently in the tail-flick test. However, a combination of 5.0 N + 84 A mg/kg exerted greater analgesic effect compared with 5.0 N mg/kg alone. The data obtained demonstrate that acetaminophen may enhance the antinociceptive activity of nefopam. Thus, coadministration of nefopam with acetaminophen warrants clinical evaluation.

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Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT7 receptors

Cited by 74 publications

References 48 publications

Paracetamol: Update on its Analgesic Mechanism of Action

Paracetamol: Update on its Analgesic Mechanism of Action

Spinal and peripheral adenosine A1 receptors contribute to antinociception by tramadol in the formalin test in mice

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

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