Acetaminophen-induced antinociception via central 5-HT2A receptors
Introduction
In spite of the wide use of acetaminophen as an analgesic, its mechanism of action is still unclear. It is still not known whether acetaminophen acts peripherally, centrally or both. Since it is a very poor inhibitor of cyclooxygenase-2, which is involved in inflammation, but a good inhibitor of cyclooxygenase-1, which is not, it apparently exerts its analgesic effects via central actions (Bowman and Rand, 1980, Flower et al., 1980, Jackson et al., 1984). Various mechanisms have been proposed for acetaminophen-induced analgesia, i.e. central inhibition of prostaglandin synthesis, modulation of the central L-arginine-nitric oxide pathway (Bjorkman et al., 1994), modulation of nociceptive transmission in spinal and supraspinal pathways (Hunskaar et al., 1985), etc. as central 5-HT systems may play a role in antinociception.
A relationship between 5-HT system and acetaminophen has been demonstrated previously. The analgesic activity of acetaminophen was reduced in rats in which the 5-HT pathways were lesioned with intrathecal 5,6-dihydroxytryptamine (Tjølsen et al., 1991). A significant increase of 5-HT levels in pons and cerebral cortex was reported in acute administration of acetaminophen in experimental animals (Pini et al., 1996). Chronic use of acetaminophen could deplete 5-HT from platelets and eventually up-regulate the 5-HT2A receptors on platelet membranes in migraine patients (Srikiatkhachorn and Anthony, 1996). The present study has been conducted to further investigate the acute and chronic effects of acetaminophen on antinociceptive activity and central 5-HT2A receptors. Frontal cortex and brainstem were selected for study as frontal cortex plays an important role in modification of nociceptive perception and brainstem is a major source of central 5-HT neurons.
Section snippets
Materials
[Phenyl-4-3H]spiperone (specific activity 23 Ci/mmol) was purchased from Amersham International, UK. Ketanserin was a gift from Janssen Research Foundation (Beerse, Belgium). 4-Acetaminophenol (Acetaminophen; N-acetyl-para-aminophenol) was purchased from Sigma Chemical Co., St. Louis, MO and propylene glycol (1,2-propanediol) from Carlo Erba. All other chemicals and reagents were of the purest commercially available grade, purchased mainly from E. Merck (Darmstadt, Germany) and May & Baker Ltd.
Acute and chronic effect of acetaminophen treatment on antinociceptive activity
The results revealed the tail flick latency for control and treated groups with acetaminophen 400 mg/kg/day after 90 min, 15 and 30 days were 8.52±1.18, 16.52±4.48, 25.79±4.78 and 6.46±0.36 s, respectively. A significant increase of tail flick latency was observed in the treated rats with acetaminophen after 90 min and 15 days, but not 30-day treated rats, as compared to that in control rats (Table 1).
Acute effect of acetaminophen treatment on central 5-HT2A receptors
After 90 min of acetaminophen administration, [3H]spiperone binding was performed in frontal
Discussion
The result of this study demonstrated that both acute and chronic administration of acetaminophen altered the central 5-HT system. Down-regulation of 5-HT2A receptors in frontal cortex membrane was observed in both acute and chronic acetaminophen-treated groups. However, the degree of receptor down-regulation became less evidenced after administration of acetaminophen for 30 days. Concomitantly, the increase of tail flick latency was observed after acute and chronic administration of
Acknowledgements
The authors gratefully acknowledge the Asahi Glass Foundation for supporting this study.
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Present address: Department of Anatomy, Faculty of Science, Rangsit University, Pathumthanee, Thailand.