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Acetaminophen-induced antinociception via central 5-HT2A receptors
Authors:Anan Srikiatkhachorn  Naovarut Tarasub  Piyarat Govitrapong  
Institution:a Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;b Neuro-Behavioural Biology Center, Institute of Science and Technology for Research and Development, Mahidol University, Salaya, Nakornpathom 73170, Thailand
Abstract:Acetaminophen is one of the most widely used analgesic drugs. Although the mechanism of analgesic action of acetaminophen is still not known, the involvement of the central serotonin (5-hydroxytryptamine: 5-HT) system is one possibility. In the present study, we examined the antinociceptive effect of acute and chronic intraperitoneally (i.p.) administered acetaminophen by tail flick latency measurements in the rat. A significantly increased tail flick latency was observed in acute and 15-day acetaminophen-treated rats, but not in 30-day acetaminophen-treated rats, at a dose of 400 mg/kg/day. To investigate the plasticity of receptors at postsynaptic membrane, we conducted a series of experiments by radioligand binding method on frontal cortex and brainstem membrane. The technique involved radioligand binding with phenyl-4-3H]spiperone and ketanserin for studying 5-HT2A receptor characteristics. A significant decrease in the maximum number of 5-HT2A binding sites (Bmax) was demonstrated in all treatment groups with acetaminophen 300 and 400 mg/kg on frontal cortex membrane, whereas the value of the dissociation equilibrium constant (Kd) remained unchanged. The down-regulation of 5-HT2A binding sites in frontal cortex was of a lesser magnitude after 30 days of treatment and the tail flick latency was as in the control animals. These results suggest that down-regulation of 5-HT2A receptor in response to 5-HT release is a major step in the mechanism underlying analgesia produced by this agent. On the contrary, chronic use of acetaminophen may result in 5-HT depletion, which in turn produces re-adaptation of postsynaptic 5-HT2A receptors. These data provide further evidence for a central 5-HT-dependent antinociceptive effect of acetaminophen.
Keywords:antinociception  serotoninergic transmission  paracetamol  serotonin 2a receptor
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