Thesis (Ph.D.)--Chulalongkorn University, 1997

Paracetamol is the most widely used analgesic drug. Although the mechanism of analgesic action of paracetamol is still not known, the involvement of central serotonin (5-hydroxytryptamine: 5-HT) system is one possibilitty. The antinociceptive effect of acute and chronic intraperitoneally (i.p.) administered paracetamol was assessed by tail flick latency measurements in the rat. A significantly increased tail flick latency was observed in acute and 15-day paracetamol-treated rats, but not in 30-day paracetamol-treated rats, at a dose of 400 mg/kg. By using platelets as a neuronal model, our results revealed a significant increase in platelet 5-HT content in 15-day paracetamol treated groups at a dose of 300 and 400 mg/kg compared to control groups (7024.67+_905.97, 7342.83+_1041.35 and 3911.32+_438.07 ng/10x10x10x10x10x10x10x10 platelets, respectively, p<0.01). A significant increase was also observed in platelet 5-HIAA content in 30-day paracetamol-treated groups at a dose of 300 and 400 mg/kg compared to control groups (13788.65+_2373.95, 13866.77+_2517.06 and 7116.84+_1199.23 ng/10x10x10x10x10x10x10x10 platelets, respectively, p<0.01). To investigate the plasticity of receptors at pre- and post synaptic 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 serotonin receptor characteristics and [3H]-imipramine and fluoxetine for studying 5-HT uptake sites characteristics. A significant decrease in the maximum number of 5-HT2A binding sites (Bmax) was demonstrated in all treatment groups with paracetamol 300 and 400 mg/kg on frontal cortex membrane, whereas the value of dissociation equilibrium constant (Kd) remained unchanged. An increase in the maximum number of 5-HT2A binding sites was observed in 30-day paracetamol-treated rats, compared with 15-day paracetamol-treated rats at a dose of 400 mg/kg (0.94+_0.01 and 1.34+_0.13 pmol/mg protein, respectively). In contrast to 5-HT2A receptors, a significant increase in the maximum number of 5-HT uptake sites was demonstrated in all treatment groups with paracetamol 300 and 400 mg/kg on frontal cortex membrane, whereas the value of dissociation equilibrium constant remained unchange. A decrease in the maximum number of 5-HT uptake sites was observed in 30-day paracetamol-treated rats as compared with 15-day paracetamol-treated rat at a dose of 400 mg/kg (4.59+_0.52 and 2.71+_0.18 pmol/mg protein, respectively). Such changes of 5-HT2A receptors and 5-HT uptake sites was not observed on brainstem membranes. The post synaptic receptors became down-regulated whereas the uptake sites were up-regulated in frontal cortex membranes of acute and 15-day paracetamol treatments. These occured concomitantly with an increase in platelet 5-HT level and antinociceptive activity. These abnormalities of receptors were normalizable after 30-day paracetamol treatments. From these results we suggest that down-regulation of 5-HT2A receptor in reponse to 5-HT release is a major step in mechanism underlying analgesia produced by this agent. Such increased 5-HT level at the synaptic cleft may induce up-take sites. On the contrary, chronic use of paracetamol may result in 5-HT depletion which in turn produces re-adaptation of post-synaptic 5-HT2A receptor and pre-synaptic 5-HT uptake sites. These data provide provide further evidence for a central 5-HT dependent antinociceptive effect of paracetamol.