Effects of chronic paracetamol administration on serotonergic neurotransmission

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.