Effect of chronic analgesic exposure on the central serotonin system: A possible mechanism of analgesic abuse headache

Objective.-To investigate the effects of chronic analgesic exposure on the central serotonin system and the relationship between the serotonin system and the analgesic efficacy of nonnarcotic analgesics. Methods.-Paracetamol was administered daily to adult male Wistar rats for a period of 15 or 30 days. Analgesic efficacy was measured by the tail flick test. After completion of the treatment protocol, the rats were humanely k illed, and the frontal cortex and brain stem were isolated. Characteristics of the specific binding of the 5-HT2A serotonin receptor and the serotonin transporter were studied using a radioligand binding technique, Platelet s erotonin was determined by high-performance liquid chromatography. Results.-Chronic paracetamol administration resulted in a significant decre ase in the maximum number of 5-MT2A binding sites and an increase in the ma ximum number of 5-HT transporter binding sites in frontal cortical membrane (P<.001). Changes in the central 5-HT system were associated with a rise i n platelet 5-HT levels. The degree of receptor downregulation, as well as t ransporter upregulation, became less evident after more prolonged drug admi nistration. Readaptation of serotonin receptors and transporters coincided with the decrease in the analgesic efficacy of paracetamol, as well as a fa ll in platelet 5-HT levels. Conclusions.-These findings provide further evidence in support of an invol vement of the 5-HT system in the antinociceptive activity of simple nonnarc otic analgesics. Plasticity of this neurotransmitter system after chronic a nalgesic exposure may lead to the loss of analgesic efficacy and, in its mo re extreme form, may produce analgesic-related painful conditions, for exam ple, analgesic abuse headache.