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 killed, 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 serotonin was determined by high-performance liquid chromatography.


RESULTS
Chronic paracetamol administration resulted in a significant decrease in the maximum number of 5-HT2A binding sites and an increase in the maximum 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 in platelet 5-HT levels. The degree of receptor downregulation, as well as transporter upregulation, became less evident after more prolonged drug administration. Readaptation of serotonin receptors and transporters coincided with the decrease in the analgesic efficacy of paracetamol, as well as a fall in platelet 5-HT levels.


CONCLUSIONS
These findings provide further evidence in support of an involvement of the 5-HT system in the antinociceptive activity of simple nonnarcotic analgesics. Plasticity of this neurotransmitter system after chronic analgesic exposure may lead to the loss of analgesic efficacy and, in its more extreme form, may produce analgesic-related painful conditions, for example, analgesic abuse headache.
Srikiatkhachorn
A
A
Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Tarasub
N
N
Govitrapong
P
P
D000082:Acetaminophen / Q000008:administration & dosage* / Q000009:adverse effects; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004334:Drug Administration Schedule; D020773:Headache Disorders / Q000209:etiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins
D018712:Analgesics, Non-Narcotic; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D000082:Acetaminophen