Serotonergic and opiatergic modifications induced by paracetamol as a model for daily chronic headache with analgesic overuse

The chronic use of analgesic compounds may contribute to the chronicization of headache. It has been proposed that these headaches associated with daily drug use are due to a rebound effect in a vicious circle drug-headache–drug that mimics drug abuse (Post RM, Silberstein SD, Neurology; 44: 37-4,1994).There are several models to study experimental headaches in relation to acute antimigraine therapy (DeVries et al, Europ J Pharmacol 375: 61-74, 1999), whereas are lacking animal modelsf or daily chronic headache.Paracetamol is a drug widely used to treat headache, and often used in chronic headache sufferers. To explore the possible influence of this drug we performed a study to evaluate the effects of this drug on serotonergic and opiatergic systems in the rat brain after a sub-chronic administration.7 male Wistar rats groups of 8 animals were treated for 7 days with paracetamol i.p. at the dose of 400 mg/kg dissolved in a vehicle volume of 10 ml/kg or vehicle. Animals were submitted to hot-plate test every day at time 2,8 and 24 hours after drug administration. After this test one group of animals was sacrificed every day; the day 1 and 7 also control group were killed. Brains were dissected to determine the presence of binding sites for 5HT2 receptors in cerebral cortex by binding 3H-ketanserin and for opiate receptors by competitive binding with 3H-DAMGO.The results were analysed with Student’s test and Mann-Whitney U test for motor activity. Data were expressed as mean } S.E. Motor activity was not different in vehicle or in paracetamol treated rats at days 1 and 7 ( P> 0.05) . The % of MPE in hotplate test was 5.1}3.2 and 4.7}2.5 at day 1 and 7 for vehicle treated rats, and 24.5}8 and 19.7}4.3 at day 1 and 7 for paracetamol treated rats (P<0.05 vs. ctrl). The maximum bindingcapacity (Bmax )for ketanserin in cortical areas was 254}9.7 and 245}10.5 fmol mg/prot at day 1 and 7 respectively (P>0.5).Paracetamol treated rats Bmax was 194}12.3 and 187}21 fmol mg/prot at day 1 and 7 respectively for ketanserin ( p>0.05), and 250}32 and 170}24 fmol mg/prot at day 1 and 7 respectively for DAMGO (P<0.05). Treatment reduced significantly both types of receptor with respect to vehicle.Repeated doses of paracetamol do not induce tolerance in hotplate test. This treatment induces, as expected, a stable reduction of Bmax in cerebral cortex of 5-HT2 and receptors. These receptors were reduced after a week treatment, whereas the antinociceptive activity was maintained. These data suggest that the prolonged antinociceptive effect of paracetamol is linked more to serotonergic than opiatergic system.This lack of tolerance in analgesic effect of paracetamol could be important to explain the choice of this drug by patients suffering from chronic headaches.