Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT₇ receptors.

Although some studies have shown the essential role of descending serotonergic pathways and spinal 5-HT(1A), 5-HT(2A), or 5-HT(3) receptors in the antinociceptive effects of paracetamol, other studies have presented conflicting results, and the particular subtype of spinal 5-HT receptors involved in paracetamol-induced analgesia remains to be clarified. Recent studies have demonstrated the importance of spinal 5-HT(7) receptors in descending serotonergic pain inhibitory pathways. In this study, we investigated the role of descending serotonergic pathways and spinal 5-HT(7) receptors compared with 5-HT(3) and 5-HT(2A) receptors in the antinociceptive and antihyperalgesic effects of paracetamol. Tail-flick, hot plate and plantar incision tests were used to determine nociception in male BALB/c mice. Lesion of serotonergic bulbospinal pathways was performed by intrathecal (i.th.) injection of 5,7-dihydroxytryptamine (5,7-DHT), and spinal 5-HT levels were measured by HPLC. To evaluate the particular subtypes of the spinal 5-HT receptors, the selective 5-HT(7), 5-HT(3) and 5-HT(2A) receptor antagonists SB 269970, ondansetron and ketanserin, respectively, were given i.th. after oral administration of paracetamol. Oral paracetamol (200, 400 and 600 mg/kg) elicits dose-dependent antinociceptive and antihyperalgesic effects. I.th. pretreatment with 5,7-DHT (50 μg) sharply reduced 5-HT levels in the spinal cord. Depletion of spinal 5-HT totally abolished the antinociceptive and antihyperalgesic effects of paracetamol. I.th. injection of SB 2669970 (10 μg) blocked the antinociceptive and antihyperalgesic effects of paracetamol, but ondansetron and ketanserin (10 μg) did not. Our findings suggest that systemic administration of paracetamol may activate descending serotonergic pathways and spinal 5-HT(7) receptors to produce a central antinociceptive and antihyperalgesic effects.