Abstract
The mechanism of analgesic action of paracetamol (acetominophen) remains still unknown. However, a relationship between serotonergic system and the effect of paracetamol has been previously demonstrated. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. To determine whether the 5-HT1A and 5-HT1B receptors are involved in the antinociceptive effect of paracetamol, we evaluated the effect of paracetamol (0.125–1 g/kg i.p.) followed by different antagonists [WAY 100,635 (0.8 mg/kg s.c.) and SB 216,641 (0.8 mg/kg s.c.)] or agonists [8-OH-DPAT (0.125 mg/kg s.c.) and CP 93,129 (0.125 mg/kg s.c.)] of 5-HT1A and 5-HT1B receptors, respectively, in the rat model of formalin-induced pain. We demonstrated that paracetamol administration showed a dose-dependent antinociceptive effect in the formalin test. WAY 100,635 (5-HT1A antagonist) induced an increase in the antinociceptive effect of paracetamol at 250 mg/kg doses. Conversely, 8-OH-DPAT (5-HT1A agonist) decreased the antinociceptive effect of paracetamol at 500–1000 mg/kg doses. However, SB216641 (5-HT1B antagonist) modified weakly the antinociceptive effect of paracetamol at 250 mg/kg doses and CP 93,129 (5-HT1B agonist) not produce a clear effect in the antinociceptive effect of paracetamol. These results suggest that the antinociceptive effect of paracetamol can be enhanced mainly by compounds having 5-HT1A antagonist properties in the formalin test and maybe by 5-HT1B receptors antagonists.
Highlights
Paracetamol has been extensively studied as analgesic for pain relief in many clinical settings but its mechanism of action still is under considerable debate
The analgesic effects of paracetamol are attenuated by drugs that act via inhibition of serotonergic, opioid and cannabinoid systems (Pickering et al, 2006; Toussaint et al, 2010) suggesting that a number of neurotransmitter system may be involved in the central antinociceptive mechanism of paracetamol, in particular, serotonergic pathways
Experiments were repeated with 1000 mg/kg of paracetamol and one-way ANOVA revealed a significant effect of 8-OHDPAT on the antinociceptive effect of paracetamol in both phases of the formalin test (Phase 1: F3,31 = 9.41, P < 0.0001; Phase 2: F3,31 = 49.53; P < 0.0001) (Fig. 3B). 8-OH-DPAT modified the antinociceptive effect of paracetamol, it induced a significant increase of the number of flinches in both phases in paracetamol 1000 mg/kg treated animals. These results show that 5-HT1A agonist, 8-OH-DPAT, decreased the antinociceptive effect of paracetamol suggesting the possible role of the 5-HT1A receptors in the antinociceptive mechanism of paracetamol
Summary
Paracetamol (acetaminophen) has been extensively studied as analgesic for pain relief in many clinical settings but its mechanism of action still is under considerable debate. The analgesic effects of paracetamol are attenuated by drugs that act via inhibition of serotonergic, opioid and cannabinoid systems (Pickering et al, 2006; Toussaint et al, 2010) suggesting that a number of neurotransmitter system may be involved in the central antinociceptive mechanism of paracetamol, in particular, serotonergic pathways. Paracetamol treatment induces a significant increase in 5-HT levels in the brainsterm (Courade et al, 2001) Another hypothesis that has surfaced is that the analgesic action of systemically administered paracetamol could be attributed to spinal 5-HT (5-HT3 and 5-HT7) receptors mediated the enhanced neurotransmitter release in the descending serotonergic pathway, which is responsible for modulation of pain at the spinal level (Dogrul et al, 2012). Other studies report a serotonergic facilitatory modulation onto the spinal cord through 5-HT3 in different pain models (Bannister et al, 2015; Sikandar et al, 2012)
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