Involvement of 5-HT1A/1B receptors in the antinociceptive effect of paracetamol in the rat formalin test.

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.

Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats.

BACKGROUND: Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. METHODS: The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. RESULTS: While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus. CONCLUSIONS: These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. SIGNIFICANCE: S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus.