Arsenic decreases antinociceptive activity of paracetamol: Possible involvement of serotonergic and endocannabinoid receptors

• We evaluated whether arsenic (AS) can reduce paracetamol (AP)-mediated analgesia.
• 5-HT level and 5-HT1A, 5-HT2A and CB1 receptors expression were assessed in brain.
• AS reduced AP-mediated analgesia and rise in 5-HT level with no effect on 5-HT1A.
• AS reduced AP-induced down-regulation of 5-HT2A and reversed up-regulation of CB1.
• Inhibition of analgesia may relate to interference with 5-HT2A and CB1 receptors.

We assessed whether repeated arsenic exposure can decrease paracetamol-mediated antinociception by modulating serotonergic and endocannabinoid pathways. Rats were preexposed to elemental arsenic (4 ppm) as sodium arsenite through drinking water for 28 days. Next day paracetamol's (400 mg/kg, oral) antinociceptive activity was assessed through formalin-induced nociception. Serotonin content and gene expression of 5-HT1A, 5-HT2A and CB1 receptors were evaluated in brainstem and frontal cortex. Arsenic decreased paracetamol-mediated analgesia. Paracetamol, but not arsenic, increased serotonin content in these regions. Arsenic attenuated paracetamol-mediated increase in serotonin level. Paracetamol did not alter 5-HT1A expression, but caused down-regulation of 5-HT2A and up-regulation of CB1 receptors. Arsenic down-regulated these receptors. However, paracetamol-mediated down-regulation of 5-HT2A was more pronounced. Arsenic did not modify paracetamol's effect on 5-HT1A expression, but reduced paracetamol-mediated down-regulation of 5-HT2A and reversed up-regulation of CB1 receptors. Results suggest arsenic reduced paracetamol-induced analgesia possibly by interfering with pronociceptive 5-HT2A and antinociceptive CB1 receptors.