The Effect of a 5-HT2A Receptor Antagonist on Pain-Related Behavior, Endogenous 5-Hydroxytryptamine Production, and the Expression 5-HT2A Receptors in Dorsal Root Ganglia in a Rat Lumbar Disc Herniation Model

In Brief Study Design. Controlled, interventional, animal study. Objective. To evaluate the effect of a 5-HT2A receptor antagonist on pain-related behavior, endogenous 5-hydroxytryptamine (5-HT) plasma levels, and expression of 5-HT2A receptors in dorsal root ganglia (DRGs) in a rat lumbar disc herniation model. Summary of Background Data. Application of nucleus pulposus on the nerve root induces immediate peripheral 5-HT production and the expression of 5-HT2A receptors in the adjacent DRG. However, the efficacy of a 5-HT2A receptor antagonist for pain relief in this situation and the mechanism remain unknown. Methods. Autologous nucleus pulposus was applied to the left L5 nerve root of 91 adult female Sprague-Dawley rats. The selective 5-HT2A receptor antagonist sarpogrelate hydrochloride (SPG; 1 mg/kg or 10 mg/kg) or vehicle was administered orally once a day from 1 to 21 days postoperatively. Von Frey tests were used to test pain behavior before and after surgery. To assess the effect of SPG on endogenous 5-HT release surrounding the inflamed nerve root, we measured levels of 5-hydroxyindole acetic acid, a 5-HT metabolite, in plasma. Expression of 5-HT2A receptors in the left L5 DRG was examined with immunoblotting. Results. The higher dose (10 mg/kg) of SPG significantly improved the mechanical withdrawal thresholds from 5 to 21 days after surgery compared with vehicle treatment. 5-hydroxyindole acetic acid in plasma was not significantly different among any groups at any time points. Both doses of SPG inhibited the expression of 5-HT2A receptors after surgery compared with vehicle treatment. Conclusion. A selective 5-HT2A receptor antagonist attenuated pain-related behavior and suppressed 5-HT2A receptor expression in the DRG, but did not affect peripheral 5-HT production. Selective 5-HT2A receptor antagonists may attenuate sciatica by blocking and downregulating 5-HT2A receptors in DRGs in lumbar disc herniation. Level of Evidence: NA Serotonin 5-hydroxytryptamine is a potential agent for treating sciatica due to lumbar disc herniation. We demonstrate that a 5-HT2A receptor antagonist attenuated pain-related behavior and suppressed 5-HT2A receptor expression in dorsal root ganglia without affecting 5-hydroxytryptamine production. Such antagonists may attenuate sciatica by blocking and downregulating 5-HT2A receptors in dorsal root ganglia in lumbar disc herniation.