Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson's Disease

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 mu mol/L) and palosetron (10 mu mol/L), but not 5-HT3 receptor agonist m-CPBG (30 mu mol/L) and SR 57,727 (10 mu mol/L), 5-HT1A receptor agonist 8-OH DPAT (10 mu mol/L) and eptapirone (10 mu mol/L) and 5-HT1A receptor antagonist WAY-100635 (10 mu mol/L) and p-MPPI (10 mu mol/L). Intrathecal injection of ondansetron (0.1 mg/kg) but not m-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg), and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

Automated summary

Pain in Parkinson's disease (PD) is a major factor affecting the life quality of PD patients. Traditional therapeutic drugs lacking efficacy on PD-related pain suggest the involvement of a mechanism outside the dopamine system. Previous studies have shown that decreased serotonin levels in the spinal dorsal horn (SDH) are associated with increased pain sensitivity in a 6-OHDA-induced PD model. In this study, we found that inhibition of spinal 5-HT3 receptors and reduction of SDH neuronal excitability can alleviate hyperalgesia in PD rats. These findings provide a novel mechanism and potential therapeutic strategy for pain management in PD patients.