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

Abstract

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor healthrelated quality of life. However, classic therapeutic drugs supplying dopamine have limited therapeutic effect on PD related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study has demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-HT) contents in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been con rmed 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 researches have shown that 5-HT1A receptor and 5-HT3 receptor played a key role in pain transmission in the spinal cord. Thus, we hypothesize that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons and the functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA 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 µmol/L), but not 5-HT3 receptor agonist M-CPBG (30 µmol/L), 5-HT1A receptor antagonist 8-OH DPAT (10 µmol/L)and agonist WAY-100635 (10 µmol/L). Intrathecal injection with 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) signi cantly attenuated the mechanical hyperalgesia and thermal hyperalgesia of 6-OHDA rats. Therefore, the present study suggests that inhibition of 5-HT3 receptor relieves hyperalgesia in PD rats by reducing the excitability of SDH neurons. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

No Evidence of Sensory Neuropathy in a Traditional Mouse Model of Idiopathic Parkinson’s Disease

“…These data are reminiscent of data from primates, showing that MPTP, which primarily kills DA neurons in the brain, fails to cause extensive changes in gut motility or may even increase it [63]. Additionally, previous sensory testing revealed increased sensitivity to heat or pin-point pressure in rats lesioned with 6-OHDA [64,65], another traditional method of inducing dopaminergic cell loss in the SNpc. However, PD patients show increased sensitivity to cold pain most consistently [52].…”

The Underlying Mechanisms of Sleep Deprivation Exacerbating Neuropathic Pain

“… 75 For example, intrathecal injection of 5-HT3 receptor antagonists significantly attenuated mechanical nociceptive hyperalgesia and thermal nociceptive hypersensitivity in 6-hydroxydopamine lesioned rats. 76 The effectiveness of 5-hydroxytryptamine reuptake inhibitors in the treatment of various clinical pain conditions (eg fibromyalgia) further demonstrates the involvement of 5-HT receptors in pain regulation. 77 , 78 In genetic studies, polymorphisms in monoamine metabolism and transport have been shown to correlate with the diagnosis or severity of fibromyalgia, such as serotonin 5-HT 2A receptor and 5-HT transporter.…”

Functional Dimerization of Serotonin Receptors: Role in Health and Depressive Disorders

“…The 5-HT7 receptor plays a role in regulating essential physiological processes such as circadian rhythms, the sleep-wake cycle, thermoregulation, learning and memory formation, and nociception [146]. Additionally, the expression of 5-HT7 has been identified in spinal cord [147], liver [148], immune system cells [123,149], heart, and kidneys [150].…”