Behavioral, Cellular and Molecular Responses to Cold and Mechanical Stimuli in Rats with Bilateral Dopamine Depletion in the Mesencephalic Dopaminergic Neurons.

Pain is the major non-motor symptom in Parkinson's disease (PD). Preclinical studies have mostly investigated mechanical pain by considering the decrease in a nociceptive threshold. Only a few studies have focused on thermal pain in animal models of PD. Therefore, the goal of this study was to assess the thermal nociceptive behavior of rats subjected to 6-hydroxydopamine (6-OHDA) administration, which constitutes an animal model of PD. Thermal plate investigation demonstrated significant thermal sensitivity to cold temperatures of 10 °C and 15 °C, and not to higher temperatures, in 6-OHDA-lesioned rats when compared with sham. 6-OHDA-lesioned rats also showed cold allodynia as demonstrated by a significant difference in the number of flinches, latency and reaction time to acetone stimulus. Ropinirole administration, a dopamine receptor 2 (D2R) agonist, blocked the acetone-induced cold allodynia in 6-OHDA-lesioned rats. In addition, mechanical hypersensitivity and static allodynia, as demonstrated by a significant difference in the vocalization threshold and pain score respectively, were noticed in 6-OHDA-lesioned rats. Acetone stimulus induced a significant increase in extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation, a pain process molecular marker, in the spinal dorsal horn (SDH), the insular and cingulate cortices in 6-OHDA-lesioned rats when compared to sham. In 6-OHDA-lesioned rats, there was a significant augmentation in the expression of both protein kinase C gamma (PKCγ) and glutamate decarboxylase 67 (GAD67) in the SDH. This highlighted an increase in excitation and a decrease in inhibition in the SDH. Overall, the present study demonstrated a clear cold thermal hypersensitivity, in addition to a mechanical one, in 6-OHDA-lesioned rats.

Nigrostriatal dopamine depletion promoted an increase in inhibitory markers (parvalbumin, GAD67, VGAT) and cold allodynia.

Pain constitutes the major non-motor symptom in Parkinson's disease (PD). Its mechanism is still poorly understood although an increase in excitation or a decrease in inhibition have been reported in preclinical studies. The aim of this study was to investigate gamma aminobutyric acid (GABA) inhibition in the 6-hydroxydopamine (6-OHDA) PD rat model. Therefore, the expression of three inhibitory markers parvalbumin, glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) was evaluated, besides cold allodynia, in bilateral 6-OHDA lesioned rat. There was a significant increase in the expression of the three markers labeling within the spinal dorsal horn (SDH) of 6-OHDA lesioned rats. In parallel, there was also an increase of the excitatory marker protein kinase C gamma (PKCγ) . PKCγ cells have a crucial role in pain chronicity and are regulated by GABAergic influences. Central dopamine depletion induced an increase in excitation as reveled by an increase in cFOS expression upon acetone stimulus and the presence of cold allodynia. In addition, dopamine depletion induced increased expression in inhibitory markers, which may reflect a disinhibition or a decreased inhibition in 6-OHDA lesioned rats.