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.