Hormonal mechanisms in the paraventricular nuclei associated with hyperalgesia in Parkinson's disease model rats

Pain is a major non-motor symptom of Parkinson's disease (PD). The relationship between hyperalgesia and neuropeptides originating from paraventricular nucleus (PVN) in 6-hydroxydopamine (6-OHDA) rats has already been investigated for oxytocin (OXT), but not yet for arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH). The present study aimed to investigate the alterations in these neuropeptides following nociceptive stimulation in PD model rats and to examine the mechanisms of hyperalgesia. Dopaminergic nigrostriatal lesions were induced by injecting 6-OHDA into the medial forebrain bundle. Subcutaneous formalin injection into the vibrissa pad was performed in rats as a nociceptive stimulus in the orofacial region. Dopamine depletion's effect on nociception was assessed by counting the p-ERK-immunoreactive (-IR) cells in the trigeminal spinal subnucleus caudalis (Vc). The PD model rats induced by 6-OHDA injection (6-OHDA rats) showed a significantly higher number of p-ERK-IR cells in the Vc than the sham rats, confirming hyperalgesia in 6-OHDA rats. Then, we investigated the immunohistochemical responses to OXT, AVP, and CRH cells in the PVN and examined the changes in blood levels of these neuropeptides. As a result, formalin injection increased neuronal activity and blood levels of OXT and CRH in sham rats, but these were suppressed in the 6-OHDA rats. Contrarily, neuronal activity and blood level of AVP were unaffected by nociceptive stimuli and were significantly lower in 6-OHDA rats than in sham rats. Our findings suggest that OXT and CRH suppression is linked to hyperalgesia in PD, whereas AVP does not directly influence the observed hyperalgesia.