Bilateral Parkinson’s disease model rats exhibit hyperalgesia to subcutaneous formalin administration into the vibrissa pad

Abstract

We bilaterally injected 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats and developed bilateral Parkinson’s disease (PD) model rats in order to experimentally investigate the neural mechanisms underlying the alteration of nociception in the orofacial region of patients with PD. We explored the effects of dopamine depletion on nociception by investigating behavioral responses (face rubbing) triggered by subcutaneous administration of formalin into the vibrissa pad. We also assessed the number of c-Fos–immunoreactive (c-Fos-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Subcutaneous formalin administration evoked a two-phase increase in face rubbing. We observed the first increase 0–5 min after formalin administration (first phase) and the second increase 10–60 min after administration (second phase). The number of face rubbing behaviors of 6OHDA–injected rats did not significantly change compared with saline–injected rats in both phases. Significant increase of c-Fos-IR cells in the Vc was found in 6-OHDA–injected rats after formalin administration compared with those in saline–injected rats after formalin administration. We also assessed expression of c-Fos-IR cells in the paraventricular nucleus (PVN), and significant decrease of c-Fos-IR cells in the PVN of 6-OHDA–injected rats was found. Taken together, these findings suggest that bilateral dopaminergic denervation evoked by 6-OHDA administration causes hyperalgesia in the trigeminal region and the PVN may be involved in the hyperalgesia.

Changes in the analgesic mechanism of oxytocin can contribute to hyperalgesia in Parkinson’s disease model rats

“…The mechanisms underlying this hyperalgesia were examined by measuring the c-Fos expression in brain regions related to the DPIS, and the findings showed no differences in the number of c-Fos-IR cells in the vlPAG, LC, and NRM between 6-OHDA-lesioned and sham-operated rats receiving formalin injections. However, in the formalin injection group, 6-OHDA-lesioned rats exhibited a significant decrease in the number of c-Fos-IR cells in the ipsilateral PVN when compared to the sham-operated rats, and this finding was also in agreement with previous studies [19, 21]. Further examination showed that the number of c-Fos-IR cells in the ipsilateral mPVN and dpPVN of 6-OHDA-lesioned rats did not significantly differ by injection status (i.e., formalin injection vs no injection groups).…”

“…Previous studies investigating the cause of hyperalgesia in PD model rats have largely focused on the DPIS [3, 23, 24]. One study demonstrated a significant bilateral decrease in c-Fos-immunoreactive (-IR) cells in the PVN of PD model rats after SC injection of formalin into the vibrissa pad [19], while another observed similar results unilaterally in the hind paws of PD model rats [21]. The current study aimed to elucidate the mechanism underlying hyperalgesia in PD by examining DPIS neuronal nuclei activity.…”

“…Previous evidence suggests that PD induced in rats by unilateral and bilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), striatum, or substantia nigra can result in allodynia and hyperalgesia after subcutaneous (SC) injection of formalin into the hind limbs and vibrissa pad [15][16][17][18][19][20][21]. However, the mechanism underlying this hyperalgesia remains unclear, with some studies suggesting that changes in the descending pain inhibitory system (DPIS) associated with reduced function of the nigrostriatal pathway may facilitate excitatory neurotransmission in the spinal dorsal horn and trigeminal spinal subnucleus caudalis (Vc) leading to hyperalgesia [3,[22][23][24][25][26][27].…”

Dopaminergic Modulation of Orofacial Mechanical Hypersensitivity Induced by Infraorbital Nerve Injury

“…Thirty minutes prior to surgery, ION-CCI rats received an i.p. injection of desipramine hydrochloride (20 mg/kg, Sigma, St. Louis, MO, USA) to protect noradrenergic neurons and fibers [48,49]. ION-CCI rats then were anesthetized by i.p.…”

“…administration of saline solution mixed with 2.0 mg/kg midazolam, 2.5 mg/kg butorphanol, and 0.375 mg/kg medetomidine and placed in a stereotaxic apparatus (Narishige, Tokyo, Japan) with the incisor bar set 3.3 mm below the level of the ear bars. Next, 2 mg of 6-OHDA (Sigma, St. Louis, MO, USA) in 1 mL of sterile saline containing 0.01% ascorbic acid was injected into the left A11 nucleus [15,48,49]. Stereotaxic coordinates for the 6-OHDA injection site were 3.9 mm caudal to the bregma, 0.5 mm left of the midline, and 7 mm ventral to the dural surface.…”