Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion

Abstract

Neuropathic pain resulting from spinal cord injury is often accompanied by maladaptive plasticity of the central nervous system, including the opioid receptor-rich periaqueductal gray (PAG). Evidence suggests that sensory signaling via the PAG is robustly modulated by dopamine D1- and D2-like receptors, but the effect of damage to the spinal cord on D1 and D2 receptor protein expression and function in the PAG has not been examined. Here we show that 21 days after a T10 or C6 spinothalamic tract lesion, both mice and rats display a remarkable decline in the expression of D1 receptors in the PAG, revealed by western blot analysis. These changes were associated with a significant reduction in hindpaw withdrawal thresholds in lesioned animals compared to sham-operated controls. We investigated the consequences of diminished D1 receptor levels by quantifying D1-like receptor-mediated phosphorylation of ERK1,2 and CREB, events that have been observed in numerous brain structures. In naïve animals, western blot analysis revealed that ERK1,2, but not CREB phosphorylation was significantly increased in the PAG by the D1-like agonist SKF 81297. Using immunohistochemistry, we found that SKF 81297 increased ERK1,2 phosphorylation in the PAG of sham animals. However, in lesioned animals, basal pERK1,2 levels were elevated and did not significantly increase after exposure to SKF 81297. Our findings provide support for the hypothesis that molecular adaptions resulting in a decrease in D1 receptor expression and signaling in the PAG are a consequence of SCL.

Partially brain effects of injection of human umbilical cord mesenchymal stem cells at injury sites in a mouse model of thoracic spinal cord contusion

“…The ACC effectively regulates pain and emotion by activating the PAG. Deep brain stimulation of the PAG decreases neuropathic pain in humans (Voulalas et al, 2017 ). Our study indicated that the expression of CGRP, SP and C-Fos increased, and that of KCC2 decreased, in the ACC and PAG in models of SCI, whereas the expression of CGRP, SP and C-Fos decreased, and that of KCC2 increased, after HU-MSC injection.…”

“…Deep brain stimulation to the PAG has been found to decrease neuropathic pain in humans. Moreover, cannabis receptors, purinergic receptors, glutaminergic receptors, serotonergic receptors and adrenergic receptors in the PAG are believed to be associated with pain models (Voulalas et al, 2017 ).…”

Painful stimulation increases spontaneous blink rate in healthy subjects

“…A subpopulation of dopaminergic neurons within the ventrolateral periaqueductal grey (PAG), a brain area included in the descending pain modulatory system 20 , projects to brain regions known to be involved in pain modulation [21][22][23][24] . Both D1-like and D2-like dopamine receptors are expressed within the ventrolateral PAG [25][26][27] and have been shown to contribute to antinociception 15,[28][29][30] .…”