D1 receptors in the anterior cingulate cortex modulate basal mechanical sensitivity threshold and glutamatergic synaptic
- PDF / 1,880,876 Bytes
- 15 Pages / 595.276 x 790.866 pts Page_size
- 26 Downloads / 182 Views
RESEARCH
Open Access
D1 receptors in the anterior cingulate cortex modulate basal mechanical sensitivity threshold and glutamatergic synaptic transmission Soroush Darvish-Ghane1†, Clémentine Quintana2†, Jean-Martin Beaulieu2* and Loren J. Martin1,3*
Abstract The release of dopamine (DA) into target brain areas is considered an essential event for the modulation of many physiological effects. While the anterior cingulate cortex (ACC) has been implicated in pain related behavioral processes, DA modulation of synaptic transmission within the ACC and pain related phenotypes remains unclear. Here we characterized a Crispr/Cas9 mediated somatic knockout of the D1 receptor (D1R) in all neuronal subtypes of the ACC and find reduced mechanical thresholds, without affecting locomotion and anxiety. Further, the D1R high-efficacy agonist SKF 81297 and low efficacy agonist (±)-SKF-38393 inhibit α-amino-3-hydroxy-5-methyl-4isoxazolepropionic receptor (AMPAR) currents in the ACC. Paradoxically, the D1R antagonists SCH-23390 and SCH 33961 when co-applied with D1R agonists produced a robust short-term synergistic depression of AMPAR currents in the ACC, demonstrating an overall inhibitory role for D1R ligands. Overall, our data indicate that absence of D1Rs in the ACC enhanced peripheral sensitivity to mechanical stimuli and D1R activation decreased glutamatergic synaptic transmission in ACC neurons. Keywords: Dopamine, Anterior cingulate cortex, AMPA receptors, D1 receptors, D2 receptors, CFA, Inflammation, Hypersensitivity
Introduction Dopamine (DA) binds to two classes of G proteincoupled receptor subtypes (GPCRs), classified as D1-like (D1/D5) and D2-like (D2–D4) receptors [1, 2]. A number of clinical and genetic association studies suggest that D2-like receptor mediated mechanisms have antinociceptive properties [3–6]. Yet, the role of D1-like receptors in pain modulation remains less clear. Emerging * Correspondence: [email protected]; [email protected] † Soroush Darvish-Ghane and Clémentine Quintana contributed equally to this work. 2 Department of Pharmacology and Toxicology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada 1 Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada Full list of author information is available at the end of the article
evidence has shown that ablation of spinally projecting dopaminergic neurons reduced the maintenance of longlasting priming hyperalgesia in both sexes [7], however, spinal D5 receptors seem to play a critical role in males whereas females are more dependent on D1 receptors [8]. These studies are consistent with existing evidence supporting the pro-nociceptive effect of dopamine via a spinal D1/D5 mechanism [9]. In humans, greater functional connectivity of corticostriatal projections predict pain persistence suggesting a potential role of dopaminergic pathways in chronic pain [10]. Direct evidence from rodent studies show that dopaminergic projections from the ventral tegmental area (VTA) to the me
Data Loading...
