Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1- and D2-receptor-expressing neurons

Daisuke Sato,Minoru Narita,Yusuke Hamada,Frank Porreca,Naoko Kuzumaki,Akihiro Yamanaka,Ryosuke Matsui,Hideki Tamura,Dai Watanabe,Moe Watanabe,Yukari Suda,Tomohisa Mori,Edita Navratilova,Emiko Senba,Kenichi Tanaka,Michiko Narita

doi:10.1186/s13041-021-00896-2

Abstract

Emerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.

Highlights

Parkinson’s disease is widely thought to be caused by a hypodopaminergic environment due to the degeneration of central dopaminergic neurons, and is associated with chronic pain in approximately 30–50% of patients [1, 2]
A growing body of evidence suggests that the nucleus accumbens (NAc), which is one of the major terminals of ventral tegmental area (VTA) dopaminergic neurons, is critically involved in emotional functions and reward-related behaviors, and pain control [3, 29, 30]
We first confirmed that bilateral microinjection of either the selective D1-receptor agonist Chloro-APB or the selective D2-receptor agonist quinpirole into the NAc medial shell (NAcMed) and NAc lateral shell (NAcLat), both of which highly expressed D1- and D2-receptors, transiently, but significantly, reversed the reduction in the pain threshold in mice with partial sciatic nerve ligation

Summary

Introduction

Parkinson’s disease is widely thought to be caused by a hypodopaminergic environment due to the degeneration of central dopaminergic neurons, and is associated with chronic pain in approximately 30–50% of patients [1, 2]. We determined if the microinjection of dopamine D1- and D2-receptor agonists or antagonists into each subregion of the NAc could produce relief of neuropathic pain in mice. By using optogenetic techniques to directly and manipulate target MSN activities, we attempted to investigate whether selective stimulation of D1-receptor-expressing neurons and selective suppression of D2-receptor-expressing neurons, in the three subregions of the NAc could produce antinociceptive effects in mice. Generation of D1‐cre and D2‐cre knock‐in mice C57BL/6-Drd1atm1(cre)Phsh (D1-cre) and C57BL/6Drd2tm1(cre)Phsh (D2-cre) mice, which were based on a C57BL/6 genetic background, were created at Cyagen Biosciences Inc. Two exons of Drd1a gene (NCBI Reference Sequence: NM_001291801.1), which is located on mouse chromosome 13, have been identified, with the ATG start codon in exon 2 and TGA atop codon in exon 2 (Transcript: Drd201 ENSMUST 00000021932.5). To generate the 2 A-Cre knock-in at the mouse Drd1a or Drd locus in C57BL/6 mice, the mixture of Cas mRNA, sgRNA, and Drd1-2ACre or Drd2-2A-Cre targeting vector, which can replace the TGA stop codon with 2A-Cre cassette according to CRISPR-Cas technology, was injected into mouse fertilized egg, the eggs were transferred to surrogate mothers to obtain founder knock-in mice on the B6 background

Method

Result

Findings

Discussion