The dopamine D1–D2DR complex in the rat spinal cord promotes neuropathic pain by increasing neuronal excitability after chronic constriction injury

• Published in: Experimental & molecular medicine 2021, 53(0), , pp.1-15
• Main Authors: Bao, Yi-Ni, Dai, Wen-Ling, Fan, Ji-Fa, Ma, Bin, Li, Shan-Shan, Zhao, Wan-Li, Yu, Bo-Yang, Liu, Ji-Hua
• Format: Article
• Language: English
• Subjects: 13; 13/1; 14; 14/1; 14/19; 14/34; 631/378/340; 631/378/87; 64; 82; 82/1; 96; 96/1; 96/34; Agonists; Animals; Antagonists; Behavior, Animal; Biomarkers; Biomedical and Life Sciences; Biomedicine; Ca2+/calmodulin-dependent protein kinase II; Calcium (intracellular); Calcium - metabolism; Cells, Cultured; Chronic pain; Cyclic AMP response element-binding protein; Disease Models, Animal; Disease Susceptibility; Dopamine; Dopamine Antagonists - pharmacology; Dopamine D1 receptors; Dopamine D2 Receptor Antagonists - pharmacology; Dopamine D2 receptors; Excitability; Hypersensitivity; Intracellular; Male; MAP kinase; Medical Biochemistry; Molecular Medicine; Multiprotein Complexes - metabolism; Neuralgia - diagnosis; Neuralgia - etiology; Neuralgia - metabolism; Neurons; Neuropathy; Pain; Pain Measurement; Pain perception; Phosphorylation; Protein Binding; Protein kinase C; Rats; Receptors, Dopamine D1 - antagonists & inhibitors; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Sensory Receptor Cells - metabolism; Signal Transduction; Spinal cord; Spinal cord injuries; Spinal Cord Injuries - complications; Spinal Cord Injuries - diagnosis; Spinal Cord Injuries - etiology; Spinal Cord Injuries - metabolism; Stem Cells; Therapeutic targets; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00563-5

Dopamine D1 receptor (D1DR) and D2 receptor (D2DR) are closely associated with pain modulation, but their exact effects on neuropathic pain and the underlying mechanisms remain to be identified. Our research revealed that intrathecal administration of D1DR and D2DR antagonists inhibited D1–D2DR complex formation and ameliorated mechanical and thermal hypersensitivity in chronic constriction injury (CCI) rats. The D1–D2DR complex was formed in the rat spinal cord, and the antinociceptive effects of D1DR and D2DR antagonists could be reversed by D1DR, D2DR, and D1–D2DR agonists. Gαq, PLC, and IP3 inhibitors also alleviated CCI-induced neuropathic pain. D1DR, D2DR, and D1–D2DR complex agonists all increased the intracellular calcium concentration in primary cultured spinal neurons, and this increase could be reversed by D1DR, D2DR antagonists and Gαq, IP3, PLC inhibitors. D1DR and D2DR antagonists significantly reduced the expression of p-PKC γ, p-CaMKII, p-CREB, and p-MAPKs. Levo -corydalmine ( l -CDL), a monomeric compound in Corydalis yanhusuo W.T. Wang, was found to obviously suppress the formation of the spinal D1–D2DR complex to alleviate neuropathic pain in CCI rats and to decrease the intracellular calcium concentration in spinal neurons. l- CDL-induced inhibition of p-PKC γ, p-MAPKs, p-CREB, and p-CaMKII was also reversed by D1DR, D2DR, and D1–D2DR complex agonists. In conclusion, these results indicate that D1DR and D2DR form a complex and in turn couple with the Gαq protein to increase neuronal excitability via PKC γ, CaMKII, MAPK, and CREB signaling in the spinal cords of CCI rats; thus, they may serve as potential drug targets for neuropathic pain therapy. Chronic pain: Cutting communication for nerve pain signals Insights into dopamine-mediated neuronal activity in the spinal cord may lead to more effective relief for some chronic pain patients. Up to 10% of adults worldwide live with some form of pain due to nerve damage (neuropathy), and few treatment options are available. The neurotransmitter dopamine is thought to regulate pain-related signaling in the spinal cord, and researchers led by Ji-Hua Liu and Bo-Yang Yu of China Pharmaceutical University, Nanjing, have identified a way to interfere with this signaling. Working with a rat neuropathic pain model, the researchers focused on a protein complex that acts as a receptor for dopamine in spinal neurons. Once activated, this complex initiates cellular processes that mediate the pain response