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

Abstract

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.

Combination of paeoniflorin and liquiritin alleviates neuropathic pain by lipid metabolism and calcium signaling coordination

“…Consequently, IP3 activates IP3R in the endoplasmic reticulum to mobilize intracellular Ca2+ ( Samways and Henderson, 2006 ). In addition to IP3, PLC also generates diacylglycerol, diacylglycerol, and/or Ca2+ activate PKC, which can promote the activation of transcription factors, such as CREB, to further enhance pain transmission ( Bao et al, 2021 ). Therefore, PL may alleviate NP by coordinating the calcium signaling and lipid metabolism to suppress PKC signaling transduction ( Figure 6 ).…”

Lotusine ameliorates propionic acid‐induced autism spectrum disorder‐like behavior in mice by activating D1 dopamine receptor in medial prefrontal cortex

“…DRD1 activation leads to increased c‐fos expression (Gerfen, 2022; Numa et al, 2019), a marker of neuronal activity. Notably, DRD1 stimulation triggers the activation of protein kinase A, CaMKII, and protein kinase C through coupling to Gα s (Bao et al, 2021; Gao & Wolf, 2007). This complex signaling pathway ultimately results in the phosphorylation of the GluA1 subunit of the AMPA receptor at Ser 845 and Ser 831, leading to increased AMPA receptor surface expression and conductivity (Barria et al, 1997).…”

Identification of potential key circular RNAs related to cognitive impairment after chronic constriction injury of the sciatic nerve

“…A chronic neuropathic pain model was constructed through chronic constriction injury (CCI) of the sciatic nerve as described previously ( Bao et al, 2021 ). Briefly, rats were anesthetized with sodium pentobarbital (50 mg/kg), and an incision was made in the left thigh to expose the sciatic nerve with almost transverse running, which was visible between the anterior and posterior groups of muscles.…”