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Background: Dopamine receptors have been reported to be involved in pain, while the exact effects and mechanism in bone cancer pain have not been fully explored. Methods: Bone cancer pain model was created by implanting walker 256 mammary gland carcinoma into right tibia bone cavity. Primary cultured spinal neurons were used for in vitro evaluation. FLIPR, western-blot, immunofluorescence, and Co-IP were used to detect cell signaling pathway. Results: Our results indicated that spinal dopamine D1 receptor (D1DR) and spinal dopamine D2 receptor (D2DR) could form heteromers in TCI rats, and antagonizing spinal D1DR and D2DR reduced heteromers formation and alleviated TCI-induced bone cancer pain. Further results indicated that D1DR or D2DR antagonist induced antinociception in TCI rats could be reversed by D1DR, D2DR, and D1/D2DR heteromer agonists. And Gq, IP3, and PLC inhibitors also attenuated TCI-induced bone cancer pain. In vitro results indicated that D1DR or D2DR antagonist decreased the Ca 2+ oscillations upregulated by D1DR, D2DR, and D1/D2DR heteromer agonists in activated primary cultured spinal neurons. Moreover, inhibition of D1/D2DR heteromers induced antinociception in TCI rats was partially mediated by the CaMKII and MAPKs pathway. In addition, a natural compound levo -Corydalmine ( l- CDL), could inhibit D1/D2DR heteromers and attenuate bone cancer pain. Results: Inhibition of spinal D1/D2DR heteromers via l- CDL decreases excitability in spinal neurons, which might present new therapeutic strategy for bone cancer pain., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).) more...

We propose a model for synaptic plasticity based on a calcium signaling cascade. The model simplifies the full signaling pathways from a calcium influx to the phosphorylation (potentiation) and dephosphorylation (depression) of glutamate receptors that are gated by fictive C1 and C2 catalysts, respectively. This model is based on tangible chemical reactions, including fictive catalysts, for long-term plasticity rather than the conceptual theories commonplace in various models, such as preset thresholds of calcium concentration. Our simplified model successfully reproduced the experimental synaptic plasticity induced by different protocols such as (i) a synchronous pairing protocol and (ii) correlated presynaptic and postsynaptic action potentials (APs). Further, the ocular dominance plasticity (or the experimental verification of the celebrated Bienenstock-Cooper-Munro theory) was reproduced by two model synapses that compete by means of back-propagating APs (bAPs). The key to this competition is synapse-specific bAPs with reference to bAP-boosting on the physiological grounds., (Copyright © 2019 Elsevier Ltd. All rights reserved.) more...