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Optogenetic Activation of Dopamine Receptor D1 and D2 Neurons in Anterior Cingulate Cortex Differentially Modulates Trigeminal Neuropathic Pain

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Abstract

Anterior cingulate cortex (ACC) is a critical brain center for chronic pain processing. Dopamine signaling in the brain has been demonstrated to contribute to descending pain modulation. However, the role of ACC dopamine receptors in chronic neuropathic pain remains unclear. In this study, we investigated the effect of optogenetic activation of ACC dopamine receptors D1- and D2-expressing neurons on trigeminal neuropathic pain. Chronic constriction injury of infraorbital nerve (CCI-ION) was carried out to induce trigeminal neuropathic pain in mice. We conducted optogenetic stimulation to specifically activate D1- and D2-expressing neurons in the ACC. Western blotting and immunofluorescence staining were used to examine ACC D1 and D2 expression and localization. The von Frey and real-time place preference tests were performed to measure evoked mechanical pain and nonreflexive emotional pain behaviors, respectively. We observed that dopamine receptors D1 and D2 in the ACC are primarily expressed in excitatory neurons and that the D2 receptor is differentially regulated in the early and late phases of trigeminal neuropathic pain. Optogenetic activation of D1-expressing neurons in the ACC markedly exacerbates CCI-ION-induced trigeminal neuropathic pain in both early and late phases, but optogenetic activation of D2-expressing neurons in the ACC robustly ameliorates such pain in its late phase. Our results suggest that dopamine receptors D1 and D2 in the ACC play different roles in the modulation of trigeminal neuropathic pain.

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Abbreviations

ACC:

anterior cingulate cortex

CCI-ION:

chronic constriction injury of infraorbital nerve

ChR2:

channelrhodopsin 2

GFAP:

glial fibrillary acidic protein

Iba1:

ionized calcium binding adapter molecule 1

NeuN:

neuronal nuclei

PAX2:

paired box 2

RTPP:

real-time place preference

Sp5C:

spinal trigeminal nucleus caudalis

TLX3:

T cell leukemia 3

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Acknowledgments

We thank Dr. Mary Kay Lobo (University of Maryland School of Medicine) for providing D1-Cre and D2-Cre transgenic mice.

Funding

This work was supported by the National Institutes of Health Grants R01 DE022880 (F.T.) and K02 DE023551 (F.T.).

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Authors and Affiliations

  1. Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX, USA

    Sufang Liu, Hui Shu, Joshua Crawford, Yajing Ma & Feng Tao

  2. Department of Physiology and Neurobiology, Zhengzhou University School of Medicine, Zhengzhou, Henan, China

    Sufang Liu & Yajing Ma

  3. Department of Anesthesiology, Zhengzhou University School of Medicine, Zhengzhou, Henan, China

    Changsheng Li

  4. Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, 3302 Gaston Ave., Dallas, TX, 75246, USA

    Feng Tao

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Contributions

All authors read and approved the manuscript. S.L. and F.T.: conceptualization; S.L. and J.C.: methodology; H.S., Y.M., and C.L.: data analysis; S.L.: writing (original draft); F.T.: writing (review and editing); and F. T.: funding acquisition.

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Correspondence to Feng Tao.

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Liu, S., Shu, H., Crawford, J. et al. Optogenetic Activation of Dopamine Receptor D1 and D2 Neurons in Anterior Cingulate Cortex Differentially Modulates Trigeminal Neuropathic Pain. Mol Neurobiol 57, 4060–4068 (2020). https://doi.org/10.1007/s12035-020-02020-2

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