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Attenuation of Reserpine-Induced Pain/Depression Dyad by Gentiopicroside Through Downregulation of GluN2B Receptors in the Amygdala of Mice

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Abstract

Epidemiological studies demonstrate that pain frequently occurs comorbid with depression. Gentiopicroside (Gent) is a secoiridoid compound isolated from Gentiana lutea that exhibits analgesic properties and inhibits the expression of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the anterior cingulate cortex of mice. However, the effects of Gent on the reserpine-induced pain/depression dyad and its underlying mechanisms are unclear. Reserpine administration (1 mg/kg subcutaneous daily for 3 days) caused a significant decrease in the nociceptive threshold as evidenced by the reduced paw withdrawal latency in response to a radiant heat source and mechanical allodynia. Behavioral detection indicated a significant increase in immobility time during a forced swim test, as well as decreased time in the central area and total travel distance in an open field test. Furthermore, reserpinized animals exhibited increased oxidative stress. Systemic Gent administration dose-dependently ameliorated the behavioral deficits associated with reserpine-induced pain/depression dyad. At the same time, the decrease in biogenic amine levels (norepinephrine, dopamine, and serotonin) was integrated with the increase in caspase-3 levels and GluN2B-containing NMDA receptors in the amygdala of the reserpine-injected mice. Gent significantly reversed the changes in the levels of biogenic amines, caspase-3, and GluN2B-containing NMDA receptors in amygdala. However, Gent did not affect the expression of GluN2A-containing NMDA receptors. The inhibitory effects of Gent on oxidative stress were occluded by simultaneous treatment of GluN2B receptors antagonist Ro25-6981. Our study provides strong evidence that Gent inhibits reserpine-induced pain/depression dyad by downregulating GluN2B receptors in the amygdala.

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Abbreviations

5-HT:

Serotonin

BLA:

Basolateral amygdala

CAT:

Catalase

CeA:

Central nucleus amygdala

CNS:

Central nervous system

DA:

Dopamine

Gent:

Gentiopicroside

LA:

Lateral amygdala

MDA:

Malondialdehyde

NE:

Norepinephrine

NMDA:

N-methyl-d-aspartate

OP:

Open field

PWL:

Paw withdrawal latency

TST:

Tail suspension test

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Acknowledgments

This research was supported by National Natural Science Foundation of China, Nos. 31070923, 31271126, 31271144, 2011ZXJ09106-01C, and 2011KTCL03-12.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, 710032, China

    Shui-bing Liu, Hong-ju Guo, Zhen Tian, Nan Zhang & Ming-gao Zhao

  2. Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Rong Zhao

  3. Department of Orthopaedics, Lan Zhou General Hospital of Chinese People’s Liberation Army, Lan Zhou, 730050, China

    Xu-sheng Li

  4. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Guo-dong Gao

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  1. Shui-bing Liu
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  4. Hong-ju Guo
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  5. Zhen Tian
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  6. Nan Zhang
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Correspondence to Guo-dong Gao or Ming-gao Zhao.

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Shui-bing Liu, Rong Zhao, and Xu-sheng Li have contributed equally to this work.

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Liu, Sb., Zhao, R., Li, Xs. et al. Attenuation of Reserpine-Induced Pain/Depression Dyad by Gentiopicroside Through Downregulation of GluN2B Receptors in the Amygdala of Mice. Neuromol Med 16, 350–359 (2014). https://doi.org/10.1007/s12017-013-8280-8

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