title: Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice.
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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Shui-bing
authors.initials: SB
authors.lastname: Liu
authors.forename: Rong
authors.initials: R
authors.lastname: Zhao
authors.forename: Xu-sheng
authors.initials: XS
authors.lastname: Li
authors.forename: Hong-ju
authors.initials: HJ
authors.lastname: Guo
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tian
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Guo-dong
authors.initials: GD
authors.lastname: Gao
authors.forename: Ming-gao
authors.initials: MG
authors.lastname: Zhao
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001679:Biogenic Amines / Q000096:biosynthesis; D001923:Brain Chemistry / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D059350:Chronic Pain / Q000503:physiopathology; D003863:Depression / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D057888:Iridoid Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D017288:Pain Threshold / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012110:Reserpine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D013314:Stress, Mechanical; D013550:Swimming
chemical_list: D000700:Analgesics; D001679:Biogenic Amines; D018691:Excitatory Amino Acid Antagonists; D057888:Iridoid Glucosides; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; C012997:gentiopicroside; D012110:Reserpine; C505409:Casp3 protein, mouse; D053148:Caspase 3