Curcumin Improves Chronic Pain Induced Depression Through Regulating Serum Metabolomics in a Rat Model of Trigeminal Neuralgia

Abstract

Background: Depression is a prevalent and complex psychiatric disorder with high incidence in patients with chronic pain. The underlying pathogenesis of chronic pain-induced depression is complicated and remains largely unclear. An integrated analysis of endogenous substance-related metabolisms would help to understand the molecular mechanism of chronic pain-induced depression. Curcumin was reported to exert various health benefits, such as anti-depression, antioxidant, antineoplastic, analgesia, and anti-inflammation.

Objective: The aim of this study was to analyze the biomarkers related to depression in serum and to evaluate the anti-depression properties of curcumin in a chronic pain-induced depression model of rats.

Design: This is a randomized, controlled experiment.

Setting: This study was conducted at the Experimental Animal Center, Beijing Friendship Hospital, Capital Medical University.

Methods: Trigeminal neuralgia (TN) was produced by injecting 4 µL, 10% cobra venom saline solution into the infraorbital nerve (ION). Curcumin was administered by gavage twice a day from post-operation day (POD) 15 to POD 42. Mechanical allodynia was assessed using von Frey filaments. Sucrose preference and forced swimming tests were performed to evaluate depression-like behaviors. The metabolomics analysis was preceded by LCMS-IT-TOF and multivariate statistical methods for sample detection and biomarker screening.

Results: Cobra venom intra-ION injection led to chronic mechanical allodynia, reduced sucrose preference, and prolonged immobility during forced swimming. Curcumin treatment alleviated chronic mechanical allodynia, regained sucrose preference, and reduced immobility time. Differential analysis identified 30 potential metabolites changed under TN condition. The integrated analyses further revealed two major metabolic changes by comparing the serums from sham operated rats, TN rats, and TN rats treated with curcumin: 1) ether lipid metabolism; and 2) glycerophospholipid metabolism, and suggested that curcumin may improve chronic pain-induced depression by regulating these two types of lipid metabolisms.

Conclusion: Ether lipid and glycerophospholipid metabolism might be two of the pathways with the most potential related to chronic pain induced-depression; and curcumin could alleviate chronic pain induced-depression by modulating these two pathways. These results provide further insights into the mechanisms of chronic pain-induced depression and may help to identify potential targets for anti-depression properties of curcumin.

Keywords: chronic pain; curcumin; depression; metabolomics; trigeminal neuralgia.

Figure 1

Curcumin alleviated mechanical allodynia induced by cobra venom intra-ION injection. (A) Schematic for the timeline of surgery (cobra venom or sterile saline injection) and curcumin administrations. (B) Mechanical allodynia induced by cobra venom intra-ION injection was attenuated by curcumin treatment. Two-way ANOVA, *P<0.05 vs the sham group, #P<0.05 vs the cobra venom group, n=8 or 9.

Figure 2

The effects of curcumin treatment on depression behaviors observed in rats with chronic pain. (A) Sucrose preferences were progressively reduced in rats with TN, and recovered by curcumin treatment. (B) Immobility time during forced swimming were progressively increased in rats with TN and normalized after curcumin treatment. Two-way ANOVA, *P<0.05 vs the sham group, #P<0.05 vs the cobra venom group, n=8 or 9.

Figure 3

Score-Plot of principal component analysis for different groups of rats. (A) Score-Plot of PCA for the serum samples collected from different groups 6 weeks after surgery. Black, sham group; Red, TN+vehicle group; and Blue, TN+curcumin group. (B) Score-Plot PCA for the serum samples collected at different time points after cobra venom intra-ION injection. Green, week 1; Orange, week 2; Grey, week 4; and Violet, week 6.

Figure 4

Partial least-squares discriminant analysis of metabolomics data in different experimental groups. (A) Score plot. Black, sham group; Red, TN group, and Blue, TN+ curcumin group. (B) 100-permutation test. (C) loading plot. (D) VIP value plot.

Figure 5

Serum metabolic profiling. (A) Heatmap of metabolic profiles at different time points after cobra venom intra-ION injection. (B) Heatmap of metabolic profiles in different groups of rats.

Figure 6

Pathway enrichment analysis of metabolites changed by curcumin treatment. (A) Pathway analysis of the effects of curcumin treatment on (a) Ether lipid metabolism, (b) Glycerophospholipid metabolism, (c) Pentose and glucuronate interconversions, and (d) Starch and sucrose metabolism in TN rats. (B) Glycerophospholipid metabolism (C04598: 2-Acetyl-1-alkyl-sn-glycero-3-phosphocholine, C04317: 1-Alkyl-2-lyso-sn-glycero-3-phosphocholine). (C) Ether lipid metabolism (C00157: Phosphatidylcholine, C04230: 1-Acyl-sn-glycero-3-phosphocholine. C03033: Glucuronide). (D–F) The enrichment pathway analysis of the effects of curcumin treatment in TN rats.

Figure 7

The effects of curcumin treatment on the expression of serum metabolite in TN rats. Differentially expressed metabolite pathways and their associated signaling networks (potential biomarkers were labeled by green solid box.).