Chronic Curcumin Treatment Normalizes Depression-Like Behaviors in Mice with Mononeuropathy: Involvement of Supraspinal Serotonergic System and GABAA Receptor
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Psychopharmacology (2014) 231:2171–2187 DOI 10.1007/s00213-013-3368-2 ORIGINAL INVESTIGATION Chronic curcumin treatment normalizes depression-like behaviors in mice with mononeuropathy: involvement of supraspinal serotonergic system and GABAA receptor Xin Zhao & Chuang Wang & Jun-Fang Zhang & Li Liu & Ai-Ming Liu & Qing Ma & Wen-Hua Zhou & Ying Xu Received: 31 July 2013 /Accepted: 18 November 2013 /Published online: 3 December 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract behaviors, which was abolished by chemical depletion of Rationale Comorbid depression is commonly observed in brain serotonin rather than noradrenaline. The paralleled individuals who suffer from neuropathic pain, which necessi- antinociceptive and antidepressant-like actions of curcumin tates improved treatment. Curcumin, a phenolic compound seem to be pharmacologically segregated, since intrathecal derived from Curcuma longa, possesses both antinociceptive and intracerebroventricular injection of methysergide, a non- and antidepressant-like activities in animal studies, suggesting selective 5-HT receptor antagonist, separately counteracted its possible usefulness in treating this comorbidity. the two actions of curcumin. Further, this antidepression was Objective We investigated the effect of curcumin on abrogated by repeated co-treatment with 5-HT1A receptor depressive-like behaviors in mice with mononeuropathy, and antagonist WAY-100635 and greatly attenuated by acute co- explored the mechanism(s). treatment with GABAA receptor antagonist bicuculline. Methods Chronic constriction injury (CCI) was produced by Conclusion Curcumin can normalize the depressive-like be- loosely ligating the sciatic nerves in mice. The nociceptive haviors of neuropathic mice, which may be independent of the behaviors were examined using Hargreaves test, and the concurrent analgesic action and possibly mediated via the depressive-like behaviors were determined by forced swim supraspinal serotonergic system and downstream GABAA test (FST) and tail suspension test (TST). receptor. Results After CCI injury, the neuropathic mice developed nociceptive and depressive-like behaviors, as shown by ther- Keywords Curcumin . Depression . Neuropathic pain . mal hyperalgesia in Hargreaves test and protracted immobility Serotonin . GABAA time in FST and TST. Chronic treatment of neuropathic mice with curcumin (45 mg/kg, p.o., twice per day for 3 weeks) corrected their exacerbated nociceptive and depressive-like Introduction Neuropathic pain is commonly a chronic and debilitating * : : < : < : : X. Zhao ( ) C. Wang J. F. Zhang A. M. Liu Q. Ma disease that is significantly associated with mood disorders W.<H. Zhou : Y. Xu Department of Pharmacology, School of Medical Science, (Gustorff et al. 2008; Yalcin et al. 2011;Alba-Delgadoetal. Ningbo University, Ningbo, Zhejiang Province 315211, China 2013), especially depression (Gonçalves et al. 2008;Huetal. e-mail: [email protected] 2009). The high prevalence of this comorbidity intensifies the Y. Xu unpleasant feelings of patients and deteriorates their overall e-mail: [email protected] life qualities. Indeed, the comorbid depression is not just reported in neuropathic patients, several other lines of evi- L. Liu Department of Respiratory Medicine, West China Hospital, dence also demonstrated the co-occurrence of depression in Sichuan University, Chengdu, Sichuan Province 610041, China up to 70 % patients with chronic pain (Bair et al. 2003;Arnow et al. 2006), and patients suffering from chronic pain are more Y. Xu vulnerable to major depression (Ohayon and Schatzberg Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, 2003). Reciprocally, pain is one of the most common com- Morgantown, WV 26506-9128, USA plaints in patients with depression (Leo. 2005), and depressive 2172 Psychopharmacology (2014) 231:2171–2187 symptoms may exacerbate or predict chronic pain (Magni antidepressant-like effect engendered by curcumin may be et al. 1994; Wang et al. 2012). Thus, pursuing improved independent of the concurrent analgesic effect and mediated treatments for this comorbidity is imperative. Recent years, by supraspinal serotonergic system and downstream GABAA despite progressively accumulating researches have been un- receptor. dertaken to investigate the relationship and mechanisms for this comorbidity of chronic pain and depression (Yalcin et al. 2011; Kim et al. 2012; Alba-Delgado et al. 2013), relative few Methods studies evaluated the effects of drugs, especially that used to mitigate neuropathic pain, on the comorbid emotional disabil- Animals and housing ities such as depression. Pharmacotherapy is one of the most important therapeutic Adult male ICR mice, 6–7 weeks old upon arrival (obtained options for the treatment of neuropathic pain (Jackson 2006). from the Laboratory Animal Center of Chinese Academy of Specifically, this intractable pain is poorly responsive to many Sciences, Shanghai, China), were used in the present study. prototypical analgesics, such as morphine and nonsteroidal Animals were housed in groups (four to six per cage) with anti-inflammatory drugs (Arnér and Meyerson 1988;Voetal. chow and water available ad libitum, in a temperature- 2009). In the guidelines of pharmacological treatment against controlled environment with a light/dark cycle of 12:12 h neuropathic pain, antidepressants together with anticonvul- (lights on 7:00 AM). The experiments were carried out in a sants are ranked as fist-line drugs (Attal et al. 2010). Although quiet room where the temperature was maintained at 22± widely used for many years, these drugs could not satisfy the 0.5 °C with a relative humidity of 60±2 %. All experimental clinical need for palliating neuropathic pain in many patients, procedures and animal handing were approved by the Ningbo inasmuch as their limited efficacy and associated adverse side University Committee on Animal Care and Use and complied effects (Micó et al. 2006). Therefore, the use of complemen- with the rules issued by International Association for the tary and alternative therapeutic strategies involving herb or Study of Pain on the use of experimental animals. The authors phytomedicine may provide new ways to ameliorate this further ensure that all efforts were made to minimize animal refractory disease. suffering and the number used. One such herb with possible therapeutic utility is Curcuma longa, which has been used as a traditional Chinese medicine Animal surgery to treat mental disorders since ancient times (Shishodia et al. 2005). As a principal ingredient of C. longa,curcumin(1,7- A chronic constriction injury (CCI) or sham procedure was bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5-dione, performed in mice (7–8 weeks old) as described by Bennett C21H20O6, the chemical structure shown in Fig. 1a) has been and Xie (1988), with minor modifications (Zhao et al. 2012). shown to possess a variety of pharmacological activities, Briefly, the mice were anesthetized by intraperitoneal (i.p.) including antioxidant, anti-inflammatory, cancer chemopre- injection of pentobarbital sodium (65 mg/kg). The right com- ventive, and neuroprotective actions (Radhakrishna Pillai mon sciatic nerve was exposed at the nerve of the midthigh et al. 2004; Yadav et al. 2005; Reeta et al. 2010). Our previous and, proximal to the sciatic nerve trifurcation, three ligations studies delved into the CNS potentials of curcumin, with focus (4/0 silk threads, with 1 mm spacing) were loosely tied around on its antidepressant-like effect in some animal models (Xu it until a brief twitch was seen in the respective hind limb. The et al. 2005, 2007). Recently, we revealed that curcumin en- surgical area was dusted with streptomycin and the incision genders analgesic activities against neuropathic pain (Zhao was sutured. In sham-operated animals, the sciatic nerve was et al. 2012). The concurrent antinociceptive and exposed but not ligated. antidepressant-like activities exerted by curcumin prompted us to investigate, in the present study, whether it possesses Drugs and pharmacological treatments therapeutic potentials in treating the comorbid depression induced by chronic neuropathic pain. The following drugs were used: β-funaltrexamine (irrevers- We addressed this subject by examining the profiles indic- ible μ-opioid receptor antagonist), bicuculline (GABAA re- ative of depressive-like behaviors in mice, i.e., immobility ceptor antagonist), curcumin, diazepam (injection, 10 mg/ time in forced swim test (FST) and tail suspension test 2 ml), isamoltane (5-HT1B receptor antagonist), methysergide (TST). Moreover, we investigated the mechanisms underlying (non-selective 5-HT receptor antagonist), ondansetron (5-HT3 the antidepressant-like action by curcumin in the context of receptor antagonist), ritanserin (5-HT2A/2C receptor antago- neuropathic pain. Our results showed that chronic, but not nist), and WAY-100635 (5-HT1A receptor antagonist). acute, curcumin treatment can normalize the pain-related Bicuculline, isamoltane, and methysergide were purchased (hyperalgesia to heat stimuli) and depressive-like behaviors from Tocris Bioscience. Diazepam was purchased from Tian- in mice with mononeuropathy. The pronounced jin Pharmaceutical Co., Ltd. (Tianjin, China). All the Psychopharmacology (2014) 231:2171–2187 2173 Fig. 1 Chemical structure of A curcumin (Cur) and schematic of OCH3 chronic curcumin treatment. a Chemical structure of curcumin. HO b Fifteen days after chronic OH construction