- Email: [email protected]
Effects of UCMS-induced depression on nociceptive behaviors induced by electrical stimulation of the dura mater
Neuroscience Letters 551 (2013) 1–6
Contents lists available at SciVerse ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Plenary article
Effects of UCMS-induced depression on nociceptive behaviors induced by electrical stimulation of the dura mater Mingjie Zhang a,b , Wei Dai a , Jingyao Liang a , Xiaoyan Chen a , Yueqing Hu a , Bingqian Chu a,b , Meiyan Pan a , Zhao Dong a , Shengyuan Yu a,∗ a b
Department of Neurology, Chinese PLA General Hospital, Beijing 100853, PR China School of Medicine, Nankai University, Tianjin 300071, PR China
h i g h l i g h t s • • • •
Nociceptive behaviors were increased in the UCMS group. One of nociceptive behaviors correlated with depressive-like behaviors. No significant differences were observed in the plasma level of CGRP and SP after stimulation. The impact of depression on migraines probably does not depend on the peripheral afferent pathway.
a r t i c l e
i n f o
Article history: Received 21 February 2013 Received in revised form 17 April 2013 Accepted 19 April 2013 Keywords: Depression Migraine Nociceptive behavior CGRP SP
a b s t r a c t The comorbidity between migraine and depression not only provides a major treatment challenge, but also represents a heavy burden on society. However, the relationship between depression and migraine and their molecular biological mechanisms remain unclear. This study investigated the effects of depression elicited by unpredictable chronic mild stress (UCMS) on trigeminovascular nociception in conscious rats and detected a concentration of calcitonin gene-related peptide (CGRP) and substance P (SP) in the external jugular vein. We divided the rats into four groups: control-stimulated (C/S), controlnonstimulated (C/NS), UCMS-stimulated (U/S), and UCMS-nonstimulated (U/NS). We stimulated the dura mater adjacent to the superior sagittal sinus of rats in the C/S and U/S groups and observed their nociceptive behaviors. We found significant differences between the UCMS and control groups in weight, sucrose preference, and locomotor behavior. Nociceptive behaviors (number of head flicks and headturning time) were significantly increased in the U/S compared with the C/S group, and head-turning time correlated with depressive-like behaviors. The plasma level of SP was increased significantly in the U/NS compared with the C/NS group. However, no significant differences involving the other groups were observed. UCMS-induced depression can exacerbate trigeminovascular nociception, making rats more sensitive to pain. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Migraine is a common, recurring, episodic neurological disorder for which the 1-year prevalence is 9.3% in China [30] and 11% worldwide [22]. Depression is also one of the most common disabling diseases, and WHO estimates that major depressive disorder will become the second leading contributor to the disease burden by the year 2020, second only to ischemic heart disease [20]. In epidemi-
Abbreviations: UCMS, unpredictable chronic mild stress; OB, olfactory bulbectomy; CGRP, calcitonin gene-related peptide; SP, substance P; SSRIs, selective serotonin reuptake inhibitors. ∗ Corresponding author. Tel.: +86 10 55499118; fax: +86 10 88283167. E-mail addresses: [email protected], [email protected] (S. Yu). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.04.038
ological studies, depressed patients have a more than three-fold relative risk compared with non-depressed patients of developing migraine. Likewise, migraineurs had a more than three-fold relative risk compared with non-migraine patients of developing depression [12,23]. Additionally, this bidirectional relationship is specific to migraine and does not hold for other severe headaches [23]. The comorbidity between migraine and depression not only makes therapy complex, but also represents a heavy burden on society. The mechanisms underpinning the correlation between migraine and depression, which are the subject of the current study, are far from clear [2,4]. Both migraine and depression are associated with reduced serotonergic availability and positive responses to selective serotonin reuptake inhibitors (SSRIs), suggesting that the disorders may ultimately share dysfunction in central 5-HT
2
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
availability [1,9]. An epidemiological survey showed that women have a higher prevalence of depression and migraine, especially around menses. Upregulation of the sympathetic system and downregulation of the serotonergic and GABAergic systems because of the sudden drop in estrogen may be a/the reason [14]. Allodynia, as a marker of central sensitization, is common in both migraine and depression, suggesting that central sensitization may be involved in the comorbidity and chronicity [13]. These mechanisms have been established based on populationbased studies and do not rest on a firm theoretical foundation, which is one reason that mechanistic studies are difficult. Our laboratory established a model to simulate migraine attacks by electrical stimulation of the rat dura on the superior sagittal sinus, which offers a tool for studying the mechanisms of migraine [7]. In previous work, we found that nociceptive behaviors (grooming and head flicks) were significantly enhanced in olfactory bulbectomy (OB) rats, a classical animal model of agitated depression, compared with sham-operated rats, and that these nociceptive behaviors were correlated with depressive-like behaviors. Plasma levels of substance P (SP), but not plasma calcitonin gene-related peptide (CGRP), were increased significantly in OB rats. However, the OB model has some limitations [29]. The unpredictable-chronic-mild-stress (UCMS) animal model is one of the classic models of depression. The animals are subjected to a variety of unpredictable mild stressors every day, and the paradigm is analogous to stressors in everyday human life. Moreover, the decrease in sucrose preference after long-term mild stress reflects anhedonia, which is a central symptom of endogenous depression and is very similar to human clinical depression [28]. This depression model may be better than other animal models in face and construct validity [29]. In this study, we investigated the effects of depression elicited by unpredictable chronic mild stress (UCMS) on trigeminovascular nociception behaviors in conscious rats and determined levels of calcitonin gene-related peptide (CGRP) and substance P (SP) in the external jugular vein to explore the molecular biological mechanisms of the comorbidity between depression and migraine. 2. Materials and methods 2.1. Animals Male Sprague–Dawley (SD) rats (n = 40; Vital River Ltd., PR China) weighing 220–250 g were used. All rats were housed individually at a constant temperature (22 ± 2 ◦ C) under standard lighting conditions (12/12-h dark/light cycle with the lights turned on at 07:00 am) and were gently handled 3–5 min per day by the experimenter for at least 1 week before beginning the experiment. The experimental procedures were approved by the Committee on Animal Use for Research and Education of the Laboratory Animals Center, General Hospital of Chinese People’s Liberation Army (Beijing, PR China) and were consistent with the ethical guidelines recommended by the International Association for the Study of Pain in conscious animals [31]. Efforts were made to minimize the animals’ suffering. 2.2. Experimental design Rats were randomly assigned to two groups, the control and UCMS groups. Control and UCMS-exposed animals were kept in separate rooms to allow independent manipulation of their environments. The rats in the control group were housed with food and water freely available, but the rats in UCMS group were subjected to 6 weeks of mild, unpredictable stressors. Body weights were measured and sucrose preference tests were conducted weekly during
the UCMS procedure. Open field tests were performed before and after the 6-week UCMS procedure. Based on the 6-week procedure, electrodes were implanted on the dura mater adjacent to the superior sagittal sinus in all rats. Then, the two groups were divided into four sub-groups: the UCMS and stimulated (U/S, n = 10), UCMS and non-stimulated (U/NS, n = 10), control and stimulated (C/S, n = 10), and control and non-stimulated (C/NS, n = 10) groups. Nociceptive behaviors were video-recorded and observed on the fourth day after electrode implantation by electrical stimulation for 5 min. Rats in the U/NS and C/NS group were not subjected to electrical stimulation (but electrodes were implanted, and they were video-recorded). After the procedure, CGRP and SP levels in the external jugular vein were determined by radioimmunoassay performed as described previously by Liang et al. [12]. 2.3. Experimental details The chronically stress and depression behavioral tests (like sucrose preference tests and open field tests) procedure were modified from the procedure used by Shi et al. [19]. Stimulation electrode implantation, nociceptive behavioral tests were performed as described previously by Liang et al. [12]. The rats in the U/S and C/S groups were electrically stimulated with monophasic square-wave pulses (0.25 ms in pulse duration, 20 Hz in stimuli frequency, 2.0–3.5 mA in current intensity) for 30 min [7,12,25]. No electrical stimulation was given to the electrodes connected with the rats in the U/NS and C/NS groups. 2.4. Statistical analysis SPSS 13.0 and Origin 8.0 software were used for statistical analyses and graph generation. One-way ANOVA with a Student–Newman–Keuls test for multiple comparisons was used to compare differences among groups. Student’s t-test was used when two groups were compared. Relationships between nociceptive behaviors and depressive-like behaviors and between plasma SP levels and depressive-like or nociceptive behaviors were examined with Pearson correlation coefficients. Data are presented as means ± SEM. A value of P < 0.05 was deemed to indicate statistical significance. 3. Results 3.1. UCMS model On the day before the initiation of the UCMS, no significant difference in the body weights of rats in the UCMS and control groups was observed (235.50 ± 4.60 g vs 230.05 ± 3.44 g, P = 0.217). However, rats in the UCMS group gained weight more slowly than did rats in the control group during the 6-week experiment. One week after the experiment was initiated, we found a significant difference in the body weights of the groups(254.57 ± 5.09 g vs 273.60 ± 6.92 g, P = 0.006), and 6 weeks later, the difference had increased (361.14 ± 10.38 vs 442.09 ± 14.40, P = 0.000) (Fig. 1A). The results of the sucrose preference test are shown in Fig. 1B. A significant reduction was found in sucrose preference after 6 weeks in the UCMS group (P = 0.004). Locomotor (number of crossing) behaviors in the open field test were significantly decreased following UCMS exposure (43.40 ± 5.13 vs 64.20 ± 5.97, P = 0.041) (Fig. 1C) compared with the control group. However, we found no significant differences in the exploratory behaviors of the UCMS and control groups (8.93 ± 1.34 vs 11.93 ± 1.51, P = 0.702) (Fig. 1D). In fact, after 6 weeks of the experiment, the locomotor behaviors of both the UCMS and control groups were significantly lower than
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
3
Fig. 1. Changes in body weight and depressive-like behaviors after 6-week experiment. (A) Body weight. In contrast to the control group, rats in the UCMS group gained weight more slowly. (B) Sucrose preference. After six weeks of UCMS, a significant reduction was found in sucrose preference in the UCMS-exposed rats. (C) Locomotor behaviors. Locomotor behaviors were significantly decreased following UCMS exposure compared with the control group. (D) Exploratory behavior. No significantly differences were found in exploratory behaviors of the UCMS and control groups. Data are presented as means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, compared to their respective control group. # P < 0.05, ## P < 0.01, compared to their own group 6 weeks before.
they were 6 weeks earlier (UCMS group, P = 0.001; control group, P = 0.010).
3.2. Effects of UCMS-induced depression on nociceptive behavior In our previous work, two kinds of nociceptive behavior were observed: head-flicks and grooming. Grooming was characterized by rubbing the face or scratching the head with the limbs, and a head-flick was characterized by rapid and arrhythmic twitching. In the present study, another nociceptive behavior was added, head-turning. Head-turning was characterized by turning the head to one side and keeping this posture for a while, with or without the contralateral forelimb stretching to the other side. Head flicks were measured by number, and grooming and head-turning were quantified in terms of activity time(s). These nociceptive behaviors elicited by electrical stimulation were assessed on the fourth day after the stimulation electrodes were implanted. The electric current was a little higher in UCMS group, but this difference was not statistically significant (P = 0.061). As shown in Fig. 2A–D, the number of head flicks (18.00 ± 1.44) and the headturning time (33.44 ± 5.97 s) were increased markedly in rats in the U/S compared with those in the C/S group (10.77 ± 1.58, P = 0.006; 15.78 ± 2.95 s, P = 0.027) in response to electrical stimulation. We observed no significant difference in the grooming time of the UCMS and control groups (17.33 ± 4.59 vs 10.11 ± 2.83, P = 0.222).
A significant negative correlation was observed between the head-turning time induced by electrical stimulation and travel distance (r = −0.449, P = 0.047, see Fig. 2F) and sucrose preference (r = −0.577, P = 0.008, see Fig. 2H). However, the relationship between head flicks and travel distance or sucrose preference did not show a linear correlation (r = −0.373, P = 0.105; r = −0.298, P = 0.201, see Fig. 2E and G). 3.3. Effects of UCMS-induced depression on plasma CGRP and SP levels Fig. 3A shows the blood concentration of CGRP in the external jugular vein. No significant differences were observed among groups under the electrically-stimulated condition. As shown in Fig. 3B, plasma SP levels were increased significantly in the U/NS group compared with the C/NS group (P = 0.015), but no significant difference was observed between the U/S and C/S groups after the 30-min stimulation. 4. Discussion The present study investigated the effects of depression elicited by UCMS on trigeminovascular nociception behaviors in conscious rats and measured levels of CGRP and SP in the external jugular vein. The results showed that nociceptive behaviors (number of head flicks and head-turning time) were increased significantly in
4
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
Fig. 2. Effects of UCMS-induced depression on nociceptive behavior. (A) Stimulation intensity. The electric current was a little higher in UCMS group, but this difference was not statistically significant. (B–D) Nociceptive behavior. Response to electrical stimulation, the number of head flicks (C) and head-turning time (D), but not the total grooming time, were significantly increased in rats in the U/S group compared with those in the C/S group. A significant negative correlated was observed between the head-turning time induced by electrical stimulation and travel distance (F) and sucrose preference (H). However, the relationship between head flicks and travel distance or sucrose preference did not show a linear correlation (E and G). Data are presented as means ± SEM. *P < 0.05, **P < 0.01, compared to their respective control group.
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
Fig. 3. Effects of UCMS-induced depression on plasma CGRP and SP levels. (A) No significant differences were observed among groups under the electrically stimulated condition in plasma CGRP levels. (B) Plasma SP levels were increased significantly in the U/NS group compared with the C/NS group, no significantly difference was observed between U/S group and C/S group after the 30-min stimulation. Data are presented as means ± SEM. *P < 0.05, compared to their respective control group.
the U/S compared with the C/S group and that head-turning time was negatively correlated with depressive-like behaviors. Plasma levels of SP were increased in the U/NS compared with the C/NS group. However, we found no significant difference in the levels of CGRP or SP in the other groups. Both head-flicking and head-turning behaviors induced by electrical stimulation on dura mater adjacent to the superior sagittal sinus are reduced by rizatriptan benzoate, a specific anti-migraine drug [7]. They were rarely observed in normal rats, but another common behavior, grooming could often be observed in normal rats (Fig. 2B), which might suggest that head-flicking and head-turning represent more serious pain-related behaviors. Our results showed the number of head flicks and the head-turning time but not grooming time were increased markedly in rats in the U/S group, which suggested depression induced by UCMS lead to more intense pain in rats. In clinical studies, patients suffering from major depressive disorder show increased pain thresholds and tolerance of cold, heat, pressure, and electrical stimuli compared with healthy controls [3,18]. However, patients with depression have significantly lower ischemic muscle pain thresholds and tolerance than do healthy subjects [3,18]. The results of animal studies are also not uniform. Most have shown that sensitivity to pain decreases significantly with noxious radiant heat stimuli in the OB model and with thermal and
5
mechanical stimuli in the UCMS model [17,19,24], but there were objections [6]. The responses to pain induced by formalin injection into the hind paw are apparently all the same; higher sensitivity was found in OB rats, UCMS rats, and WKY rats [6,19,24]. In our study, we also found higher sensitivity to electrical stimulation of the dura mater surrounding the superior sagittal sinus in UCMS and OB rats [12]. There may be several reasons for these results. Perhaps there are two kinds of pain. One, surface pain induced by cold, heat, or electrical stimuli directly applied to the skin, produces hypoalgesia in depressed patients. The other, deep somatic pain induced by intramuscular ischemia, hind-paw injection, or dura-mater stimulation, produces hyperalgesia in depressed patients. Thus, two mechanisms may be involved in pain pathways. A pain message involves two-way traffic, including ascending and descending pathways. Pain information is relayed along Aı and C fibers to the spinal cord, then along the spinothalamic tract to the thalamus; it finally reaches the brain’s somatosensory cortex and limbic structures. Additionally, descending pathways modulate pain sensitivity. The brain uses these pathways to send chemical substances and nerve impulses back down to the cells in the spinal cord to act against the pain message sent up by pain receptors [27]. Lautenbacher and Krieg focused on the spinal and subcortical stages [11]. They thought that the processing of nociceptive stimuli was diminished during these stages, leading not only to hypoalgesia but also to insufficient activation of pain inhibitory systems. However, why does depression influence surface pain, and why does deep somatic pain not use the same pathways? Ward et al. supposed that the spinothalamic tract may be affected by an increase in the activity of endogenous opioids, resulting in reduced pain sensitivity in the skin [26]. Stahl and Briley suggested that levels of central serotonin (5-HT) and norepinephrine (NE) were low in depressed patients, which disturbed the descending pathways [21]. The reasons for these seemingly paradoxical results are far from clear. At the very least, we can draw the conclusion that depression induced by UCMS increases sensitivity to deep somatic pain in rats, indicating that depression may lead to disorders of central neurotransmitters or structural changes in the spinal or superspinal stage, resulting in enhanced pain messages in ascending pathways or decreased pain inhibition in descending pathways. However, we cannot offer more precise conclusions at this time. Further molecular biology research on the central nervous system is needed. Calcitonin gene-related peptide (CGRP) and substance P (SP) are both neuropeptides that mediate nociception. In nociception, the activated trigeminovascular system releases neuropeptides, leading to vasodilation and plasma extravasation. This is the mechanism of a migraine attack [8]. It has been demonstrated that the main function of SP is to lead to plasma extravasation and that the main function of CGRP is to dilate arteries to increase blood flow [16]. Few studies on SP and CGRP levels in depression have been conducted. Mathe first found increased CGRP in the cerebrospinal fluid of patients with depression versus healthy controls (P < 0.001) in 1994 [15]. Next, Bondy found elevated levels of plasma SP in patients with depression. After taking an antidepressant for 4 weeks, patients whose SP level decreased showed a better prognosis [5]. Later, Hartman discovered that the levels of CGRP and SP in female patients with depression were not only higher than were those in healthy controls but also showed a circadian rhythm [10]. Few animal studies have focused on the levels of CGRP and SP in depression models. In the present study, we found no differences in the levels of CGRP or SP between the UCMS and control groups after electrical stimulation. We showed a higher sensitivity to pain in rats in UCMS group than in the control group. However, the stimulation intensity did not significantly differ, and there was no statistically significant difference in the levels of CGRP and SP. Thus, we supposed that the pain-message afferents in the peripheral nerves of
6
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
the U/S and C/S groups may not differ. This suggests that depression may lead to disorders in the spinal or superspinal stage, consistent with Lautenbacher’s hypothesis that “hyperalgesia to endogenous painful sensations is due to the insufficient activation of inhibitory systems” [11]. 5. Conclusions In summary, UCMS-induced depression can exacerbate trigeminovascular nociception, making the rats more sensitive to pain. However, we found no significant differences in the levels of CGRP or SP in the C/S and U/S groups, indicating that the impact of depression on migraines probably does not depend on the peripheral afferent pathway. Further, molecular biology research on the central nervous system, especially the ascending or descending pathways during the spinal or superspinal stage, is needed. Acknowledgment The funding support of the National Science Foundation Committee (NSFC) in China is gratefully acknowledged (grants 30970417 and 81171058). References [1] M. aan het Rot, S.J. Mathew, D.S. Charney, Neurobiological mechanisms in major depressive disorder, CMAJ 180 (2009) 305–313. [2] F. Antonaci, G. Nappi, F. Galli, G.C. Manzoni, P. Calabresi, A. Costa, Migraine and psychiatric comorbidity: a review of clinical findings, J. Headache Pain 12 (2011) 115–125. [3] K.J. Bar, S. Brehm, M.K. Boettger, S. Boettger, G. Wagner, H. Sauer, Pain perception in major depression depends on pain modality, Pain 117 (2005) 97–103. [4] S.M. Baskin, T.A. Smitherman, Migraine and psychiatric disorders: comorbidities, mechanisms, and clinical applications, Neurol. Sci. 30 (Suppl. 1) (2009) S61–S65. [5] B. Bondy, T.C. Baghai, C. Minov, C. Schule, M.J. Schwarz, P. Zwanzger, R. Rupprecht, H.J. Moller, Substance P serum levels are increased in major depression: preliminary results, Biol. Psychiatry 53 (2003) 538–542. [6] N.N. Burke, E. Hayes, P. Calpin, D.M. Kerr, O. Moriarty, D.P. Finn, M. Roche, Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions, Neuroscience 171 (2010) 1300–1313. [7] Z. Dong, L. Jiang, X. Wang, S. Yu, Nociceptive behaviors were induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus in conscious adult rats and reduced by morphine and rizatriptan benzoate, Brain Res. 1368 (2011) 151–158. [8] P.J. Goadsby, Migraine pathophysiology, Headache 45 (Suppl. 1) (2005) S14–S24. [9] E. Hamel, Serotonin and migraine: biology and clinical implications, Cephalalgia 27 (2007) 1293–1300.
[10] J.M. Hartman, A. Berger, K. Baker, J. Bolle, D. Handel, A. Mannes, D. Pereira, D. St Germain, D. Ronsaville, N. Sonbolian, S. Torvik, K.A. Calis, T.M. Phillips, G. Cizza, Quality of life and pain in premenopausal women with major depressive disorder: the POWER Study, Health Qual. Life Outcomes 4 (2006) 2. [11] S. Lautenbacher, J.C. Krieg, Pain perception in psychiatric disorders: a review of the literature, J. Psychiatr. Res. 28 (1994) 109–122. [12] J. Liang, S. Yu, Z. Dong, X. Wang, R. Liu, X. Chen, Z. Li, The effects of OB-induced depression on nociceptive behaviors induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus, Brain Res. 1424 (2011) 9–19. [13] C. Lovati, D. D’Amico, P. Bertora, Allodynia in migraine: frequent random association or unavoidable consequence? Expert Rev. Neurother. 9 (2009) 395–408. [14] V.T. Martin, M. Behbehani, Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis – Part I, Headache 46 (2006) 3–23. [15] A.A. Mathe, H. Agren, L. Lindstrom, E. Theodorsson, Increased concentration of calcitonin gene-related peptide in cerebrospinal fluid of depressed patients. A possible trait marker of major depressive disorder, Neurosci. Lett. 182 (1994) 138–142. [16] A. May, P.J. Goadsby, Substance P receptor antagonists in the therapy of migraine, Expert Opin. Investig. Drugs 10 (2001) 673–678. [17] F. Pinto-Ribeiro, A. Almeida, J.M. Pego, J. Cerqueira, N. Sousa, Chronic unpredictable stress inhibits nociception in male rats, Neurosci. Lett. 359 (2004) 73–76. [18] C. Schwier, A. Kliem, M.K. Boettger, K.J. Bar, Increased cold-pain thresholds in major depression, J. Pain 11 (2010) 287–290. [19] M. Shi, J.Y. Wang, F. Luo, Depression shows divergent effects on evoked and spontaneous pain behaviors in rats, J. Pain 11 (2010) 219–229. [20] G.E. Simon, Social and economic burden of mood disorders, Biol. Psychiatry 54 (2003) 208–215. [21] S. Stahl, M. Briley, Understanding pain in depression, Hum. Psychopharmacol. 19 (Suppl. 1) (2004) S9–S13. [22] L. Stovner, K. Hagen, R. Jensen, Z. Katsarava, R. Lipton, A. Scher, T. Steiner, J.A. Zwart, The global burden of headache: a documentation of headache prevalence and disability worldwide, Cephalalgia 27 (2007) 193–210. [23] P. Torelli, D. D’Amico, An updated review of migraine and co-morbid psychiatric disorders, Neurol. Sci. 25 (Suppl. 3) (2004) S234–S235. [24] W. Wang, W.J. Qi, Y. Xu, J.Y. Wang, F. Luo, The differential effects of depression on evoked and spontaneous pain behaviors in olfactory bulbectomized rats, Neurosci. Lett. 472 (2010) 143–147. [25] X. Wang, S. Yu, Z. Dong, L. Jiang, The Fos expression in rat brain following electrical stimulation of dura mater surrounding the superior sagittal sinus changed with the pre-treatment of rizatriptan benzoate, Brain Res. 1367 (2011) 340–346. [26] N.G. Ward, V.L. Bloom, S. Dworkin, J. Fawcett, N. Narasimhachari, R.O. Friedel, Psychobiological markers in coexisting pain and depression: toward a unified theory, J. Clin. Psychiatry 43 (1982) 32–41. [27] F. Wei, M. Gu, Y.X. Chu, New tricks for an old slug: Descending serotonergic system in pain, Sheng Li Xue Bao 64 (2012) 520–530. [28] P. Willner, Chronic mild stress (CMS) revisited: consistency and behaviouralneurobiological concordance in the effects of CMS, Neuropsychobiology 52 (2005) 90–110. [29] H.C. Yan, X. Cao, M. Das, X.H. Zhu, T.M. Gao, Behavioral animal models of depression, Neurosci. Bull. 26 (2010) 327–337. [30] S. Yu, R. Liu, G. Zhao, X. Yang, X. Qiao, J. Feng, Y. Fang, X. Cao, M. He, T. Steiner, The prevalence and burden of primary headaches in China: a population-based door-to-door survey, Headache 52 (2012) 582–591. [31] M. Zimmermann, Ethical guidelines for investigations of experimental pain in conscious animals, Pain 16 (1983) 109–110.
Contents lists available at SciVerse ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Plenary article
Effects of UCMS-induced depression on nociceptive behaviors induced by electrical stimulation of the dura mater Mingjie Zhang a,b , Wei Dai a , Jingyao Liang a , Xiaoyan Chen a , Yueqing Hu a , Bingqian Chu a,b , Meiyan Pan a , Zhao Dong a , Shengyuan Yu a,∗ a b
Department of Neurology, Chinese PLA General Hospital, Beijing 100853, PR China School of Medicine, Nankai University, Tianjin 300071, PR China
h i g h l i g h t s • • • •
Nociceptive behaviors were increased in the UCMS group. One of nociceptive behaviors correlated with depressive-like behaviors. No significant differences were observed in the plasma level of CGRP and SP after stimulation. The impact of depression on migraines probably does not depend on the peripheral afferent pathway.
a r t i c l e
i n f o
Article history: Received 21 February 2013 Received in revised form 17 April 2013 Accepted 19 April 2013 Keywords: Depression Migraine Nociceptive behavior CGRP SP
a b s t r a c t The comorbidity between migraine and depression not only provides a major treatment challenge, but also represents a heavy burden on society. However, the relationship between depression and migraine and their molecular biological mechanisms remain unclear. This study investigated the effects of depression elicited by unpredictable chronic mild stress (UCMS) on trigeminovascular nociception in conscious rats and detected a concentration of calcitonin gene-related peptide (CGRP) and substance P (SP) in the external jugular vein. We divided the rats into four groups: control-stimulated (C/S), controlnonstimulated (C/NS), UCMS-stimulated (U/S), and UCMS-nonstimulated (U/NS). We stimulated the dura mater adjacent to the superior sagittal sinus of rats in the C/S and U/S groups and observed their nociceptive behaviors. We found significant differences between the UCMS and control groups in weight, sucrose preference, and locomotor behavior. Nociceptive behaviors (number of head flicks and headturning time) were significantly increased in the U/S compared with the C/S group, and head-turning time correlated with depressive-like behaviors. The plasma level of SP was increased significantly in the U/NS compared with the C/NS group. However, no significant differences involving the other groups were observed. UCMS-induced depression can exacerbate trigeminovascular nociception, making rats more sensitive to pain. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Migraine is a common, recurring, episodic neurological disorder for which the 1-year prevalence is 9.3% in China [30] and 11% worldwide [22]. Depression is also one of the most common disabling diseases, and WHO estimates that major depressive disorder will become the second leading contributor to the disease burden by the year 2020, second only to ischemic heart disease [20]. In epidemi-
Abbreviations: UCMS, unpredictable chronic mild stress; OB, olfactory bulbectomy; CGRP, calcitonin gene-related peptide; SP, substance P; SSRIs, selective serotonin reuptake inhibitors. ∗ Corresponding author. Tel.: +86 10 55499118; fax: +86 10 88283167. E-mail addresses: [email protected], [email protected] (S. Yu). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.04.038
ological studies, depressed patients have a more than three-fold relative risk compared with non-depressed patients of developing migraine. Likewise, migraineurs had a more than three-fold relative risk compared with non-migraine patients of developing depression [12,23]. Additionally, this bidirectional relationship is specific to migraine and does not hold for other severe headaches [23]. The comorbidity between migraine and depression not only makes therapy complex, but also represents a heavy burden on society. The mechanisms underpinning the correlation between migraine and depression, which are the subject of the current study, are far from clear [2,4]. Both migraine and depression are associated with reduced serotonergic availability and positive responses to selective serotonin reuptake inhibitors (SSRIs), suggesting that the disorders may ultimately share dysfunction in central 5-HT
2
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
availability [1,9]. An epidemiological survey showed that women have a higher prevalence of depression and migraine, especially around menses. Upregulation of the sympathetic system and downregulation of the serotonergic and GABAergic systems because of the sudden drop in estrogen may be a/the reason [14]. Allodynia, as a marker of central sensitization, is common in both migraine and depression, suggesting that central sensitization may be involved in the comorbidity and chronicity [13]. These mechanisms have been established based on populationbased studies and do not rest on a firm theoretical foundation, which is one reason that mechanistic studies are difficult. Our laboratory established a model to simulate migraine attacks by electrical stimulation of the rat dura on the superior sagittal sinus, which offers a tool for studying the mechanisms of migraine [7]. In previous work, we found that nociceptive behaviors (grooming and head flicks) were significantly enhanced in olfactory bulbectomy (OB) rats, a classical animal model of agitated depression, compared with sham-operated rats, and that these nociceptive behaviors were correlated with depressive-like behaviors. Plasma levels of substance P (SP), but not plasma calcitonin gene-related peptide (CGRP), were increased significantly in OB rats. However, the OB model has some limitations [29]. The unpredictable-chronic-mild-stress (UCMS) animal model is one of the classic models of depression. The animals are subjected to a variety of unpredictable mild stressors every day, and the paradigm is analogous to stressors in everyday human life. Moreover, the decrease in sucrose preference after long-term mild stress reflects anhedonia, which is a central symptom of endogenous depression and is very similar to human clinical depression [28]. This depression model may be better than other animal models in face and construct validity [29]. In this study, we investigated the effects of depression elicited by unpredictable chronic mild stress (UCMS) on trigeminovascular nociception behaviors in conscious rats and determined levels of calcitonin gene-related peptide (CGRP) and substance P (SP) in the external jugular vein to explore the molecular biological mechanisms of the comorbidity between depression and migraine. 2. Materials and methods 2.1. Animals Male Sprague–Dawley (SD) rats (n = 40; Vital River Ltd., PR China) weighing 220–250 g were used. All rats were housed individually at a constant temperature (22 ± 2 ◦ C) under standard lighting conditions (12/12-h dark/light cycle with the lights turned on at 07:00 am) and were gently handled 3–5 min per day by the experimenter for at least 1 week before beginning the experiment. The experimental procedures were approved by the Committee on Animal Use for Research and Education of the Laboratory Animals Center, General Hospital of Chinese People’s Liberation Army (Beijing, PR China) and were consistent with the ethical guidelines recommended by the International Association for the Study of Pain in conscious animals [31]. Efforts were made to minimize the animals’ suffering. 2.2. Experimental design Rats were randomly assigned to two groups, the control and UCMS groups. Control and UCMS-exposed animals were kept in separate rooms to allow independent manipulation of their environments. The rats in the control group were housed with food and water freely available, but the rats in UCMS group were subjected to 6 weeks of mild, unpredictable stressors. Body weights were measured and sucrose preference tests were conducted weekly during
the UCMS procedure. Open field tests were performed before and after the 6-week UCMS procedure. Based on the 6-week procedure, electrodes were implanted on the dura mater adjacent to the superior sagittal sinus in all rats. Then, the two groups were divided into four sub-groups: the UCMS and stimulated (U/S, n = 10), UCMS and non-stimulated (U/NS, n = 10), control and stimulated (C/S, n = 10), and control and non-stimulated (C/NS, n = 10) groups. Nociceptive behaviors were video-recorded and observed on the fourth day after electrode implantation by electrical stimulation for 5 min. Rats in the U/NS and C/NS group were not subjected to electrical stimulation (but electrodes were implanted, and they were video-recorded). After the procedure, CGRP and SP levels in the external jugular vein were determined by radioimmunoassay performed as described previously by Liang et al. [12]. 2.3. Experimental details The chronically stress and depression behavioral tests (like sucrose preference tests and open field tests) procedure were modified from the procedure used by Shi et al. [19]. Stimulation electrode implantation, nociceptive behavioral tests were performed as described previously by Liang et al. [12]. The rats in the U/S and C/S groups were electrically stimulated with monophasic square-wave pulses (0.25 ms in pulse duration, 20 Hz in stimuli frequency, 2.0–3.5 mA in current intensity) for 30 min [7,12,25]. No electrical stimulation was given to the electrodes connected with the rats in the U/NS and C/NS groups. 2.4. Statistical analysis SPSS 13.0 and Origin 8.0 software were used for statistical analyses and graph generation. One-way ANOVA with a Student–Newman–Keuls test for multiple comparisons was used to compare differences among groups. Student’s t-test was used when two groups were compared. Relationships between nociceptive behaviors and depressive-like behaviors and between plasma SP levels and depressive-like or nociceptive behaviors were examined with Pearson correlation coefficients. Data are presented as means ± SEM. A value of P < 0.05 was deemed to indicate statistical significance. 3. Results 3.1. UCMS model On the day before the initiation of the UCMS, no significant difference in the body weights of rats in the UCMS and control groups was observed (235.50 ± 4.60 g vs 230.05 ± 3.44 g, P = 0.217). However, rats in the UCMS group gained weight more slowly than did rats in the control group during the 6-week experiment. One week after the experiment was initiated, we found a significant difference in the body weights of the groups(254.57 ± 5.09 g vs 273.60 ± 6.92 g, P = 0.006), and 6 weeks later, the difference had increased (361.14 ± 10.38 vs 442.09 ± 14.40, P = 0.000) (Fig. 1A). The results of the sucrose preference test are shown in Fig. 1B. A significant reduction was found in sucrose preference after 6 weeks in the UCMS group (P = 0.004). Locomotor (number of crossing) behaviors in the open field test were significantly decreased following UCMS exposure (43.40 ± 5.13 vs 64.20 ± 5.97, P = 0.041) (Fig. 1C) compared with the control group. However, we found no significant differences in the exploratory behaviors of the UCMS and control groups (8.93 ± 1.34 vs 11.93 ± 1.51, P = 0.702) (Fig. 1D). In fact, after 6 weeks of the experiment, the locomotor behaviors of both the UCMS and control groups were significantly lower than
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
3
Fig. 1. Changes in body weight and depressive-like behaviors after 6-week experiment. (A) Body weight. In contrast to the control group, rats in the UCMS group gained weight more slowly. (B) Sucrose preference. After six weeks of UCMS, a significant reduction was found in sucrose preference in the UCMS-exposed rats. (C) Locomotor behaviors. Locomotor behaviors were significantly decreased following UCMS exposure compared with the control group. (D) Exploratory behavior. No significantly differences were found in exploratory behaviors of the UCMS and control groups. Data are presented as means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, compared to their respective control group. # P < 0.05, ## P < 0.01, compared to their own group 6 weeks before.
they were 6 weeks earlier (UCMS group, P = 0.001; control group, P = 0.010).
3.2. Effects of UCMS-induced depression on nociceptive behavior In our previous work, two kinds of nociceptive behavior were observed: head-flicks and grooming. Grooming was characterized by rubbing the face or scratching the head with the limbs, and a head-flick was characterized by rapid and arrhythmic twitching. In the present study, another nociceptive behavior was added, head-turning. Head-turning was characterized by turning the head to one side and keeping this posture for a while, with or without the contralateral forelimb stretching to the other side. Head flicks were measured by number, and grooming and head-turning were quantified in terms of activity time(s). These nociceptive behaviors elicited by electrical stimulation were assessed on the fourth day after the stimulation electrodes were implanted. The electric current was a little higher in UCMS group, but this difference was not statistically significant (P = 0.061). As shown in Fig. 2A–D, the number of head flicks (18.00 ± 1.44) and the headturning time (33.44 ± 5.97 s) were increased markedly in rats in the U/S compared with those in the C/S group (10.77 ± 1.58, P = 0.006; 15.78 ± 2.95 s, P = 0.027) in response to electrical stimulation. We observed no significant difference in the grooming time of the UCMS and control groups (17.33 ± 4.59 vs 10.11 ± 2.83, P = 0.222).
A significant negative correlation was observed between the head-turning time induced by electrical stimulation and travel distance (r = −0.449, P = 0.047, see Fig. 2F) and sucrose preference (r = −0.577, P = 0.008, see Fig. 2H). However, the relationship between head flicks and travel distance or sucrose preference did not show a linear correlation (r = −0.373, P = 0.105; r = −0.298, P = 0.201, see Fig. 2E and G). 3.3. Effects of UCMS-induced depression on plasma CGRP and SP levels Fig. 3A shows the blood concentration of CGRP in the external jugular vein. No significant differences were observed among groups under the electrically-stimulated condition. As shown in Fig. 3B, plasma SP levels were increased significantly in the U/NS group compared with the C/NS group (P = 0.015), but no significant difference was observed between the U/S and C/S groups after the 30-min stimulation. 4. Discussion The present study investigated the effects of depression elicited by UCMS on trigeminovascular nociception behaviors in conscious rats and measured levels of CGRP and SP in the external jugular vein. The results showed that nociceptive behaviors (number of head flicks and head-turning time) were increased significantly in
4
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
Fig. 2. Effects of UCMS-induced depression on nociceptive behavior. (A) Stimulation intensity. The electric current was a little higher in UCMS group, but this difference was not statistically significant. (B–D) Nociceptive behavior. Response to electrical stimulation, the number of head flicks (C) and head-turning time (D), but not the total grooming time, were significantly increased in rats in the U/S group compared with those in the C/S group. A significant negative correlated was observed between the head-turning time induced by electrical stimulation and travel distance (F) and sucrose preference (H). However, the relationship between head flicks and travel distance or sucrose preference did not show a linear correlation (E and G). Data are presented as means ± SEM. *P < 0.05, **P < 0.01, compared to their respective control group.
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
Fig. 3. Effects of UCMS-induced depression on plasma CGRP and SP levels. (A) No significant differences were observed among groups under the electrically stimulated condition in plasma CGRP levels. (B) Plasma SP levels were increased significantly in the U/NS group compared with the C/NS group, no significantly difference was observed between U/S group and C/S group after the 30-min stimulation. Data are presented as means ± SEM. *P < 0.05, compared to their respective control group.
the U/S compared with the C/S group and that head-turning time was negatively correlated with depressive-like behaviors. Plasma levels of SP were increased in the U/NS compared with the C/NS group. However, we found no significant difference in the levels of CGRP or SP in the other groups. Both head-flicking and head-turning behaviors induced by electrical stimulation on dura mater adjacent to the superior sagittal sinus are reduced by rizatriptan benzoate, a specific anti-migraine drug [7]. They were rarely observed in normal rats, but another common behavior, grooming could often be observed in normal rats (Fig. 2B), which might suggest that head-flicking and head-turning represent more serious pain-related behaviors. Our results showed the number of head flicks and the head-turning time but not grooming time were increased markedly in rats in the U/S group, which suggested depression induced by UCMS lead to more intense pain in rats. In clinical studies, patients suffering from major depressive disorder show increased pain thresholds and tolerance of cold, heat, pressure, and electrical stimuli compared with healthy controls [3,18]. However, patients with depression have significantly lower ischemic muscle pain thresholds and tolerance than do healthy subjects [3,18]. The results of animal studies are also not uniform. Most have shown that sensitivity to pain decreases significantly with noxious radiant heat stimuli in the OB model and with thermal and
5
mechanical stimuli in the UCMS model [17,19,24], but there were objections [6]. The responses to pain induced by formalin injection into the hind paw are apparently all the same; higher sensitivity was found in OB rats, UCMS rats, and WKY rats [6,19,24]. In our study, we also found higher sensitivity to electrical stimulation of the dura mater surrounding the superior sagittal sinus in UCMS and OB rats [12]. There may be several reasons for these results. Perhaps there are two kinds of pain. One, surface pain induced by cold, heat, or electrical stimuli directly applied to the skin, produces hypoalgesia in depressed patients. The other, deep somatic pain induced by intramuscular ischemia, hind-paw injection, or dura-mater stimulation, produces hyperalgesia in depressed patients. Thus, two mechanisms may be involved in pain pathways. A pain message involves two-way traffic, including ascending and descending pathways. Pain information is relayed along Aı and C fibers to the spinal cord, then along the spinothalamic tract to the thalamus; it finally reaches the brain’s somatosensory cortex and limbic structures. Additionally, descending pathways modulate pain sensitivity. The brain uses these pathways to send chemical substances and nerve impulses back down to the cells in the spinal cord to act against the pain message sent up by pain receptors [27]. Lautenbacher and Krieg focused on the spinal and subcortical stages [11]. They thought that the processing of nociceptive stimuli was diminished during these stages, leading not only to hypoalgesia but also to insufficient activation of pain inhibitory systems. However, why does depression influence surface pain, and why does deep somatic pain not use the same pathways? Ward et al. supposed that the spinothalamic tract may be affected by an increase in the activity of endogenous opioids, resulting in reduced pain sensitivity in the skin [26]. Stahl and Briley suggested that levels of central serotonin (5-HT) and norepinephrine (NE) were low in depressed patients, which disturbed the descending pathways [21]. The reasons for these seemingly paradoxical results are far from clear. At the very least, we can draw the conclusion that depression induced by UCMS increases sensitivity to deep somatic pain in rats, indicating that depression may lead to disorders of central neurotransmitters or structural changes in the spinal or superspinal stage, resulting in enhanced pain messages in ascending pathways or decreased pain inhibition in descending pathways. However, we cannot offer more precise conclusions at this time. Further molecular biology research on the central nervous system is needed. Calcitonin gene-related peptide (CGRP) and substance P (SP) are both neuropeptides that mediate nociception. In nociception, the activated trigeminovascular system releases neuropeptides, leading to vasodilation and plasma extravasation. This is the mechanism of a migraine attack [8]. It has been demonstrated that the main function of SP is to lead to plasma extravasation and that the main function of CGRP is to dilate arteries to increase blood flow [16]. Few studies on SP and CGRP levels in depression have been conducted. Mathe first found increased CGRP in the cerebrospinal fluid of patients with depression versus healthy controls (P < 0.001) in 1994 [15]. Next, Bondy found elevated levels of plasma SP in patients with depression. After taking an antidepressant for 4 weeks, patients whose SP level decreased showed a better prognosis [5]. Later, Hartman discovered that the levels of CGRP and SP in female patients with depression were not only higher than were those in healthy controls but also showed a circadian rhythm [10]. Few animal studies have focused on the levels of CGRP and SP in depression models. In the present study, we found no differences in the levels of CGRP or SP between the UCMS and control groups after electrical stimulation. We showed a higher sensitivity to pain in rats in UCMS group than in the control group. However, the stimulation intensity did not significantly differ, and there was no statistically significant difference in the levels of CGRP and SP. Thus, we supposed that the pain-message afferents in the peripheral nerves of
6
M. Zhang et al. / Neuroscience Letters 551 (2013) 1–6
the U/S and C/S groups may not differ. This suggests that depression may lead to disorders in the spinal or superspinal stage, consistent with Lautenbacher’s hypothesis that “hyperalgesia to endogenous painful sensations is due to the insufficient activation of inhibitory systems” [11]. 5. Conclusions In summary, UCMS-induced depression can exacerbate trigeminovascular nociception, making the rats more sensitive to pain. However, we found no significant differences in the levels of CGRP or SP in the C/S and U/S groups, indicating that the impact of depression on migraines probably does not depend on the peripheral afferent pathway. Further, molecular biology research on the central nervous system, especially the ascending or descending pathways during the spinal or superspinal stage, is needed. Acknowledgment The funding support of the National Science Foundation Committee (NSFC) in China is gratefully acknowledged (grants 30970417 and 81171058). References [1] M. aan het Rot, S.J. Mathew, D.S. Charney, Neurobiological mechanisms in major depressive disorder, CMAJ 180 (2009) 305–313. [2] F. Antonaci, G. Nappi, F. Galli, G.C. Manzoni, P. Calabresi, A. Costa, Migraine and psychiatric comorbidity: a review of clinical findings, J. Headache Pain 12 (2011) 115–125. [3] K.J. Bar, S. Brehm, M.K. Boettger, S. Boettger, G. Wagner, H. Sauer, Pain perception in major depression depends on pain modality, Pain 117 (2005) 97–103. [4] S.M. Baskin, T.A. Smitherman, Migraine and psychiatric disorders: comorbidities, mechanisms, and clinical applications, Neurol. Sci. 30 (Suppl. 1) (2009) S61–S65. [5] B. Bondy, T.C. Baghai, C. Minov, C. Schule, M.J. Schwarz, P. Zwanzger, R. Rupprecht, H.J. Moller, Substance P serum levels are increased in major depression: preliminary results, Biol. Psychiatry 53 (2003) 538–542. [6] N.N. Burke, E. Hayes, P. Calpin, D.M. Kerr, O. Moriarty, D.P. Finn, M. Roche, Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions, Neuroscience 171 (2010) 1300–1313. [7] Z. Dong, L. Jiang, X. Wang, S. Yu, Nociceptive behaviors were induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus in conscious adult rats and reduced by morphine and rizatriptan benzoate, Brain Res. 1368 (2011) 151–158. [8] P.J. Goadsby, Migraine pathophysiology, Headache 45 (Suppl. 1) (2005) S14–S24. [9] E. Hamel, Serotonin and migraine: biology and clinical implications, Cephalalgia 27 (2007) 1293–1300.
[10] J.M. Hartman, A. Berger, K. Baker, J. Bolle, D. Handel, A. Mannes, D. Pereira, D. St Germain, D. Ronsaville, N. Sonbolian, S. Torvik, K.A. Calis, T.M. Phillips, G. Cizza, Quality of life and pain in premenopausal women with major depressive disorder: the POWER Study, Health Qual. Life Outcomes 4 (2006) 2. [11] S. Lautenbacher, J.C. Krieg, Pain perception in psychiatric disorders: a review of the literature, J. Psychiatr. Res. 28 (1994) 109–122. [12] J. Liang, S. Yu, Z. Dong, X. Wang, R. Liu, X. Chen, Z. Li, The effects of OB-induced depression on nociceptive behaviors induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus, Brain Res. 1424 (2011) 9–19. [13] C. Lovati, D. D’Amico, P. Bertora, Allodynia in migraine: frequent random association or unavoidable consequence? Expert Rev. Neurother. 9 (2009) 395–408. [14] V.T. Martin, M. Behbehani, Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis – Part I, Headache 46 (2006) 3–23. [15] A.A. Mathe, H. Agren, L. Lindstrom, E. Theodorsson, Increased concentration of calcitonin gene-related peptide in cerebrospinal fluid of depressed patients. A possible trait marker of major depressive disorder, Neurosci. Lett. 182 (1994) 138–142. [16] A. May, P.J. Goadsby, Substance P receptor antagonists in the therapy of migraine, Expert Opin. Investig. Drugs 10 (2001) 673–678. [17] F. Pinto-Ribeiro, A. Almeida, J.M. Pego, J. Cerqueira, N. Sousa, Chronic unpredictable stress inhibits nociception in male rats, Neurosci. Lett. 359 (2004) 73–76. [18] C. Schwier, A. Kliem, M.K. Boettger, K.J. Bar, Increased cold-pain thresholds in major depression, J. Pain 11 (2010) 287–290. [19] M. Shi, J.Y. Wang, F. Luo, Depression shows divergent effects on evoked and spontaneous pain behaviors in rats, J. Pain 11 (2010) 219–229. [20] G.E. Simon, Social and economic burden of mood disorders, Biol. Psychiatry 54 (2003) 208–215. [21] S. Stahl, M. Briley, Understanding pain in depression, Hum. Psychopharmacol. 19 (Suppl. 1) (2004) S9–S13. [22] L. Stovner, K. Hagen, R. Jensen, Z. Katsarava, R. Lipton, A. Scher, T. Steiner, J.A. Zwart, The global burden of headache: a documentation of headache prevalence and disability worldwide, Cephalalgia 27 (2007) 193–210. [23] P. Torelli, D. D’Amico, An updated review of migraine and co-morbid psychiatric disorders, Neurol. Sci. 25 (Suppl. 3) (2004) S234–S235. [24] W. Wang, W.J. Qi, Y. Xu, J.Y. Wang, F. Luo, The differential effects of depression on evoked and spontaneous pain behaviors in olfactory bulbectomized rats, Neurosci. Lett. 472 (2010) 143–147. [25] X. Wang, S. Yu, Z. Dong, L. Jiang, The Fos expression in rat brain following electrical stimulation of dura mater surrounding the superior sagittal sinus changed with the pre-treatment of rizatriptan benzoate, Brain Res. 1367 (2011) 340–346. [26] N.G. Ward, V.L. Bloom, S. Dworkin, J. Fawcett, N. Narasimhachari, R.O. Friedel, Psychobiological markers in coexisting pain and depression: toward a unified theory, J. Clin. Psychiatry 43 (1982) 32–41. [27] F. Wei, M. Gu, Y.X. Chu, New tricks for an old slug: Descending serotonergic system in pain, Sheng Li Xue Bao 64 (2012) 520–530. [28] P. Willner, Chronic mild stress (CMS) revisited: consistency and behaviouralneurobiological concordance in the effects of CMS, Neuropsychobiology 52 (2005) 90–110. [29] H.C. Yan, X. Cao, M. Das, X.H. Zhu, T.M. Gao, Behavioral animal models of depression, Neurosci. Bull. 26 (2010) 327–337. [30] S. Yu, R. Liu, G. Zhao, X. Yang, X. Qiao, J. Feng, Y. Fang, X. Cao, M. He, T. Steiner, The prevalence and burden of primary headaches in China: a population-based door-to-door survey, Headache 52 (2012) 582–591. [31] M. Zimmermann, Ethical guidelines for investigations of experimental pain in conscious animals, Pain 16 (1983) 109–110.