Chronic pain and depression often occur together, but the mechanisms behind their comorbid relationship have been elusive, leaving physicians to prescribe treatments that address symptoms, rather than root causes. In translational research that could lead to better therapies, Jianren Mao and colleagues at Massachusetts General Hospital in Boston, US, report that upregulation of the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the brain, in response to either pain or stress, could account for the link between pain and depression and offer a novel target for joint treatment of both conditions.
The study, published in the July 2 Journal of Clinical Investigation, shows that in rodents exhibiting comorbid pain and depressive behaviors, IDO1 levels in the hippocampus jump. That alters the balance of tryptophan metabolites, including the neurotransmitter serotonin. Inhibiting IDO1 normalizes tryptophan metabolism and alleviates both pain and depressive behaviors, the investigators show. The researchers also report that plasma levels of IDO1 and its inducer, the inflammatory cytokine interleukin 6 (IL-6), are increased in patients with chronic pain and depression, hinting that the rodent results may reflect what is happening in people.
“This is a seminal paper that will give us a new approach to the problem of chronic pain and depression,” said Juan-Antonio Micó of the University of Cadiz in Spain, who studies pain and depression, and the analgesic effects of antidepressant drugs. “I think IDO1 is an interesting target for developing new drugs” that attack both conditions at once, said Micó, who was not involved in the study.
The path to IDO1
In search of common roots of pain and depression, Mao and colleagues focused on tryptophan metabolism in the brain, and the role of cytokines therein. Tryptophan, an essential amino acid, is metabolized to serotonin, a neurotransmitter that controls mood and pain. Tryptophan can also be metabolized to kynurenine, some of whose derivatives contribute to neurotoxicity and, via interaction with glutamate receptors, to pain and depression as well (for a review, see Dantzer et al., 2008). IDO1 catalyzes the formation of kynurenine from tryptophan, which leaves less tryptophan available for serotonin production. Previous research implicated IDO1 in depression, but had only hinted at a function for the enzyme in pain, Mao said. In addition, proinflammatory cytokines like IL-6 play a role in pain and depression, and some induce IDO1, which suggested that those cytokines might drive comorbidity through regulation of the enzyme.
To investigate the mechanisms behind comorbid pain and depression, the researchers needed an animal model that captured both conditions. They found that, in rats, persistent painful inflammation caused by injection of complete Freund’s adjuvant (CFA)—a common model of arthritis—was accompanied by depressive behaviors, including prolonged immobility in a forced swimming test and decreased activity in an open field test. The depressive behaviors correlated with thermal hyperalgesia after CFA injection, suggesting a comorbid association.
To determine if IDO1 was involved in that relationship, first author Hyangin Kim and coworkers then looked at IDO1 expression and activity in the rats. They found increased IDO1 mRNA and protein levels in the hippocampus, and also documented increased kynurenine/tryptophan ratios and decreased serotonin/tryptophan ratios, both consistent with increased IDO1 activity. A social stress-induced rat model of depression also showed increases in thermal and mechanical pain sensitivity, and in that model, too, IDO1 levels rose. Likewise, a small, cross-sectional group of patients with chronic back pain and depression had elevated plasma IDO1 levels and kynurenine/tryptophan ratios compared to healthy controls, suggesting a role for IDO1 in comorbid pain and depression in people.
To learn whether inhibiting IDO1 could quell pain and depression, the researchers administered a small-molecule IDO1 inhibitor, L-1-methyl-tryptophan, to the CFA-treated rats. After intraperitoneal or hippocampal injection of the inhibitor, the rats displayed diminished nociceptive and depressive behaviors, and normalized ratios of tryptophan metabolites in the hippocampus. Deletion of the Ido1 gene in mice had a similar effect. “We demonstrate that both conditions—pain and depression—can be modulated simultaneously by targeting a single pathway,” Mao said.
A final set of experiments implicated IL-6 as a mediator of IDO1 action: Rats with CFA-induced inflammatory pain and depression exhibited increased plasma IL-6 protein and hippocampal Il6 mRNA levels, while hippocampal injection of IL-6 antiserum reversed IDO1 upregulation and alleviated the rats’ painful hypersensitivity and depressive behaviors. Further studies indicated that IL-6 boosted IDO1 expression via the JAK/STAT signaling pathway. In support of a similar role for IL-6 in people, the patients with chronic back pain and depression also exhibited elevated plasma IL-6 levels.
Into the clinic?
The goal now for Mao and colleagues is to translate their preclinical findings on IDO1 inhibition into humans, a task made easier because IDO1 inhibitors are already being developed for depression and cancer treatment. Mao is also hopeful that IDO1-targeted therapies will allow clinicians to treat patients proactively—to prevent people with chronic pain, for example, from also falling into depression—rather than just treating depression if and when it presents. “We don’t need to simply resolve these kinds of [comorbid] conditions through symptomatic management—we can actually prevent the interaction between pain and depression in the first place, by normalizing tryptophan metabolic pathways,” he said.
While Micó agrees that targeting IDO1 and tryptophan metabolism is a promising approach to treating comorbid pain and depression, he said the strategy may have limited efficacy when that pain is neuropathic, given evidence that noradrenaline (produced from tyrosine, not tryptophan), rather than serotonin, is more important in that setting. Mao concurs that the current work on IDO1 needs to be expanded to other pain conditions.
Finally, the current study adds to growing evidence for hippocampal involvement in pain pathophysiology. One recent paper reported a range of hippocampal abnormalities after nerve injury-induced pain in mice, as well as reduced hippocampal volume in patients with chronic pain (see PRF related news story on Mutso et al., 2012); other studies suggest that proinflammatory cytokines in the hippocampus are important in chronic pain (Ren et al., 2011; del Rey et al., 2011; Martuscello et al., 2012).
Comments
Robert Dantzer, University of Texas MD Anderson Cancer Center
Is indoleamine 2,3 dioxygenase at the intersection of depression and chronic pain?
This comment was coauthored with Annemieke Kavelaars, University of Illinois at Urbana-Champaign, College of Medicine, Department of Pathology, Urbana, IL
Indoleamine 2,3 dioxygenase (IDO) is an ubiquitous enzyme that is activated by inflammatory stimuli and causes the degradation of tryptophan and other indoleamines along the kynurenine pathway. This enzyme caught the attention of physiologists when Munn and Mellor demonstrated that activation of IDO by paternal antigens in pregnant mice allows embryos to avoid immune attack (1). IDO is present in all cells of the body, including brain cells. Together with tryptophan 2,3 dioxygenase that is mainly present in the liver, IDO regulates the cellular metabolism of tryptophan. At the time at which it was thought possible to control brain serotonin via the amount of tryptophan in the diet, no attention was given to IDO despite some evidence of its role in the regulation of the synthesis of brain serotonin in response to a peripheral tryptophan load (2). Brain IDO came into focus when neuropathologists showed the key role of neurotoxic kynurenine metabolites in the neuropathologies associated with infectious disorders, including HIV (3). There should not have been any major obstacle in transferring this body of knowledge from neuropathology to psychiatry, especially in view of the occurrence of neuropsychiatric disorders in patients with biochemical evidence of IDO activation (4). However, IDO remained largely ignored by psychiatrists until clinical studies in cancer patients treated with cytokines revealed an association between activation of IDO and the development of symptoms of depression (5, 6). At the time, it was still thought that the enhanced degradation of tryptophan in response to cytokine immunotherapy was responsible for a decrease in the biosynthesis of serotonin. The successful prevention of development of depression in interferon-alpha-treated cancer patients by administration of the specific serotonin reuptake inhibitor paroxetine was in line with this interpretation (7).
References
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9. O'Connor JC, Andre C, Wang Y, Lawson MA, Szegedi SS, Lestage J, Castanon N, Kelley KW, Dantzer R. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci. 2009 Apr 1;29(13):4200-9.
10. Dantzer R, O'Connor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology. 2011 Apr;36(3):426-36.
11. Kim H, Chen L, Lim G, Sung B, Wang S, McCabe MF, Rusanescu G, Yang L, Tian Y, Mao J. Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest. 2012 Aug 1;122(8):2940-54.
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Acknowledgements
NIH R01 MH079829 to RD, R01NS074999 to AK, and R01NS073939 to Kavelaars, Dantzer, Kelley
Aye-Mu Myint, Ludwig-Maximillians-University
Is Indoleamine 2,3 Dioxygenase-1 a target for treatment of chronic pain and depression?
The involvement of tryptophan depletion due to increased tryptophan degradation to kynurenine was proposed as a pathophysiological mechanism in depression since late 1960s [1]. In kynurenine shunt theory [2], it was proposed that the increased degradation of tryptophan to kynurenine, which shunted tryptophan away from the synthesis of serotonin induces serotonin depletion and depressive symptoms. In 1980, Gal and Sherman [3]has proposed the involvement of indoleamine 2,3 dioxygenase (IDO) which induces increased formation of L-kynurenine at different anatomical sites in the body, including the brain and competes with tryptophan transport into the brain as well as cellular transport and further induces substrate inhibition on tryptophan hydroxylase, impaired serotonin synthesis and depression. Based on the reports demonstrating that the IDO activity is enhanced by pro-inflammatory cytokines such as interferon-g[4, 5], and inhibited by the anti-inflammatory cytokine IL4 [6], the connection between inflammatory response system, high tryptophan degradation into kynurenine and depressive symptoms came to attention in depression research [7]. Chronic pain has high comorbidity with depression [8, 9]. Mao and group [10]has demonstrated the involvement of IDO1 in both depression and chronic pain and proposed IDO1 as a therapeutic target. While it seems promising, there are some points to be considered carefully in terms of pathophysiology and therapeutic application.
As mentioned in the comment by Dantzer, IDO has its physiological functions such as activation of IDO by paternal antigens in pregnant mice that protects embryos from allogeneic fetal rejection due to maternal immune response [11]. This induction of immune tolerance by tryptophan depletion in the cells with immune function indeed plays a role in immunology. Without this, although experimental animals could survive without problem in the well protected environment in the laboratories, can human survive without any major problem? Another point we need to consider is, where the actual problem is. Is that IDO1 activation, or immune activation, or tryptophan depletion, or further formation of neurotoxic metabolites in this tryptophan degradation pathway? The role of further downstream neurotoxic metabolites was reported [12]and several studies have confirmed in different neurodegenerative and neuroinflammatory diseases. It was also reported that the activity of another enzyme from this metabolism, kynurenine 3-monooxygenase (KMO) is also enhanced by pro-inflammatory cytokines [13]and this enzyme degrades kynurenine to 3-hydroxykynurenine which could further be degraded via several steps into neurotoxic quinolinic acid. Based on those points, imbalance in further downstream metabolites was proposed as a pathophysiological mechanism in depression [14]. Some studies have reported the imbalanced downstream metabolites in depression, either cytokine induced [15]or in major depression [16].
Another point to be considered is that pro-inflammatory state and increased tryptophan degradation to kynurenine was observed also in schizophrenia [17]a disorder which rarely has comorbidity with pain.
In addition to all these points, there is a common point of view that psychiatric disorders are not inflammatory disorders. Although these are not inflammatory disorders, a certain portion of patients have activated inflammatory response state. Again, in terms of inflammatory response, the response through cytokines such as interferon and interleukin-6 (IL6) are not the same in-vivo. Although IL6 induces IDO activity in vitro, the suppressor of cytokines signally 3 (SOCS3) gene expression induced by IL6 in vivo can degrade the IDO enzyme and it will not result in tryptophan depletion [18].
Although there are several points to be considered, Mao and colleagues have demonstrated the common pathway through IDO1 in comorbidity of depression and chronic pain and possible involvement of inflammatory response system with thorough experiments. Their report is indeed an important finding in this area of research. For the development of therapeutics, scientists still need to carefully consider several points and perform further investigations.
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