Tryptophan-Metabolizing Enzyme Connects Pain and Depression
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).
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