Association of the Serotonin and Kynurenine Pathways as Possible Therapeutic Targets to Modulate Pain in Patients with Fibromyalgia

Abstract

Fibromyalgia (FM) is a disorder characterized by widespread chronic pain, significant depression, and various neural abnormalities. Recent research suggests a reciprocal exacerbation mechanism between chronic pain and depression. In patients with FM, dysregulation of tryptophan (Trp) metabolism has been identified. Trp, an essential amino acid, serves as a precursor to serotonin (5-HT), a neuromodulator that influences mood, appetite, sleep, and pain perception through the receptors 5-HT1, 5-HT2, and 5-HT3. Additionally, Trp is involved in the kynurenine pathway, a critical route in the immune response, inflammation, and production of neuroactive substances and nicotinamide adenine dinucleotide (NAD+). The activation of this pathway by pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interferon gamma (IFN-γ), leads to the production of kynurenic acid (KYNA), which has neuroprotective properties, and quinolinic acid (QA), which is neurotoxic. These findings underscore the crucial balance between Trp metabolism, 5-HT, and kynurenine, where an imbalance can contribute to the dual burden of pain and depression in patients with FM. This review proposes a novel therapeutic approach for FM pain management, focusing on inhibiting QA synthesis while co-administering selective serotonin reuptake inhibitors to potentially increase KYNA levels, thus dampening pain perception and improving patient outcomes.

Keywords: 5-HT1A; 5-HT2; 5-HT3; 5-HTT; kynurenine acid; quinolinic acid; tryptophan.

Figure 1

Dual roles of metabolites within the kynurenine pathway, focusing on quinolinic acid and its contrast to quinuric acid in the central nervous system. Quinuric acid, which is synthesized by astrocytes from quinolinic acid, is the result of the enzymatic action of kynurenine aminotransferase (kat). This conversion process highlights the neuroprotective properties of quinuric acid. Conversely, quinolinic acid, when processed by microglia, follows a different metabolic route involving the kynurenine monooxygenase (kmo) signaling cascade. Kmo facilitates the conversion of quinolinic acid to 3-hydroxykynurenine (3-hk). The pathway continues with the transformation of 3-hk into 3-hydroxyanthranilic acid (3-haa) by the enzyme quinureninase, eventually leading back to the formation of quinolinic acid, which is known for its neurodegenerative effects. This depiction underscores the complex interplay between neuroprotective and neurodegenerative mechanisms mediated by metabolites of the kynurenine pathway.

Figure 2

The impact of L-tryptophan on fibromyalgia pathology underscores its crucial role through its metabolic products, serotonin, and kynurenine. Stress conditions prompt an increase in 3,2-dioxygenase activity, which favors the kynurenine pathway over serotonin synthesis by depleting the L-tryptophan levels in the bloodstream. Consequently, in the central nervous system (CNS), decreased availability of L-tryptophan leads to decreased serotonin levels, which can cause symptoms such as depression, pain, and sleep disturbances characteristic of fibromyalgia. Concurrently, an increase in kynurenine levels results in elevated quinolinic acid within the CNS, hinting at a neurodegenerative process propelled by inflammation, cellular stress, and increased glutamatergic activity. These interconnected pathways could contribute to the chronic pain and central sensitization observed in fibromyalgia patients, indicating that modulation of L-tryptophan and kynurenine levels is a promising direction for therapeutic intervention in the treatment of fibromyalgia symptoms.

Figure 3

Proposed intervention to mitigate pain in fibromyalgia (FM) patients, which focuses on modulating the serotonin–kynurenine pathway. This strategy involves two principal components: the administration of serotonin reuptake inhibitors (SRIs) to increase the serotonin levels in the synaptic cleft and the inhibition of 3-hydroxyanthranilic acid (3-HAA) production in microglia, thereby curtailing the synthesis of quinolinic acid. These targeted actions are designed to exert beneficial effects on pain alleviation in FM sufferers. Enhancing serotonin availability through SRIs is anticipated to improve the functionality of nociceptive pathways, potentially diminishing pain perception. Additionally, serotonin elevation may ameliorate depression symptoms, which are frequently observed in FM patients, thereby tackling both the neurochemical and the psychological dimensions of the condition. Simultaneously, the proposed intervention seeks to reduce quinolinic acid—a metabolite linked to neurodegenerative effects—and increase quinuric acid, which is known for its neuroprotective properties within the central nervous system. By decreasing the presence of quinolinic acid, it is hypothesized that there would be a concomitant reduction in the pain experienced by FM patients. This dual-focused approach aims not only to alleviate the immediate symptoms of pain but also to address the underlying neurochemical imbalances associated with FM, providing a holistic treatment strategy that encompasses both the physical and the psychological aspects of the disease.