Comorbidity of Pain and Depression in a Lumbar Disc Herniation Model: Biochemical Alterations and the Effects of Fluoxetine

Abstract

Summary of Background Data: Depression is one of the most common comorbidities in patients with chronic low back pain. However, the mechanisms of depression in chronic low back pain patients and the effect of antidepressants on the comorbidity of pain and depression need to be further explored. The establishment of the appropriate animal models and of more effective therapies is critical for this comorbidity. Lumbar disc herniation (LDH) is the most common disease that causes low back pain. The current study examined whether an LDH model shows behavioral and biochemical alterations that are in accordance with the characteristics of the comorbidity of pain and depression and tested the effect of fluoxetine (FLX) on these measures.Objective: The current study examined whether an LDH model showed the behavioral and biochemical alterations that were in accordance with the characteristics of the comorbidity of pain and depression and tested the effect of FLX on these measures.Methods: The LDH animal model was generated by the implantation of the autologous nucleus pulposus on the left L5 nerve root just proximal to the dorsal root ganglion in Wistar rats. Pain intensity was evaluated by mechanical allodynia and thermal hyperalgesia, and changes in depressive behavior were examined by the taste preference and forced swim tests. Hippocampal serotonin (5-HT) levels were measured by liquid chromatography-mass spectrometry, and tumor necrosis factor-α (TNF-α) mRNA was quantified using real-time reverse transcriptase PCR.Results: LDH resulted in chronic pain, which further induced depressive behavior that persisted for 6 weeks after surgery. There were decreased 5-HT concentrations and upregulated TNF-α mRNA levels that were accompanied by behavioral changes. FLX treatment improved depressive behavior and moderately alleviated pain through increased 5-HT concentrations, and inhibited TNF-α mRNA expression.Conclusions: In summary, our studies provide initial evidence that the LDH chronic pain model might serve as a model of the comorbidity of low back pain and depression. The finding that FLX improved depressive behavior and pain through normalized 5-HT concentrations and TNF-α mRNA expression establishes the initial mechanism of the comorbidity of pain and depression.

Neuroinflammation, Pain and Depression: An Overview of the Main Findings

“…However, ketamine, which acts on NMDA receptors, not only decreases inflammatory markers, as previously described but also inhibits the KYN/tryptophan ratio while increasing the 5-HT/tryptophan ratio (Zhang et al, 2016). Accordingly, fluoxetine increases 5-HT in the hippocampus while decreasing inflammation (Cai et al, 2019), suggesting that improving the synaptic network also affects inflammation status (Figure 4). The same rationale may apply to other treatments, such as benzodiazepines, reuptake inhibitors, and CCK2 and PKR inhibitors, which classically involve pre-and postsynaptic neurons, as described above.…”

“…Since major depression is associated with decreased serotonin levels (Haase and Brown, 2015), as in the persistent pain state (Bardin, 2011), fluoxetine improves these symptoms by increasing the amount of serotonin in the synaptic environment by selectively inhibiting the reuptake of this monoamine (Fuller et al, 1991). Although fluoxetine is the most studied selective serotonin reuptake inhibitor (SSRI) used to treat chronic pain, its use in clinical trials has been contradictory (Walker et al, 1998); however, it is effective in a preclinical lumbar disk herniation model (Cai et al, 2019). Additionally, fluoxetine plus pioglitazone or metformin, both of which are antidiabetic drugs, attenuates pain and depression with better effects than each treatment individually (Murad and Ayuob, 2015).…”

“…Indeed, manipulation of monoamines may also involve anti-inflammatory mechanisms. In a lumbar disk herniation model, fluoxetine decreases TNF-α in the hippocampus (Cai et al, 2019), while in a chronic constriction injury model, it decreases proinflammatory cytokines in the plasma, increases IL-10, decreases myelin degeneration and leukocyte infiltration in peripheral nerves and decreases astrocyte activation in the spinal cord; additionally, it has better effects when combined with antidiabetic drugs (Murad and Ayuob, 2015). Despite having similar mechanisms, amitriptyline does not improve thermal nociceptive thresholds but decreases astrocyte activation (Burke et al, 2015).…”

Depression and Pain: Use of Antidepressants

“…CLBP treatment generally consists of administering NSAIDs; however, if the pain is refractory, duloxetine is recommended because duloxetine has been proven effective in treating CLBP regardless of sex, age, and the duration and intensity of pain at a dose of 60 mg/day. Depression commonly coexists in patients with CLBP, and therefore, 91.1% of the effect of antidepressants (such as duloxetine) is estimated to be analgesic, and 8.9% is estimated to be antidepressant [ 145 ].…”

“…Most studies have focused on the HPA, neuroinflammatory factors, neurogenesis, glutamate, GABA, and various neurotransmitters and neuromodulators. In this regard, 5-HT, dopamine, and NE are the most intensely studied candidates in both the fields, chronic pain and depression [ 145 , 150 , 151 ].…”