Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: A putative animal model of fibromyalgia

Abstract

Fibromyalgia is a prevalent and burdensome disorder characterized by chronic widespread pain and complex comorbid symptoms. To develop better treatments for pain-centered fibromyalgia symptoms, there is still a need for animal models which mimic the features of fibromyalgia patients. In the present study, we have established a fibromyalgia animal model by utilizing a never-before-published pharmacological effect of reserpine. Repeated administration of reserpine (1mg/kg s.c., once daily, for three consecutive days) causes a significant decrease in the muscle pressure threshold and tactile allodynia, which are sustained for 1week or more in both male and female rats. This treatment regimen decreases the amount of biogenic amines (dopamine, norepinephrine, and 5-hydroxytryptamine) in the spinal cord, thalamus, and prefrontal cortex, which are deeply involved in pain signal processing. It also significantly increases immobility time in the forced swim test, which is indicative of depression, a common comorbid symptom of fibromyalgia. Pregabalin, duloxetine, and pramipexole significantly attenuated the reserpine-induced decrease in muscle pressure threshold, but diclofenac did not. The validity of the use of this reserpinized animal as a fibromyalgia model is demonstrated from three different aspects, i.e., face validity (manifestation of chronic pain and comorbid symptoms), construct validity (dysfunction of biogenic amine-mediated central nervous system pain control is involved), and predictive validity (similar responses to treatments used in fibromyalgia patients). This animal model is expected to contribute to the better understanding of fibromyalgia pathophysiology and the evaluation of drugs, especially those which would activate biogenic amine system.

Quetiapine Fumarate Extended‐Release for the Treatment of Major Depression With Comorbid Fibromyalgia Syndrome: A Double‐Blind, Randomized, Placebo‐Controlled Study

“…For instance, both fibromyalgia and major depression involve dysregulated transmission of central monoamine neurotransmitters, including serotonin, norepinephrine, and dopamine (10). Animal models suggest that depletion of monoaminergic neurotransmitters in the spinal cord, thalamus, and prefrontal cortex can cause chronic muscular pain, hyperalgesia, allodynia, and depression, which can be attenuated by treatment with serotonin and norepinephrine reuptake inhibitors (SNRIs) or pregabalin (11). Human studies confirm that patients with fibromyalgia have lowered levels of monoamines (12) in their cerebrospinal fluid and higher levels of substance P (13) and nerve growth factor (14).…”

Animal Models of Fibromyalgia

“…Additionally, no significant difference was noted in either blood pressure or rectal temperature between reserpine-and vehicle-treated groups. Taken together, these findings suggest that reserpine produces chronic pain symptoms and depressive conditions by influencing pathways that regulate nociception and depression (Nagakura et al, 2009). …”

“…Further, reserpine treatment also induces a depressive condition, consistent with the role biogenic amines have in the pathophysiology of depression. Because a short-term depletion of biogenic amines by tetrabenazine did not significantly affect nociceptive sensitivities, long-term depletion is likely necessary for chronic pain symptoms to develop (Nagakura et al, 2009;Oe et al, 2010). Intriguingly, in the experiment using single injection of reserpine, hyposensitivity to muscle pressure stimulus occurred in the acute phase (within 24 h) after the reserpine injection, although hypersensitivity developed in the chronic phase, i.e., on Day 2 or later after the injection.…”

“…They are housed individually in the cage and are subcutaneously administered reserpine at 1 mg/kg once daily for three consecutive days. Hyperalgesia is typically evaluated on Day 5 after the last reserpine injection (Nagakura et al, 2009). Because tenderness to palpation is a diagnostic criterion for fibromyalgia and blunt pressure loading is frequently used to estimate muscular pain thresholds in humans, the muscle pressure test is used (Petzke et al, 2003).…”

Pathological mechanisms of fibromyalgia using animal models

“…Acid-sensing ion channel 3 (ASIC3) mRNA was upregulated in the DRG. In the spinal cord, function of the descending pain inhibitory system seems to be impaired because of a dramatic depletion of serotonin (5-HT) and noradrenaline (NA) in this model 7,11) . Activated microglia is evident in the spinal dorsal horn, especially in superficial laminae I-II, resulting in central sensitization.…”