Abstract
Treatment for fibromyalgia is an unmet medical need and its pathogenesis is still poorly understood. The present study demonstrated that intermittent psychological stress (IPS), or empathy causes generalized chronic abnormal pain with female predominance. The persistence of the pain phenotype was dependent on the unpredictability of the stressor. The pain was reversed by pregabalin (PGB), duloxetine (DLX) or mirtazapine (Mir), but not by diclofenac or morphine. Differential administration of these existing medicines revealed that the sites of PGB and Mir actions exist in the brain, but not in the spinal cord, while that of DLX is preferentially in the spinal cord. It is interesting to note that the intracerebroventricular injection of PGB or Mir showed potent analgesia for 24h or longer, though systemic injection of these medicines shows anti-hyperalgesia just for several hours. These results indicate that initial intense actions in the target brain may prevent the forthcoming development of pain memory. IPS-induced abnormal pain was prevented in mice deficient of lysophosphatidic acid receptor 1 (LPA1) gene, and completely cured by the repeated intrathecal treatments with LPA1 antagonist, AM966, which did not show acute action. All these results suggest that IPS model is an experimental animal model, which mimics the pathophysiology and pharmacotherapy in fibromyalgia in clinic, and LPA1 signaling plays crucial roles in the IPS-induced fibromyalgia-like abnormal pain.
Highlights
Since animal models of neuropathic pain have been developed (Bennett and Xie, 1988; Ossipov and Porreca, 2013), much effort has been devoted to clarifying the mechanisms towards discovery of drug to treat neuropathic pain, by using physiological, anatomical (Basbaum et al, 2009; Devor, 2013) and molecular biological analyses (Ueda, 2006, 2008; Costigan et al, 2009; Kuner, 2010; Hill, 2013)
The first issue in the present study is the development of intermittent psychological stress (IPS)-induced generalized pain model in mice
Unique property is observed in the finding that the persistent pain lasting over 19 days was observed when IPS was given to mice, while transient pain lasting within 6 days was observed when intermittent foot shock (IFS), repeated psychological (RPS) and repeated foot shock stress (RFS) were given
Summary
Since animal models of neuropathic pain have been developed (Bennett and Xie, 1988; Ossipov and Porreca, 2013), much effort has been devoted to clarifying the mechanisms towards discovery of drug to treat neuropathic pain, by using physiological, anatomical (Basbaum et al, 2009; Devor, 2013) and molecular biological analyses (Ueda, 2006, 2008; Costigan et al, 2009; Kuner, 2010; Hill, 2013). Little is known of details of central pain, which is closely related to the emotional disturbance, since it is poorly characterized in terms of causes, primary and secondary loci. Fibromyalgia, a representative central and generalized pain is known to comprise an approximately 2% population ratio in developed countries (Russell et al, 1992; Clauw, 2014). Ropathy as well as central mechanisms as a causative factor in fibromyalgia (Levine and Saperstein, 2015; Clauw, 2015; Doppler et al, 2015; Ramirez et al, 2015), limited etiological information of fibromyalgia delays the reasonable diagnosis and therapy. Basic studies using animal models, which mimic pathophysiological symptoms and pharmacotherapeutical sensitivities in fibromyalgia patients, would be expected for advancing diagnosis or therapy
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