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 24 h 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.