Pathological mechanisms of fibromyalgia using animal models

Abstract

Fibromyalgia is characterized by systemic chronic pain. It accompanies a wide variety of symptoms, such as dysfunction in the autonomic nervous system, mental states, and locomotive activities. Fibromyalgia and related disorders are assumed to be heterogenous conditions with complicated pathologies driven by peripheral and central mechanisms. Using a reserpineinduced fibromyalgia model, a significant increase of mRNA expression in the dorsal root ganglion (DRG) was detected in the acid-sensing ion channel 3 (ASIC3) among several ion channels tested, which are responsible for pain, mechano-transduction, and the generation ⁄ propagation of action potentials. Behavioral mechanical hyperalgesia in this model was reversed by a selective blocker of ASIC3 (APETx2). Ex vivo single-fiber electrophysiological recordings revealed facilitation in the mechanical responses of mechano-responsive C-fibers both in the skin and muscle, whereas the proportion of mechanorespon sive C-nociceptors was paradoxically decreased. In the spinal dorsal horn microglial cells labeled with Iba1-immunoreactivity were obviously activated, especially in laminae I-II where the nociceptive input is mainly projected. Intraperitoneal injection of minocycline, which was applied preemptively and repeatedly for 4 consecutive days from 1 day before a series of reserpine injections, clearly suppressed the microglial activation and behavioral hyperalgesia. These results suggest that the increase in ASIC3 in the nociceptive afferents facili tated mechanical response of the remaining C-nociceptors, and that activated spinal microglia direct to intensify pain in this model. Pain may be further amplified by reserpine-induced dysfunction of the descending pain inhibi tory system, and by the decreased peripheral drive to this system resulting from a reduced proportion of mechano-responsive C-nociceptors.Persistent physical and psychological stress are associated with fibromyalgia. Changes in muscular nociceptors were systematically examined using two pain models induced by stress (repeated cold stress (RCS) and multiple continuous stress (MCS)). Mechanical response of C-nociceptors in RCS model was signifi cantly facilitated, whereas that in MCS model was unchanged. The result suggests that augmentation in the mechanical response of muscular C-