Src activation in the hypothalamic arcuate nucleus may play an important role in pain hypersensitivity

Src family of kinases (SFKs) has been found to play an important role in the regulation of nociception. However, how each member of this family acts in the central nervous system (CNS) structures involved in the relay and/or modulation of nociceptive signals, and thereby contributes to the formation and maintenance of pain hypersensitivity, is still a challenge. In this work, a combined study using biochemical, genetic and behavioral approaches was conducted. We found that the expression of activated SFKs in the hypothalamic arcuate nucleus (ARC) area was significantly increased following the development of inflammation induced by injection of complete freund's adjuvant (CFA) into the hind paw of rats. Furthermore, we identified that Src, but not Fyn or Lyn in the Src family, was activated, and that Src knockdown in the ARC area blocked the inflammation-induced increases in the expression of activated SFKs, the N-Methyl-D-aspartate receptor (NMDAR) GluN2B subunit and phosphorylated GluN2B at Y1472 in this region. Moreover, the CFA injection-induced allodynia and hyperalgesia, and the analgesic effect produced by systemic application of the SFK inhibitor, SU6656, were significantly diminished. However, the Src knockdown did not induce any change in the expression of activated SFKs  and the NMDAR GluN2B subunit in normal rats which were not injected with CFA. Neither the Src knockdown nor the systemic application of SU6656 affected the mechanical and thermal sensitivity of the normal rats. Thus, Src activation in the ARC may be a key event for formation and maintenance of pain hypersensitivity associated with peripheral inflammation.