NMDA-induced spinal hypersensitivity is reduced by naturally derived peptide analog [Ser(1)]Histogranin

N-methyl-D-aspartate (NMDA) receptor activation is thought to initiate a ce llular cascade of events in the spinal cord that leads to neuronal hyperact ivation and exaggerated persistent pain behaviors. Previous studies have de monstrated that implantation of adrenal medullary tissue into the spinal su barachnoid space reduces abnormal pain behaviors such as hyperalgesia and a llodynia, possibly by intervening in the NMDA hyperexcitability cascade. Hi stogranin is a 15-amino acid peptide possessing NMDA receptor antagonist ac tivity that has been isolated from adrenal medullary tissue. The present st udy examined the ability of stable analog [Ser(1)]histogranin to reduce abn ormal pain-related behaviors induced in rats by direct activation of spinal NMDA receptors. The intrathecal injection of NMDA (5.0, 10.0, 20.0 nmol) p roduced significant thermal and mechanical hyperalgesia and tactile allodyn ia in a dose-related fashion. [Ser(1)]histogranin injected intrathecally pr ior to NMDA injections dose dependently attenuated or completely blocked hy peralgesia and allodynia. In addition, [Ser(1)]histogranin administration f ollowing NMDA-induction of abnormal pain behaviors reversed these effects. These results demonstrate that a naturally derived adrenal medullary neurop eptide can prevent and reverse NMDA-mediated spinal hyperexcitability. The distinct profile and robust activity of [Ser(1)]histogranin suggest novel a lternative approaches in the management of pain and other CNS disorders inv olving abnormal excitatory neurotransmission. (C) 1998 Elsevier Science Inc .