NMDA-induced spinal hypersensitivity is reduced by naturally derived peptide analog [Ser1]histogranin

N-methyl-D-aspartate (NMDA) receptor activation is thought to initiate a cellular cascade of events in the spinal cord that leads to neuronal hyperactivation and exaggerated persistent pain behaviors. Previous studies have demonstrated that implantation of adrenal medullary tissue into the spinal subarachnoid space reduces abnormal pain behaviors such as hyperalgesia and allodynia, possibly by intervening in the NMDA hyperexcitability cascade. Histogranin is a 15-amino acid peptide possessing NMDA receptor antagonist activity that has been isolated from adrenal medullary tissue. The present study examined the ability of stable analog [Ser1]histogranin to reduce abnormal 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) produced significant thermal and mechanical hyperalgesia and tactile allodynia in a dose-related fashion. [Ser1]histogranin injected intrathecally prior to NMDA injections dose dependently attenuated or completely blocked hyperalgesia and allodynia. In addition, [Ser1]histogranin administration following NMDA-induction of abnormal pain behaviors reversed these effects. These results demonstrate that a naturally derived adrenal medullary neuropeptide can prevent and reverse NMDA-mediated spinal hyperexcitability. The distinct profile and robust activity of [Ser1]histogranin suggest novel alternative approaches in the management of pain and other CNS disorders involving abnormal excitatory neurotransmission.