Inhibition by the chromaffin cell-derived peptide serine-histogranin in the rat's dorsal horn

The heptadecapeptide histogranin, synthesized by adrenal chromaffin cells, is implicated in the analgesia produced by transplanting chromaffin cells into the spinal cord, including block of hyperalgesia mediated by NMDA-subtype glutamate receptors. To examine the neurophysiological basis for this analgesia, we applied the stable analog [Ser 1]-histogranin (SHG) by iontophoresis near extracellularly recorded wide-dynamic range (WDR) neurons in anesthetized rats. When SHG was applied during peripheral electrical stimulation of A and C fibers at 0.1 Hz, the C-fiber response was significantly inhibited but the A-fiber response was unaffected. SHG also opposed the NMDA-receptor-dependent post-tetanic facilitation (wind-up) of C-fiber responses produced by increasing the rate of peripheral afferent stimulation to 1 Hz for 20 s. To test whether block of NMDA-subtype receptors could be wholly or partially responsible for this suppression, SHG was applied during sequential pulsed iontophoresis of three agonists targeting distinct excitatory synaptic receptors: NMDA, kainate and substance P. All three excitatory effects were reversed by SHG; this reversal outlasted the 10–30 min observation period when higher SHG doses were applied (>60 nA). Histogranin therefore probably produces prolonged spinal analgesia by opposing the basal and potentiating synaptic effects of C-fibers on dorsal horn neurons. Actions besides or in addition to NMDA-receptor antagonism (e.g., agonism at inhibitory postsynaptic receptors or block of voltage-gated cation channels on C-fibers) are implied by the diversity of excitatory transmitters opposed by SHG.