Histogranin, a modified histone h4 fragment endowed with N-methyl-D-aspartate antagonist and immunostimulatory activities

2007

Neuroscience Letters

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 NMDAreceptor-dependent post-tetanic facilitation (wind-up) of C-fiber responses produced by increasing the rate of peripheral afferent stimulation to 1 Hz for 20 seconds. To test whether block of NMDAsubtype 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 minute 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 voltagegated cation channels on C-fibers) are implied by the diversity of excitatory transmitters opposed by SHG.

Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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

Hentall

Hargraves

2007

Neuroscience Letters

“…[Ser 1 ]histogranin has demonstrated antinociceptive effects in various animal models of cutaneous hypersensitivity via blockade of the NMDA receptor, but efficacy could also be mediated through other mechanisms (Hama et al, 1999; Hentall et al, 2007; Lemaire et al, 1995; Ruan and Lemaire, 2001). The lack of significant efficacy could be due to the absence in SCI rats of the substrate upon which [Ser 1 ]histogranin acts in other pain models.…”

Section: Discussionmentioning

confidence: 99%

Combinations of intrathecal gamma-amino-butyrate receptor agonists and N-methyl-d-aspartate receptor antagonists in rats with neuropathic spinal cord injury pain

Hama

European Journal of Pharmacology

2012

Underlying below-level cutaneous hypersensitivity observed following spinal cord injury (SCI) is a concurrent loss of inhibition with an increase in excitation in the spinal dorsal horn. Thus, a dual pharmacological approach, increasing spinal γ-aminobutyrate (GABA) inhibition and decreasing N-methyl-D-aspartate (NMDA) receptor-mediated excitation, could be more beneficial than either approach alone. The current study evaluated the antinociceptive effects of lumbar intrathecal (i.t.) administration of GABA receptor agonists and NMDA receptor antagonists alone and in combination in rats with neuropathic SCI pain. Rats developed markedly decreased hind paw withdrawal thresholds following an acute thoracic spinal cord compression, indicative of below-level hypersensitivity. Separately, i.t. GABAA receptor agonist muscimol and GABAB receptor agonist baclofen demonstrated dose-dependent antinociception, whereas i.t. NMDA receptor antagonist ketamine and the endogenous peptide [Ser1]histogranin, a putative NMDA receptor antagonist, demonstrated no efficacy. The combination of baclofen and ketamine resulted in a supra-additive (synergistic) antinociception whereas the combinations with muscimol were merely additive. Intrathecal pretreatment with the GABAB receptor antagonist CGP 35348 prevented the antinociceptive effect of the baclofen and ketamine combination. The data indicate that blocking spinal NMDA receptors alone is not sufficient to ameliorate SCI hypersensitivity, whereas a combined approach, simultaneous activation of spinal GABAB receptors and NMDA receptors blockade with ketamine, leads to significant antinociception. By engaging diverse pain modulating systems at the spinal level, combination drug treatment may be a useful approach in treating neuropathic SCI pain.

“…In addition, chromaffin cells release the 15‐amino acid peptide histogranin (HG), a NMDA receptor antagonist, which has been shown to be antinociceptive in rat models of chronic pain but has no effect on acute nociception, similar to small‐molecule NMDA receptor antagonists (Lemaire et al. ; Siegan et al. ).…”

Section: Introductionmentioning

confidence: 99%

Selective antinociceptive effects of a combination of the N‐methyl‐D‐aspartate receptor peptide antagonist [Ser¹]histogranin and morphine in rat models of pain

Hama

Pharmacology Res & Perspec

2014

Numerous rather than a few analgesic endogenous neuropeptides are likely to work in concert in vivo in ameliorating pain. Identification of effective neuropeptide combinations would also facilitate the development of gene or cell-based analgesics. In this study, opioid peptides endomorphin-1 (EM-1) and endomorphin-2 (EM-2) and the peptide histogranin analogue [Ser1]histogranin (SHG), which possess activity as an N-methyl-d-aspartate (NMDA) receptor antagonist, were intrathecally (i.t.) injected alone and in combination in rat models of acute and persistent pain. None of the peptides when injected alone altered hind paw responses of uninjured rats to acute noxious stimulation. EM-1 and EM-2 showed divergent efficacies in the persistent pain models. For example, EM-1 injected alone was antinociceptive in rats with neuropathic pain, whereas EM-2 demonstrated no efficacy. Demonstration of synergism was also divergent across the models. For example, while SHG combined with EM-1 did not alter the efficacy of EM-1 in rats with neuropathic pain, SHG significantly increased the efficacy of EM-1 in the formalin test. By contrast, the potency and efficacy of the peptides alone and combinations were much less than those of the reference analgesic morphine. Furthermore, morphine combined with the clinically used NMDA receptor antagonist ketamine showed synergism across a broad range of pain states. While the current set of neuropeptides could serve as a basis for analgesic therapeutics, there could be other neuropeptides with greater efficacy and potency and broader therapeutic application.