N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin

doi:10.1016/0091-3057(94)00247-G

Pharmacology Biochemistry and Behavior

Volume 50, Issue 1, January 1995, Pages 49-54

https://doi.org/10.1016/0091-3057(94)00247-G Get rights and content

Abstract

The behavioral and pharmacologic profiles of [Ser¹]histogranin ([Ser¹]HN) were assessed by monitoring its ability to displace the binding of the specific N-methyl-D-aspartate (NMDA) receptor ligand, [³H]CGP 39653, to block the convulsant effects of NMDA and other excitatory agents in mice, and to produce phencyclidine (PCP)-like behavioral effects in rats. The peptide potently inhibited [³H]CGP 39653 binding to membrane preparations of rat brain with an IC₅₀ of 198 nM and a maximal inhibition of 34% of the specific binding activity. Saturation binding experiments with [³H]CGP 39653 in the absence and presence of [Ser¹]HN (2 μM) indicated that the inhibitory effect of the peptide was noncompetititive, producing a decrease in the maximal number of binding sites (B_max of 62.5 fmol/mg protein as compared with 91.3 fmol/mg protein in control), but no significant change in the affinity (K_d of 4.5 nM as compared with 5.1 nM in control). Intracerebroventricular (ICV) injection of [Ser¹]HN (10–100 nmol) in mice evoked a dose-dependent and selective blockade of NMDA-induced convulsions. In rats, [Ser¹]HN (2.5–100 nmol, ICV) produced dose-dependent stereotypy, ataxia, and locomotion similar to those observed with PCP, at doses ranging between 50 and 400 nmol. The data indicate that [Ser¹]HN noncompetitively interacts with the NMDA receptor, an action that goes along with its in vivo NMDA receptor antagonist activity and PCP-like behavioral effects.

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When implanted into the lumbar subarachnoid space, these cells give long-lasting opioid receptor- and α-adrenoceptor-mediated antinociception (Hentall and Sagen, 2000). The adrenal medulla also synthesizes [Ser1]histogranin, a 16-amino acid peptide with a number of pharmacological properties, including possible non-competitive antagonism of the NMDA receptor (Lemaire et al., 1993; Shukla et al., 1995). [ Ser1]histogranin has demonstrated antinociceptive activity in pre-clinical pain models, presumably through the blockade of the NMDA receptor (Hama and Sagen, 2002; Hama et al., 1999; Hentall et al., 2007; Siegan et al., 1997). [
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. GABA_A receptor agonist muscimol and GABA_B 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 GABA_B 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 GABA_B receptors and NMDA receptor 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.
Inhibition by the chromaffin cell-derived peptide serine-histogranin in the rat's dorsal horn
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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 [Ser¹]-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.
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Histogranin reduced brain injury after transient focal ischemia in rats
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Excitatory amino acids (EAAs) play an important role during ischemic brain injury. In this study we examined the protective effect of histogranin (HN), an endogenous peptide that antagonizes excitatory amino acids-mediated activity noncompetitively, in an animal model of cerebral ischemia. Adult rats were anesthetized with chloral hydrate. Histogranin was given intracerebroventricularly before a 60-min middle cerebral artery occlusion (MCAo). Animals were examined for their locomotor activity 2 days after MCAo. Histogranin significantly increased locomotor activity in the stroke rats. Histogranin pretreatment reduced the volume of cerebral infarction and the caspase-3 immunoreactivity in the stroke animals. Taken together, our data suggest that histogranin is protective against ischemic brain injury. The protective effect may involve anti-apoptotic mechanisms.
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Thus, in order to observe robust efficacy in a variety of pain states and obtain the full benefits of this combination strategy, the use of an NMDA receptor antagonist that has fewer side effects than those that are currently available antagonists seems warranted. Histogranin was fist isolated from bovine adrenal medulla but its presence was also detected in various rat tissues including the adrenal and pituitary glands and brain (Lemaire et al., 1995; Shukla et al., 1995). The peptide was identified in chromaffin granules and is released from adrenal glands upon stimulation.
Opiates may be used to attenuate chronic pain, but long-term use is complicated by the possible increase in pain over time, escalating dose requirements, and untoward side effects. Adjuncts such as ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, may be added to opiates to provide more consistent analgesia. However, the unwanted motor side effects of NMDA receptor antagonists prevent their widespread clinical usage. In the current study, an analogue of the naturally-derived peptide histogranin, [Ser¹]histogranin (SHG), an NMDA receptor modulator without adverse side effects like those in current clinical use, was evaluated for its potential to enhance the antinociceptive effect of intrathecal morphine in the rat formalin test. Intrathecal injection of a combination of SHG and morphine resulted in significantly reduced hind paw flinching compared with morphine alone in the first and second phases. The effective dose of SHG used in the combination had no efficacy when tested alone. These results were similar to the increased efficacy that was obtained with a combination of ketamine and morphine. Thus, enhancement of opiate efficacy is possible using a novel peptide NMDA receptor modulator with a potentially improved safety profile.
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ArticleN-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin

Abstract

Brain Res. Bull.

Neurosci. Lett.

Neurosci. Lett.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol. Mol. Pharmacol. Sec.

Exp. Neurol.

Eur. J. Pharmacol.

Accurate freehand injection into the lateral brain ventricle of the conscious mouse

J. Appl. Physiol.

Excitatory amino acid receptors in the vertebrate central nervous system

Pharmacol. Rev.

Kynurenate inhibition of cell excitation decreases stroke size and deficits

Ann. Neurol.

Selective blockade of N-methyl-D-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: Relationship with phencyclidine-like behavioral effects

J. Pharmacol. Exp. Ther.

Article
N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser¹]histogranin