Stereoselectivity of opiate antagonists in rat hippocampus and neocortex: Responses to (+) and (−) isomers of naloxone

doi:10.1016/0306-4522(82)90027-6

Neuroscience

Volume 7, Issue 7, July 1982, Pages 1691-1702

https://doi.org/10.1016/0306-4522(82)90027-6 Get rights and content

Abstract

The relative potencies of the (+) and (−) isomers of naloxone in antagonizing electrophysiological responses to d-alanine²-methionine enkephalinamide were compared in rat frontal cortex and hippocampus. In the in vitro hippocampus, the (−) isomer was found to be at least a 100 times more potent than the (+) isomer in antagonizing opiate-induced changes in field potentials. Similar stereoselectivity was observed in vivo in both frontal cortex and hippocampus in terms of the antagonism of enkephalin-induced changes in spontaneous cell firing. The direct effects of (+) and (−)-naloxone were examined as well. In hippocampus both in vivo and in vitro, no differential effect was observed, whereas in the neocortex (−)-naloxone was considerably more potent than the (+) isomer in eliciting depressions of spontaneous activity. These direct effects of naloxone in the cortex do not appear to be due to an antagonism of the effects of endogenously released opioids.

These results demonstrate that the stereoselectivity of naloxone isomers in antagonizing electrophysio logical responses to opiates in the cortex and hippocampus parallels that previously observed in other brain regions and in other tissues. In addition, they suggest that naloxone may have interactions with other unknown opiate (or possibly non-opiate) receptors which are of physiological significance.

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Long-term potentiation (LTP) of mossy fiber responses in area CA3 of the rat hippocampus in vivo is blocked by naloxone, an opioid receptor antagonist, in a stereospecific and dose-dependent manner. LTP of commissural afferents to the same population of CA3 pyramidal cells is not attenuated by naloxone. This suggests that opioid receptors are involved in a mechanism of LTP induction that is specific to mossy fiber synapses, and that endogenous opioid peptides, presumably released as a result of mossy fiber stimulation, may be necessary for the induction of mossy fiber LTP. The naloxone sensitivity is limited to the induction phase of LTP, since naloxone does not reverse previously established LTP. These data suggest that LTP at the mossy fiber-CA3 synapse constitutes an NMDA receptor-independent, opioid receptor-dependent, form of hippocampal synaptic plasticity.
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Endogenous opioid systems (i.e., endogenous opioids and opioid receptors) act in the trophic regulation of biological development. Opioid antagonist paradigms have served to elucidate the nature of this relationship. If growth is mediated at the level of the opioid receptor, one would expect that this interaction would be stereospecific. This study shows that daily injections of 20–60 mg/kg (−) naloxone, given chronically throughout the preweaning period, depress body weight when monitored at Day 21. Opioid challenge experiments using nociceptive measures show that these dosages of (−) naloxone invoked an opioid receptor blockade for no more than 10–12 hr/day. A dosage of 100 mg/kg (−) naloxone, which blocked the opioid receptor for 12–16 hr/day, did not alter body weight in comparison to control levels. In subsequent experiments, 40 mg/kg (−) naloxone depressed body weight of 21-day-old rats, and the wet weights of the liver, spleen, thymus, heart, and triceps surae muscle from these animals were subnormal. A dosage of 40 mg/kg (+) naloxone did not alter growth. These results show that opioid action in regard to growth is stereospecific and dependent on the duration of opioid receptor blockade, providing additional evidence that endogenous opioid systems play an important role in developmental events.

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Stereoselectivity of opiate antagonists in rat hippocampus and neocortex: Responses to (+) and (−) isomers of naloxone

Abstract

Trends Neurosci.

Eur. J. Pharm.

Brain Res.

Pain

Neuropharmacology

Brain Res.

Brain Res.

Life Sci.

Brain Res.

Brain Res.

Life Sci.

Life Sci.

Neuropharmacology

Neuropharmacology

Neuropharmacology

Brain Res. Bull.

Brain Res.

Interhippocampal impulses—II. Apical dendritic activation of CA1 neurons

Acta physiol. scand.

Unit analysis of the hippocampal population spike

Expl Brain Res.

Effects of microiontophoretically-applied methionine enkephalin on single neurons in rat brainstem

Nature, Lond.

Differential regulation by guanine nucleotides of opiate agonist and antagonist receptor interactions

J. Neurochem.

Substance P and opiate receptors

Nature, Lond.