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Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain

1
Department of Experimental Medicine, Pharmacology Division, University of Campania “L. Vanvitelli”, 80138 Naples, Italy
2
Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430-6592, USA
3
Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430-6592, USA
4
Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430-6592, USA
5
Department of Plastic Surgery, University of Campania “L. Vanvitelli”, 80138 Naples, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(7), 1757; https://doi.org/10.3390/ijms20071757
Received: 12 March 2019 / Revised: 3 April 2019 / Accepted: 4 April 2019 / Published: 9 April 2019
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Abstract

This study investigated whether metabotropic glutamate receptor (mGluR) 5 and 8 are involved in the effect of ultramicronizedpalmitoylethanolamide (um-PEA) on the cognitive behavior and long term potentiation (LTP) at entorhinal cortex (LEC)-dentate gyrus (DG) pathway in mice rendered neuropathic by the spare nerve injury (SNI). SNI reduced discriminative memory and LTP. Um-PEA treatment started after the development of neuropathic pain had no effects in sham mice, whereas it restored cognitive behavior and LTP in SNI mice. 2-Methyl-6-(phenylethynyl) pyridine (MPEP), a selective mGluR5 antagonist, improved cognition in SNI mice and produced a chemical long term depression of the field excitatory postsynaptic potentials (fEPSPs) in sham and SNI mice. After theta burst stimulation (TBS) MPEP restored LTP in SNI mice. In combination with PEA, MPEP antagonized the PEA effect on discriminative memory and decreased LTP in SNI mice. The (RS)-4-(1-amino-1-carboxyethyl)phthalic acid (MDCPG), a selective mGluR8 antagonist, did not affect discriminative memory, but it induced a chemical LTP and prevented the enhancement of fEPSPs after TBS in SNI mice which were treated or not treated with PEA. The effect of PEA on LTP and cognitive behavior was modulated by mGluR5 and mGluR8. In particular in the SNI conditions, the mGluR5 blockade facilitated memory and LTP, but prevented the beneficial effects of PEA on discriminative memory while the mGluR8 blockade, which was ineffective in itself, prevented the favorable action of the PEA on LTP. Thus, although their opposite roles (excitatory/inhibitory of the two receptor subtypes on the glutamatergic system), they appeared to be required for the neuroprotective effect of PEA in conditions of neuropathic pain. View Full-Text
Keywords: spared nerve injury; discriminative memory; long term potentiation; lateral entorhinal cortex-dentate gyrus; ultramicronizedpamitoylethanolamide; metabotropic glutamate receptor 5 and 8 spared nerve injury; discriminative memory; long term potentiation; lateral entorhinal cortex-dentate gyrus; ultramicronizedpamitoylethanolamide; metabotropic glutamate receptor 5 and 8
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Boccella, S.; Marabese, I.; Iannotta, M.; Belardo, C.; Neugebauer, V.; Mazzitelli, M.; Pieretti, G.; Maione, S.; Palazzo, E. Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain. Int. J. Mol. Sci. 2019, 20, 1757.

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