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

Serena Boccella,Mariacristina Mazzitelli,Ida Marabese,Monica Iannotta,Enza Palazzo,Gorizio Pieretti,Carmela Belardo,Sabatino Maione,Volker Neugebauer

doi:10.3390/ijms20071757

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.

Highlights

Sensory and cognitive disorders are comorbidities of neuropathic pain in both, humans and rodents [1]
Among the pharmacological strategies for sensory and affective/cognitive disorders associated with neuropathic pain, palmitoylethanolamide (PEA), an endocannabinoid anandamide congener, has shown antinflammatory, analgesic, immunomodulatory and neuroprotective effects and to reverse cognitive impairments associated with several chronic pain conditions [16,17,18] by restoring glutamatergic transmission homeostasis [16,17,19,20,21,22]
We undertook the current study with the aim of assessing the effect of mGluR5 and mGluR8 blockade on cognitive behavior and long term potentiation (LTP) at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway, and whether the beneficial effects of ultramicronized- PEA are affected by mGluR5 and mGluR8 blockade in neuropathic pain conditions

Summary

Introduction

Sensory and cognitive disorders are comorbidities of neuropathic pain in both, humans and rodents [1]. It has been shown that mGluR activation appears indispensable for the endocannabinoid analgesic/neuroprotective action [31,32,33,34,35] and the endocannabinoid-like PEA restored neuropsychiatric behavior by modulating excitatory synapse homeostasis in the medial prefrontal cortex [17] On this basis, we undertook the current study with the aim of assessing the effect of mGluR5 and mGluR8 blockade on cognitive behavior and long term potentiation (LTP) at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway, and whether the beneficial effects of ultramicronized (um)- PEA are affected by mGluR5 and mGluR8 blockade in neuropathic pain conditions. Shaping glutamate transmission malfunctioning through mGluR manipulation may represent a strategy for ameliorating the beneficial effects of neuroprotective agents such as PEA in chronic and untreatable pain conditions

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Results

Discussion

Conclusion