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

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

doi:10.3390/ijms20071757

Cited by 19 publications

(17 citation statements)

References 75 publications

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“…PEA has no unfavorable effects at pharmacological doses [97]. In addition, several experimental works showed the beneficial effects of new PEA formulations (micronized or ultramicronized) in carrageenan-induced inflammation [98] on cognitive decline associated to neuropathic pain [99] in an Alzheimer disease model [100], tibia fracture mouse model [101], and diabetic neuropathy [102]. Recent observational clinical studies reported the beneficial use of ultramicronized PEA as an add-on therapy in patients suffering from low back pain [103] as well as in patients suffering from fibromyalgia syndrome (FMS) [104].…”

Section: New Therapeutic Strategiesmentioning

confidence: 99%

Management of Traumatic Brain Injury: From Present to Future

et al. 2020

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TBI (traumatic brain injury) is a major cause of death among youth in industrialized societies. Brain damage following traumatic injury is a result of direct and indirect mechanisms; indirect or secondary injury involves the initiation of an acute inflammatory response, including the breakdown of the blood–brain barrier (BBB), brain edema, infiltration of peripheral blood cells, and activation of resident immunocompetent cells, as well as the release of numerous immune mediators such as interleukins and chemotactic factors. TBI can cause changes in molecular signaling and cellular functions and structures, in addition to tissue damage, such as hemorrhage, diffuse axonal damages, and contusions. TBI typically disturbs brain functions such as executive actions, cognitive grade, attention, memory data processing, and language abilities. Animal models have been developed to reproduce the different features of human TBI, better understand its pathophysiology, and discover potential new treatments. For many years, the first approach to manage TBI has been treatment of the injured tissue with interventions designed to reduce the complex secondary-injury cascade. Several studies in the literature have stressed the importance of more closely examining injuries, including endothelial, microglia, astroglia, oligodendroglia, and precursor cells. Significant effort has been invested in developing neuroprotective agents. The aim of this work is to review TBI pathophysiology and existing and potential new therapeutic strategies in the management of inflammatory events and behavioral deficits associated with TBI.

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Section: New Therapeutic Strategiesmentioning

confidence: 99%

Management of Traumatic Brain Injury: From Present to Future

et al. 2020

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“…There has been reported a link between neuropathic pain (including diabetic neuropathy) and cognitive deficits in rodents (Kodama et al, 2011;Shiers et al, 2018;Boccella et al, 2019;Liang et al, 2020;Won et al, 2020) and humans (Curatolo et al, 2017;Ojeda et al, 2018;Naranjo et al, 2019). However, current therapies for neuropathic pain have not considered this relationship.…”

Section: Cognitive Deficitsmentioning

confidence: 99%

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

et al. 2020

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Metformin (biguanide) is a drug widely used for the treatment of type 2 diabetes. This drug has been used for 60 years as a highly effective antihyperglycemic agent. The search for the mechanism of action of metformin has produced an enormous amount of research to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagy and pain, among others. It was only up the end of the 1990s and beginning of this century that some of its mechanisms were revealed. Metformin induces its beneficial effects in diabetes through the activation of a master switch kinase named AMP-activated protein kinase (AMPK). Two upstream kinases account for the physiological activation of AMPK: liver kinase B1 and calcium/ calmodulin-dependent protein kinase kinase 2. Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which in turn avoids the phosphorylation of p70 ribosomal protein S6 kinase 1 and phosphatidylinositol 3kinase/protein kinase B signaling pathways and reduces cap-dependent translation initiation. Since metformin is a disease-modifying drug in type 2 diabetes, which reduces the mTORC1 signaling to induce its effects on neuronal plasticity, it was proposed that these mechanisms could also explain the antinociceptive effect of this drug in several models of chronic pain. These studies have highlighted the efficacy of this drug in chronic pain, such as that from neuropathy, insulin resistance, diabetic neuropathy, and fibromyalgia-type pain. Mounting evidence indicates that chronic pain may induce anxiety, depression and cognitive impairment in rodents and humans. Interestingly, metformin is able to reverse some of these consequences of pathological pain in rodents. The purpose of this review was to analyze the current evidence about the effects of metformin in chronic pain and three of its comorbidities (anxiety, depression and cognitive impairment).

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“…Bahi showed that systemic injection of mGlu8 receptor agonist decreases voluntary ethanol intake and ethanol-induced CPP in C57BL/6J mice [ 58 ]. Several studies have suggested that mGlu8 receptors are involved in associative learning [ 59 , 60 ]. Associative learning and synaptic long-term potentiation (LTP) depend on the same cellular mechanisms [ 61 ], which is consistent with our results regarding the inhibitory role of mGlu8 receptors in morphine induced CPP.…”

Section: Discussionmentioning

confidence: 99%

The effect of the mGlu8 receptor agonist, (S)-3,4-DCPG on acquisition and expression of morphine-induced conditioned place preference in male rats

et al. 2021

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Background The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 μg/0.5 μL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP. Results The results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 μg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP. Conclusions The findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.

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

Cited by 19 publications

References 75 publications

Management of Traumatic Brain Injury: From Present to Future

Management of Traumatic Brain Injury: From Present to Future

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

The effect of the mGlu8 receptor agonist, (S)-3,4-DCPG on acquisition and expression of morphine-induced conditioned place preference in male rats

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