PEA-OXA restores cognitive impairments associated with vitamin D deficiency-dependent alterations of the gut microbiota.

There is a growing evidence suggesting the association of vitamin D deficiency (VDD) and cognitive impairment. In this study we evaluated the possible involvement of gut microbiota in the cognitive impairments mediated by VDD and investigated the effects of pharmacological treatment with the oxazoline derivative of the aliamide palmitoylethanolamide, 2-Pentadecyl-2-oxazoline (PEA-OXA). Mice were submitted to behavioural, biochemical and electrophysiological analysis to assess whether their vitamin D status affected cognitive performance together with gut microbiota composition. In VDD mice we found cognitive malfunctioning associated with reduced neuroplasticity, indicated by impaired long term potentiation, and neuroinflammation at the hippocampal level. Importantly, PEA-OXA counteracted the cognitive impairments and modified the biochemical and functional changes induced by VDD. Additionally, PEA-OXA treatment enhanced gut microbiota diversity, which tended to be decreased by VDD only in female mice, elevated the relative abundance of lactic and butyric acid-producing families, i.e. Aerococcaceae and Butyricicoccaceae, and reversed the VDD-induced decrease of butyrate-producing beneficial genera, such as Blautia in female mice, and Roseburia in male mice. These data provide novel insights for a better understanding of the cognitive decline induced by VDD and related gut dysbiosis and its potential therapeutic treatment.

Affective and Cognitive Impairments in Rodent Models of Diabetes.

Diabetes and related acute and long-term complications have a profound impact on cognitive, emotional, and social behavior, suggesting that the central nervous system (CNS) is a crucial substrate for diabetic complications. When anxiety, depression, and cognitive deficits occur in diabetic patients, the symptoms and complications related to the disease worsen, contributing to lower quality of life while increasing health care costs and mortality. Experimental models of diabetes in rodents are a fundamental and valuable tool for improving our understanding of the mechanisms underlying the close and reciprocal link between diabetes and CNS alterations, including the development of affective and cognitive disorders. Such models must reproduce the different components of this pathological condition in humans and, therefore, must be associated with affective and cognitive behavioral alterations. Beyond tight glycemic control, there are currently no specific therapies for neuropsychiatric comorbidities associated with diabetes; animal models are, therefore, essential for the development of adequate therapies. To our knowledge, there is currently no review article that summarizes changes in affective and cognitive behavior in the most common models of diabetes in rodents. Therefore, in this review, we have reported the main evidence on the alterations of affective and cognitive behavior in the different models of diabetes in rodents, the main mechanisms underlying these comorbidities, and the applicable therapeutic strategy.

The long-term exercise after traumatic brain injury: Reharmonizing brain by sound body.

Traumatic brain injuries (TBI) refer to multiple acquired dysfunctions arising from damage to the brain caused by an external force, including rapid acceleration/deceleration and concussion. Among them, mild TBI (mTBI) accounts for most cases (up to 90%) of injuries. It is responsible for a variety of symptoms, including anxiety, depression, and cognitive impairments that remain difficult to be treated. It has been reported that regular physical activity, as well as, improving life quality, display a neuroprotective function, suggesting a possible role in post-traumatic rehabilitation. In this study, we investigated the effects of treadmill exercise in a mice mTBI model by behavioural, electrophysiological and neurochemical analysis. Daily exercise decreased anxiety, aggressive behavior, and depression in mTBI mice. Accordingly, electrophysiological and neurochemical maladaptive rearrangement occurring in the hippocampus of mTBI mice were prevented by the exercise.

Inhibition of anandamide breakdown reduces pain and restores LTP and monoamine levels in the rat hippocampus via the CB1 receptor following osteoarthritis.

Chronic pain is a persistent, complex condition that contributes to impaired mood, anxiety and emotional problems. Osteoarthritis (OA) is one of the major causes of chronic pain in adults and elderly people. A substantial body of evidence demonstrate that hippocampal neural circuits, especially monoamine dopamine and serotonin levels, contributes to negative affect and avoidance motivation experienced during pain. Current pharmacological strategies for OA patients are unsatisfying and the endocannabinoid system modulation might represent an alternative for the treatment of OA-related pain. In the present study, we used a rat model of osteoarthritis induced by intra-articular injection of sodium monoiodoacetate to assess, 28 days post-induction, the contribution of endocannabinoid system on the possible alteration in pain perception and affective behavior, in LTP and monoamine levels in the lateral entorhinal cortex-dentate gyrus pathway. The results show that OA-related chronic pain induces working memory impairment and depressive-like behavior appearance, diminishes LTP, decreases dopamine levels and increases serotonin levels in the rat dentate gyrus. URB597 administration (i.p., 1 mg/kg) reduces hyperalgesia and mechanical allodynia, improves recognition memory and depressive-live behavior, restores LTP and normalizes monoamine levels in the hippocampus. The effect was observed 60-120 min post-treatment and was blocked by AM251, which proves the action of URB597 via the CB1 receptor. Therefore, our study confirms the role of anandamide in OA-related chronic pain management at the behavioral and hippocampal levels. This article is part of the Special Issue on 'Advances in mechanisms and therapeutic targets relevant to pain'.

Homo-AMPA in the periaqueductal grey modulates pain and rostral ventromedial medulla activity in diabetic neuropathic mice.

The 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)-butyric acid, homo-AMPA, an analog of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and 2-aminoadipic acid, has shown no activity towards ionotropic and metabotropic glutamate 1, 2, 3, 4, 5, and 7 receptors (mGluR1-7), agonist activity at mGluR6 while the activity at mGluR8 was never investigated. The effect of homo-AMPA on pain control has been never investigated. In this study we evaluated the effect of intra-ventrolateral periaqueductal grey (VL PAG) microinjections of homo-AMPA on pain responses and the activity of pain-responding neurons of the rostral ventromedial medulla (RVM), the "pronociceptive" ON cells, and the "antinociceptive" OFF cells. The study was performed in control and diabetic neuropathic mice. Homo-AMPA decreased mechanical allodynia in diabetic neuropathic mice. Homo-AMPA increased also the latency to tail-flick, decreased the ongoing activity, the pain stimulus-evoked burst of firing, and the duration of the burst of the ON cells in both, control and neuropathic mice. Homo-AMPA also increased the ongoing activity, decreased and delayed the pause of the OFF cells in control mice. Unlike the retina, we did not find the transcript and protein for mGluR6 in the VL PAG. Alpha-methyl-serine-O-phosphate, a group III mGluRs antagonist, blocked the anti-allodynic effect of homo-AMPA. Considering the absence of both, mGluR6 in VL-PAG and homo-AMPA activity at mGluR4 and mGluR7 at the dose used, mGluR8 could be the target on which homo-AMPA produces the observed effects. The target of homo-AMPA capable of evoking analgesia at a very low dose and in conditions of diabetic neuropathy deserves further consideration.

MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia.

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP. TH was established through the collagenase-IV injection in thalamic ventral-posterolateral-nucleus. PEALut effects in CPSP-associated behaviors were evaluated during a 28-days observation period. We found that repeated administrations of co-ultra PEALut significantly reduced mechanical hypersensitivity after TH, as compared to vehicle, by reducing the early microglial activation in the perilesional site. Moreover, PEALut prevented the development of depressive-like behavior (21 days post-TH). These effects were associated with the restoration of synaptic plasticity in LEC-DG pathway and monoamines levels found impaired in TH mice. Hippocampal MED1 and TrkB expressions were significantly increased in TH compared to sham mice 21 days post-TH, whereas BDNF levels were decreased. PEALut restored MED1/TrkB/BDNF expression in mice. Remarkably, we found significant overexpression of MED1 in the human autoptic brain specimens after stroke, indicating a translational potential of our findings. These results pave the way for better-investigating depression in TH- induced CPSP, together with the involvement of MED1/TrkB/BDNF pathway, proposing PEALut as an adjuvant treatment.

Vitamin D Deficiency Induces Chronic Pain and Microglial Phenotypic Changes in Mice.

The bioactive form of vitamin D, 1,25-dihydroxyvitamin D (1,25D3), exerts immunomodulatory actions resulting in neuroprotective effects potentially useful against neurodegenerative and autoimmune diseases. In fact, vitamin D deficiency status has been correlated with painful manifestations associated with different pathological conditions. In this study, we have investigated the effects of vitamin D deficiency on microglia cells, as they represent the main immune cells responsible for early defense at central nervous system (CNS), including chronic pain states. For this purpose, we have employed a model of low vitamin D intake during gestation to evaluate possible changes in primary microglia cells obtained from postnatal day(P)2-3 pups. Afterwards, pain measurement and microglia morphological analysis in the spinal cord level and in brain regions involved in the integration of pain perception were performed in the parents subjected to vitamin D restriction. In cultured microglia, we detected a reactive-activated and proliferative-phenotype associated with intracellular reactive oxygen species (ROS) generation. Oxidative stress was closely correlated with the extent of DNA damage and increased ß-galactosidase (B-gal) activity. Interestingly, the incubation with 25D3 or 1,25D3 or palmitoylethanolamide, an endogenous ligand of peroxisome proliferator-activated-receptor-alpha (PPAR-α), reduced most of these effects. Morphological analysis of ex-vivo microglia obtained from vitamin-D-deficient adult mice revealed an increased number of activated microglia in the spinal cord, while in the brain microglia appeared in a dystrophic phenotype. Remarkably, activated (spinal) or dystrophic (brain) microglia were detected in a prominent manner in females. Our data indicate that vitamin D deficiency produces profound modifications in microglia, suggesting a possible role of these cells in the sensorial dysfunctions associated with hypovitaminosis D.

2-Pentadecyl-2-oxazoline ameliorates memory impairment and depression-like behaviour in neuropathic mice: possible role of adrenergic alpha2- and H3 histamine autoreceptors.

Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14 days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine level alterations after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain.

Methods for Evaluating Sensory, Affective and Cognitive Disorders in Neuropathic Rodents.

The animal models of neuropathic pain that faithfully reproduce the symptoms that occur in humans are a fundamental tool for understanding the mechanisms underlying the disease, identifying new targets, and developing effective drugs. So far, the studies aimed at describing the animal models of neuropathic pain have been focused mainly on the sensory symptoms associated with the disease consisting of mechanical allodynia and hyperalgesia, cold allodynia and hyperalgesia, and heat hyperalgesia. However, affective and cognitive comorbidities occur in patients suffering from neuropathic pain, arising in a closely associated and dependent manner on the sensory symptoms. The same occurs in animal models of neuropathic pain in which anxiety- and depressive- like behaviors and cognitive disorders are observable at different time points from the induction of neuropathy. Today there are several tests available that exploit different paradigms in rodents for measuring sensorial, affective, and cognitive behavior. This review will describe those mainly used in the scientific community. The tests mainly used are based on the motor activity of the animals tested, so it is fundamental that it remains unaffected in the model used for inducing neuropathic pain. We hope that this review will be useful to the scientific community to direct the choice towards the best, most suitable, and simplest tests for the study of the sensory, affective, and cognitive symptoms associated with neuropathic pain.

Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain.

Neuropathic pain is a pathological condition induced by a lesion or disease affecting the somatosensory system, with symptoms like allodynia and hyperalgesia. It has a multifaceted pathogenesis as it implicates several molecular signaling pathways involving peripheral and central nervous systems. Affective and cognitive dysfunctions have been reported as comorbidities of neuropathic pain states, supporting the notion that pain and mood disorders share some common pathogenetic mechanisms. The understanding of these pathophysiological mechanisms requires the development of animal models mimicking, as far as possible, clinical neuropathic pain symptoms. Among them, the Spared Nerve Injury (SNI) model has been largely characterized in terms of behavioral and functional alterations. This model is associated with changes in neuronal firing activity at spinal and supraspinal levels, and induces late neuropsychiatric disorders (such as anxious-like and depressive-like behaviors, and cognitive impairments) comparable to an advanced phase of neuropathy. The goal of this review is to summarize current findings in preclinical research, employing the SNI model as a tool for identifying pathophysiological mechanisms of neuropathic pain and testing pharmacological agent.

Altered gut microbiota and endocannabinoid system tone in vitamin D deficiency-mediated chronic pain.

Recent evidence points to the gut microbiota as a regulator of brain and behavior, although it remains to be determined if gut bacteria play a role in chronic pain. The endocannabinoid system is implicated in inflammation and chronic pain processing at both the gut and central nervous system (CNS) levels. In the present study, we used low Vitamin D dietary intake in mice and evaluated possible changes in gut microbiota, pain processing and endocannabinoid system signaling. Vitamin D deficiency induced a lower microbial diversity characterized by an increase in Firmicutes and a decrease in Verrucomicrobia and Bacteroidetes. Concurrently, vitamin D deficient mice showed tactile allodynia associated with neuronal hyperexcitability and alterations of endocannabinoid system members (endogenous mediators and their receptors) at the spinal cord level. Changes in endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were also observed in the duodenum and colon. Remarkably, the anti-inflammatory anandamide congener, palmitoylethanolamide, counteracted both the pain behaviour and spinal biochemical changes in vitamin D deficient mice, whilst increasing the levels of Akkermansia, Eubacterium and Enterobacteriaceae, as compared with vehicle-treated mice. Finally, induction of spared nerve injury in normal or vitamin D deficient mice was not accompanied by changes in gut microbiota composition. Our data suggest the existence of a link between Vitamin D deficiency - with related changes in gut bacterial composition - and altered nociception, possibly via molecular mechanisms involving the endocannabinoid and related mediator signaling systems.

The Modulation of Pain by Metabotropic Glutamate Receptors 7 and 8 in the Dorsal Striatum.

The dorsal striatum, apart from controlling voluntary movement, displays a recently demonstrated pain inhibition. It is connected to the descending pain modulatory system and in particular to the rostral ventromedial medulla through the medullary dorsal reticular nucleus. Diseases of the basal ganglia, such as Parkinson's disease, in addition to being characterized by motor disorders, are associated with pain and hyperactivation of the excitatory transmission. A way to counteract glutamatergic hyperactivation is through the activation of group III metabotropic glutamate receptors (mGluRs), which are located on presynaptic terminals inhibiting neurotransmitter release. So far the mGluRs of group III have been the least investigated, owing to a lack of selective tools. More recently, selective ligands for each mGluR of group III, in particular positive and negative allosteric modulators, have been developed and the role of each subtype is starting to emerge. The neuroprotective potential of group III mGluRs in pathological conditions, such as those characterized by elevate glutamate, has been recently shown. In the dorsal striatum, mGluR7 and mGluR8 are located at glutamatergic corticostriatal terminals and their stimulation inhibits pain in pathological conditions such as neuropathic pain. The two receptors in the dorsal striatum have instead a different role in pain control in normal conditions. This review will discuss recent results focusing on the contribution of mGluR7 and mGluR8 in the dorsal striatal control of pain. The role of mGluR4, whose antiparkinsonian activity is widely reported, will also be addressed.

Oral Cannabidiol Prevents Allodynia and Neurological Dysfunctions in a Mouse Model of Mild Traumatic Brain Injury.

Neurological dysfunctions are the most impactful and persistent consequences of traumatic brain injury (TBI). Indeed, previous reports suggest that an association between TBI and chronic pain syndromes, as well anxio-depressive behaviors, tends to be more common in patients with mild forms of TBI. At present, no effective treatment options are available for these symptoms. In the present study, we used a weight drop mild TBI mouse model to investigate the effect of a commercially available 10% Cannabidiol (CBD) oil on both the sensorial and neuropsychiatric dysfunctions associated with mild TBI through behavioral and biomolecular approaches. TBI mice developed chronic pain associated with anxious and aggressive behavior, followed by a late depressive-like behavior and impaired social interaction. Such behaviors were related with specific changes in neurotransmitters release at cortical levels. CBD oral treatment restored the behavioral alterations and partially normalized the cortical biochemical changes. In conclusion, our data show some of the brain modifications probably responsible for the behavioral phenotype associated with TBI and suggest the CBD as a pharmacological tool to improve neurological dysfunctions caused by the trauma.

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

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.

Metabotropic glutamate receptor subtype 7 in the dorsal striatum oppositely modulates pain in sham and neuropathic rats.

The study investigated the role of the metabotropic glutamate receptor subtype 7 (mGluR7) in pain signalling in the dorsal striatum of sham and neuropathic rats. Supraspinal circuitries involved in the dorsal striatum control of pain were also explored. In the sham rats, microinjection of N,N'-bis(diphenylmethyl)-1,2-ethanediamine (AMN082), a selective mGluR7 positive allosteric modulator, into the dorsal striatum, facilitated pain, increased the activity of the ON cells and inhibited the activity of the OFF cells in the rostral ventromedial medulla, and decreased glutamate levels in the dorsal striatum. Conversely, AMN082 inhibited pain and the activity of the ON cells while increased the activity of the OFF cells in rats with spared nerve injury (SNI) of the sciatic nerve. AMN082 also decreased glutamate levels in the dorsal striatum of SNI rats. The effect of AMN082 on mechanical allodynia and glutamate release was blocked by 6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydro-4(5H)-benzoxazolone (ADX71743), a selective mGluR7 negative allosteric modulator. Moreover, in the sham rats, AMN082 increased the activity of total nociceptive convergent neurons in the dorsal reticular nucleus while in the SNI rats, such activity was decreased. The administration of lidocaine into the subthalamic nucleus abolished the effect of AMN082 on the total nociceptive convergent neurons in the sham rats but not in the SNI rats. Thus, the dual effect of mGluR7 in facilitating or inhibiting pain responses may be due to the recruitment of different pathways of the basal ganglia, the indirect or direct pathway, in physiological or pathological conditions, respectively.

Spared Nerve Injury as a Long-Lasting Model of Neuropathic Pain.

This chapter describes surgical procedures for the induction of neuropathic pain using an animal model (rat or mouse) of spared nerve injury. In addition to technical details of the surgical technique, details of anesthesia and perioperative care are also included.

d-Aspartic acid ameliorates painful and neuropsychiatric changes and reduces ß-amyloid Aß1-42 peptide in a long lasting model of neuropathic pain.

Depressive symptoms and other neuropsychiatric dysfunctions are common in neurodegenerative disorders, including chronic pain and dementia. A correlation between the ß-amyloid protein accumulation and the development of depression has been suggested, however the underlying mechanisms are unknown. d-Aspartate (d-Asp) is a free d-amino acid found in the mammalian brain and involved in neurological and psychiatric processes, such as cognition and affective disorders. In this study we have investigated the effects of a repeated treatment with d-Asp in a long-lasting (12 months) model of neuropathic pain, the spared nerve injury (SNI), in mice. Specifically, we evaluated i) the pain sensitivity and related emotional/cognitive dysfunctions induced by SNI, ii) possible changes in the ß-amyloid protein accumulation in specific brain regions involved in pain mechanisms ii) possible changes in steroids level in neuropathic animals with or without d-Asp in the same brain areas. SNI mice showed an increase of the insoluble form of Aß1-42 at hippocampal level and displayed cognitive impairments, stereotypical and depressive-like behaviours. d-Asp treatment reduced abnormal behaviours and normalized the ß-amyloid protein expression. Moreover, d-Asp dramatically increased steroids level measured in the prefrontal cortex and in the hippocampus. Our findings provide new insights into pain mechanisms and suggest a possible role of ß-amyloid protein in neuropsychiatric dysfunctions associated with chronic pain.

Nociception modulation by supraspinal group III metabotropic glutamate receptors.

The modulatory actions of glutamate, the main excitatory neurotransmitter in the central nervous system (CNS), are exerted through the activation of metabotropic glutamate receptors (mGluRs). Of the eight known mGluRs (mGluR1-8), group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) are less understood because of the lack of selective ligands. Except for mGluR6, group III mGluRs are widely distributed throughout the CNS. They are mainly located on presynaptic terminals where they inhibit neurotransmitter release at glutamatergic and γ-aminobutyric acid (GABA)ergic synapses. Their location at certain synapses is considered critical for normal CNS function, which makes them potential targets in neurological and psychiatric treatments. Novel ligands that are selective for group III mGluR subtypes have recently been developed. These compounds, which mainly target allosteric sites and act as positive or negative allosteric modulators (PAMs or NAMs) of glutamate transmission, are contributing to the understanding of the functional roles of group III mGluRs in a number of pathological conditions, such as epilepsy, anxiety, neurodegenerative diseases, and chronic pain. Moreover, the presence of group III mGluRs throughout the entire pain neuraxis and particularly in the descending system suggests that these endogenous substrates that extend from the cortex to the first spinal synapse are candidates for pain control. Recent data on chronic pain alleviation by group III mGluR ligands encourage further studies as pathological pain is one of the most troublesome diseases because of the current lack of satisfactory therapy. This review summarizes recent studies on group III mGluRs in animal models of chronic pain, which evidence an opposite modulation of mGluR7 and mGluR8 on pain responses and their capability to affect pain responses only in pathological states. This article is part of the special article series "Pain".

Metabotropic Glutamate Receptor 7: From Synaptic Function to Therapeutic Implications.

Metabotropic glutamate receptor 7 (mGluR7) is localized presynaptically at the active zone of neurotransmitter release. Unlike mGluR4 and mGluR8, which share mGluR7's presynaptic location, mGluR7 shows low affinity for glutamate and is activated only by high glutamate concentrations. Its wide distribution in the central nervous system (CNS) and evolutionary conservation across species suggest that mGluR7 plays a primary role in controlling excitatory synapse function. High mGluR7 expression has been observed in several brain regions that are critical for CNS functioning and are involved in neurological and psychiatric disorder development. Until the recent discovery of selective ligands for mGluR7, techniques to elucidate its role in neural function were limited to the use of knockout mice and gene silencing. Studies using these two techniques have revealed that mGluR7 modulates emotionality, stress and fear responses. N,N`-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) was reported as the first selective mGluR7 allosteric agonist. Pharmacological effects of AMN082 have not completely confirmed the mGluR7-knockout mouse phenotype; this has been attributed to rapid receptor internalization after drug treatment and to the drug's apparent lack of in vivo selectivity. Therefore, the more recently developed mGluR7 negative allosteric modulators (NAMs) are crucial for understanding mGluR7 function and for exploiting its potential as a target for therapeutic interventions. This review presents the main findings regarding mGluR7's effect on modulation of synaptic function and its role in normal CNS function and in models of neurologic and psychiatric disorders.