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Background: Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment. Methods: Literature search includes the most relevant repositories for medical scientific literature from inception until November, 24 2021. Data collection and selection of retrieved records adhere to PRISMA criteria. Results: In agreement with a priori established protocol the search retrieved 2471 records leaving 479 results after duplicates removal. Eleven records result from title and abstract screening to meet the inclusion criteria; only 4 results are eligible for inclusion in the qualitative synthesis impeding meta-analysis. The qualitative analysis highlights the antinociceptive and anti-inflammatory efficacy of Δ8-tetrahydrocannabinol, cannabidiol and its derivative HU-308 and of new racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229. Moreover, CB2R agonists RO6871304 and RO6871085 and CB2R ligand HU910 provide evidence of anti-inflammatory efficacy. CB2 agonist HU308 reduces of 241% uveitis-induced leukocyte adhesion and changes lipidome profile. Methodological and design issues raise concern of risk of bias and the amount of studies is too small for generalization. Furthermore, the ocular pain model used can resemble only inflammatory but not neuropathic pain. Conclusions: The role of the endocannabinoid system in ocular pain is underinvestigated, since only two studies assessing the effects of cannabinoid receptors modulators on pain behavior and other two on pain-related inflammatory processes are found. Preclinical studies investigating the efficacy of cannabinoids in ocular inflammatory and neuropathic pain models are needed to pave the way for clinical translation.

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.

Introduzione: Bambini con comportamenti disattenti/iperattivi sono descritti in letteratura come avversi ai coetanei, al punto di essere ripetutamente esclusi dal gruppo dei pari (Ladd, 2006; Mrung et al., 2012). A sua volta, l’assenza di coinvolgimento in relazioni tra pari pare contribuire allo sviluppo di stati d’ansia (Gulay, 2011). Attualmente, la letteratura sembra scarna sul trovare un punto esplicativo tra i due fenomeni. Obiettivo dello studio è quello di indagare la relazione intercorrente tra le variabili Disattenzione/Iperattività, Esclusione dai pari e Ansia mostrate in contesto classe. In particolare, si ipotizza che alti livelli di Iperattività siano associati ad alti livelli di Ansia, e che questa relazione sia mediata dalla frequenza dell’Esclusione dai pari. Metodo: 116 bambini dai 7 agli 11 anni (M=9; DS=1.05; 54 F) hanno preso parte alla ricerca condotta nelle classi III e V di tre scuole primarie, della provincia di Napoli (33%), Latina (48%) e Caserta (19%). Previo consenso informato, gli insegnanti hanno osservato i comportamenti dei bambini in contesto classe, compilando la Child Behaviour Scale (CBS; Marcone & Costanzo, 2013), al fine di valutare la frequenza di tre dimensioni comportamentali: 1. Disattenzione/Iperattività; 2. Esclusione dai pari; 3. Ansia. È stata effettuata un’analisi della correlazione al fine di valutare l’associazione tra le variabili; successivamente, è stata condotta un’analisi della mediazione secondo i Four Steps di Kenny (2018), al fine di valutare l’effetto mediatore dell’Esclusione dai pari sulla relazione tra Disattenzione/Iperattività e Ansia. Risultati: La Disattenzione/Iperattività correla significativamente e positivamente con i livelli di ansia (r = .26; p < .01) e l’Esclusione dai pari (r = .35; p < .001); quest’ultima correla positivamente e significativamente con l’Ansia (r = .48; p < .001). L’analisi della mediazione evidenzia: un effetto significativo della Disattenzione/Iperattività sull’Esclusione dai pari (a = .35; p < .001; R2 = .12), un effetto significativo di quest’ultima sull’Ansia (b = .45; p < .001; R2 = .24) e un effetto significativo della Disattenzione/Iperattività sull’Ansia (c = .26; p < .01; R2 = .07.) che diviene non significativo all’inserimento del mediatore Esclusione dai pari (c’ = .10; ns). Conclusioni: L’ipotesi secondo cui la relazione tra Iperattività ed Ansia possa essere mediata dalla frequenza dell’Esclusione dai pari è stata confermata. La frequenza dell’esclusione dai pari in classe media l’influenza che l’iperattività ha sull’ansia. In tal senso, l’aumento dei livelli di ansia mostrati in classe dai bambini potrebbe dipendere più dalle dinamiche relazionali del gruppo classe che dai comportamenti disattenti e iperattivi in sé. Risulta utile fornire agli insegnanti strumenti necessari per osservare tali dinamiche e adattare le metodiche didattiche ai fenomeni sociali del gruppo classe.

Chronic pain is associated with cognitive deficits. Palmitoylethanolamide (PEA) has been shown to ameliorate pain and pain-related cognitive impairments by restoring glutamatergic synapses functioning in the spared nerve injury (SNI) of the sciatic nerve in mice. SNI reduced mechanical and thermal threshold, spatial memory and LTP at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway. It decreased also postsynaptic density, volume and dendrite arborization of DG and increased the expression of metabotropic glutamate receptor 1 and 7 (mGluR1 and mGluR7), of the GluR1, GluR1s845 and GluR1s831 subunits of AMPA receptor and the levels of glutamate in the DG. The level of the endocannabinoid 2-arachidonoylglycerol (2-AG) was instead increased in the LEC. Chronic treatment with PEA, starting from when neuropathic pain was fully developed, was able to reverse mechanical allodynia and thermal hyperalgesia, memory deficit and LTP in SNI wild type, but not in PPAR? null, mice. PEA also restored the level of glutamate and the expression of phosphorylated GluR1 subunits, postsynaptic density and neurogenesis. Altogether, these results suggest that neuropathic pain negatively affects cognitive behavior and related LTP, glutamatergic synapse and synaptogenesis in the DG. In these conditions PEA treatment alleviates pain and cognitive impairment by restoring LTP and synaptic maladaptative changes in the LEC-DG pathway. These outcomes open new perspectives for the use of the N-acylethanolamines, such as PEA, for the treatment of neuropathic pain and its central behavioural sequelae.

Over the last decade the scarcity of protein sources in the modern world lead to increased research studies on the use of insect meal in animal (De Marco et al. 2015; Biasato et al. 2016) and human nutrition (Payne et al. 2016, Stoops et al. 2016).The aim of this study was to assess the response of intestinal mucosa in poultry to dietary Tenebrio molitor (TM) meal supplementation.