Despite the importance of pain as a warning physiological system, chronic neuropathic pain is frequently caused by damage in the nervous system, followed by persistence over a long period, even in the absence of dangerous stimuli or after healing of injuries. Chronic neuropathic pain affects hundreds of millions of adults worldwide, creating a direct impact on quality of life. This pathology has been extensively characterized concerning its cellular and molecular mechanisms, and the endocannabinoid system (eCS) is widely recognized as pivotal in the development of chronic neuropathic pain. Scientific evidence has supported that phyto-, synthetic and endocannabinoids are efficient for pain management, while strong data arise from the therapeutic use of Cannabis-derived products. The use of medicinal Cannabis products is directed toward not only relieving symptoms of chronic pain, but also improving several aspects of patients’ welfare. Here, we review the involvement of eCS, along with other cellular and molecular elements, in chronic neuropathic pain pathology and how this system can be targeted for pain management.

Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide. Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders. In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimer’s disease, Parkinson’s disease and Multiple Sclerosis’s patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system. In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines.

The endocannabinoid system (ECS) refers to a complex cell-signaling system highly conserved among species formed by numerous receptors, lipid mediators (endocannabinoids) and synthetic and degradative enzymes. It is widely distributed throughout the body including the CNS, where it participates in synaptic signaling, plasticity and neurodevelopment. Besides, the olfactory ensheathing glia (OEG) present in the olfactory system is also known to play an important role in the promotion of axonal growth and/or myelination. Therefore, both OEG and the ECS promote neurogenesis and oligodendrogenesis in the CNS. Here, we investigated if the ECS is expressed in cultured OEG, by assessing the main markers of the ECS through immunofluorescence, western blotting and qRT-PCR and quantifying the content of endocannabinoids in the conditioned medium of these cells. After that, we investigated whether the production and release of endocannabinoids regulate the differentiation of oligodendrocytes co-cultured with hippocampal neurons, through Sholl analysis in oligodendrocytes expressing O4 and MBP markers. Additionally, we evaluated through western blotting the modulation of downstream pathways such as PI3K/Akt/mTOR and ERK/MAPK, being known to be involved in the proliferation and differentiation of oligodendrocytes and activated by CB1, which is the major endocannabinoid responsive receptor in the brain. Our data show that OEG expresses key genes of the ECS, including the CB1 receptor, FAAH and MAGL. Besides, we were able to identify AEA, 2-AG and AEA related mediators palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in the conditioned medium of OEG cultures. These cultures were also treated with URB597 10-9 M, a FAAH selective inhibitor, or JZL184 10-9 M, a MAGL selective inhibitor, which led to the increase in the concentrations of OEA and 2-AG in the conditioned medium. Moreover, we found that the addition of OEG conditioned medium (OEGCM) enhanced the complexity of oligodendrocyte process branching in hippocampal mixed cell cultures and that this effect was inhibited by AM251 10-6 M, a CB1 receptor antagonist. However, treatment with the conditioned medium enriched with OEA or 2-AG did not alter the process branching complexity of premyelinating oligodendrocytes, while decreased the branching complexity in mature oligodendrocytes. We also observed no change in the phosphorylation of Akt and ERK 44/42 in any of the conditions used. In conclusion, our data show that the ECS modulates the number and maturation of oligodendrocytes in hippocampal mixed cell cultures.

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Introdução Mulheres grávidas e puérperas estão sob risco maior para desenvolvimento de doença grave pelo SARS-CoV-2. Além de comprometimento respiratório, estão sujeitas a complicações obstétricas e outras manifestações atípicas. Apresentamos dois casos de gestantes com COVID-19 e cetoacidose euglicêmica. Casos CASO 1: Gestante de 23 anos, 35 semanas de idade gestacional, é admitida na UTI com quadro suspeito de COVID-19. À admissão, encontra-se taquipneica, taquicárdica e hipoxêmica. Gasometria arterial mostrava acidose metabólica grave com ânion gap elevado (pH = 6,81; HCO3 = 8 mEq/L; AG = 27,7 mEq/L). Glicemia de 176 mg/dL. EAS apresentava cetonuria, sem outras alterações. Após avaliação pela Obstetrícia, a paciente foi intubada e a gestação, interrompida, com indução do parto na UTI. Tratamento com solução glicosada intravenosa foi iniciado. Apresentou melhora progressiva, sendo extubada após 11 dias e tendo recebido alta após 25 dias de hospitalização. CASO 2: Gestante de 31 anos, com 31 semanas de idade gestacional, foi admitida na unidade por quadro de febre, congestão nasal, fadiga e dispneia com uma semana de evolução. À admissão, estava discretamente taquipneica, mas sem dessaturação em ar ambiente. Gasometria arterial mostrava acidose metabólica com ânion gap elevado, mas com pH normal (pH = 7,36; HCO3 = 16,9 mEq/L; AG = 16,3 mEq/L). EAS apresentava cetonuria. Solução glicosada intravenosa foi administrada, com correção progressiva da acidose metabólica. A paciente evoluiu com necessidade de ventilação mecânica e de interrupção da gestação. Permaneceu 20 dias intubada, recebendo alta hospitalar após 35 dias. Discussão Cetoacidose euglicêmica é uma condição incomum, mais associada a situações de jejum prolongado. Outros casos de gestantes com COVID-19 que apresentaram o quadro já foram relatados. Aporte nutricional inadequado e sintomas gastrointestinais parecem ser os fatores responsáveis pelo desenvolvimento da cetoacidose em gestantes infectadas pelo SARS-CoV-2, mesmo sem outras condições predisponentes. Esses casos ilustram a necessidade de rastreio da condição e de terapia nutricional adequada durante internação, especialmente nas pacientes que necessitam de oxigenoterapia.