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Fibromyalgia (FM) is a disorder characterized by widespread chronic pain, significant depression, and various neural abnormalities. Recent research suggests a reciprocal exacerbation mechanism between chronic pain and depression. In patients with FM, dysregulation of tryptophan (Trp) metabolism has been identified. Trp, an essential amino acid, serves as a precursor to serotonin (5-HT), a neuromodulator that influences mood, appetite, sleep, and pain perception through the receptors 5-HT1, 5-HT2, and 5-HT3. Additionally, Trp is involved in the kynurenine pathway, a critical route in the immune response, inflammation, and production of neuroactive substances and nicotinamide adenine dinucleotide (NAD+). The activation of this pathway by pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interferon gamma (IFN-γ), leads to the production of kynurenic acid (KYNA), which has neuroprotective properties, and quinolinic acid (QA), which is neurotoxic. These findings underscore the crucial balance between Trp metabolism, 5-HT, and kynurenine, where an imbalance can contribute to the dual burden of pain and depression in patients with FM. This review proposes a novel therapeutic approach for FM pain management, focusing on inhibiting QA synthesis while co-administering selective serotonin reuptake inhibitors to potentially increase KYNA levels, thus dampening pain perception and improving patient outcomes.

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The brain cortex is the structure that is typically injured in traumatic brain injury (TBI) and is anatomically connected with other brain regions, including the striatum and hypothalamus, which are associated in part with motor function and the regulation of body temperature, respectively. We investigated whether a TBI extending to the striatum could affect peripheral and core temperatures as an indicator of autonomic thermoregulatory function. Moreover, it is unknown whether thermal modulation is accompanied by hypothalamic and cortical monoamine changes in rats with motor function recovery. The animals were allocated into three groups: the sham group (sham), a TBI group with a cortical contusion alone (TBI alone), and a TBI group with an injury extending to the dorsal striatum (TBI + striatal injury). Body temperature and motor deficits were evaluated for 20 days post-injury. On the 3rd and 20th days, rats were euthanized to measure the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) levels using high-performance liquid chromatography (HPLC). We observed that TBI with an injury extending to the dorsal striatum increased core and peripheral temperatures. These changes were accompanied by a sustained motor deficit lasting for 14 days. Furthermore, there were notable increases in NA and 5-HT levels in the brain cortex and hypothalamus both 3 and 20 days after injury. In contrast, rats with TBI alone showed no changes in peripheral temperatures and achieved motor function recovery by the 7th day post-injury. In conclusion, our results suggest that TBI with an injury extending to the dorsal striatum elevates both core and peripheral temperatures, causing a delay in functional recovery and increasing hypothalamic monoamine levels. The aftereffects can be attributed to the injury site and changes to the autonomic thermoregulatory functions.

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The Coronavirus disease 2019 (COVID-19) affects several tissues, including the central and peripheral nervous system. It has also been related to signs and symptoms that suggest neuroinflammation with possible effects in the short, medium, and long term. Estrogens could have a positive impact on the management of the disease, not only due to its already known immunomodulator effect, but also activating other pathways that may be important in the pathophysiology of COVID-19, such as the regulation of the virus receptor and its metabolites. In addition, they can have a positive effect on neuroinflammation secondary to pathologies other than COVID-19. The aim of this study is to analyze the molecular mechanisms that link estrogens with their possible therapeutic effect for neuroinflammation related to COVID-19. Advanced searches were performed in scientific databases as Pub- Med, ProQuest, EBSCO, the Science Citation index, and clinical trials. Estrogens have been shown to participate in the immune modulation of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to this mechanism, we propose that estrogens can regulate the expression and activity of the Angiotensin-converting enzyme 2 (ACE2), reestablishing its cytoprotective function, which may be limited by its interaction with SARS-CoV-2. In this proposal, estrogens and estrogenic compounds could increase the synthesis of Angiotensin-(1-7) (Ang-(1-7)) that acts through the Mas receptor (MasR) in cells that are being attacked by the virus. Estrogens can be a promising, accessible, and low-cost treatment for neuroprotection and neuroinflammation in patients with COVID-19, due to its direct immunomodulatory capacity in decreasing cytokine storm and increasing cytoprotective capacity of the axis ACE2/Ang (1-7)/MasR.

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The ongoing pandemic of COVID-19 has caused more than 6.7 million tragic deaths, plus, a large percentage of people who survived it present a myriad of chronic symptoms that last for at least 6 months; this has been named as long COVID. Some of the most prevalent are painful symptoms like headache, joint pain, migraine, neuropathic-like pain, fatigue and myalgia. MicroRNAs are small non-coding RNAs that regulate genes, and their involvement in several pathologies has been extensively shown. A deregulation of miRNAs has been observed in patients with COVID-19. The objective of the present systematic review was to show the prevalence of chronic pain-like symptoms of patients with long COVID and based on the expression of miRNAs in patients with COVID-19, and to present a proposal on how they may be involved in the pathogenic mechanisms of chronic pain-like symptoms. A systematic review was carried out in online databases for original articles published between March 2020 to April 2022; the systematic review followed the PRISMA guidelines, and it was registered in PROSPERO with registration number CRD42022318992. A total of 22 articles were included for the evaluation of miRNAs and 20 regarding long COVID; the overall prevalence of pain-like symptoms was around 10 to 87%, plus, the miRNAs that were commonly up and downregulated were miR-21-5p, miR-29a,b,c-3p miR-92a,b-3p, miR-92b-5p, miR-126-3p, miR-150-5p, miR-155-5p, miR-200a, c-3p, miR-320a,b,c,d,e-3p, and miR-451a. The molecular pathways that we hypothesized to be modulated by these miRNAs are the IL-6/STAT3 proinflammatory axis and the compromise of the blood-nerve barrier; these two mechanisms could be associated with the prevalence of fatigue and chronic pain in the long COVID population, plus they could be novel pharmacological targets in order to reduce and prevent these symptoms.

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Obesity remains a global health problem. Chronic low-grade inflammation in this pathology has been related to comorbidities such as cognitive alterations that, in the long term, can lead to neurodegenerative diseases. Neuroinflammation or gliosis in patients with obesity and type 2 diabetes mellitus has been related to the effect of adipokines, high lipid levels and glucose, which increase the production of free radicals. Cerebral gliosis can be a risk factor for developing neurodegenerative diseases, and antioxidants could be an alternative for the prevention and treatment of neural comorbidities in obese patients. AIM: Identify the immunological and oxidative stress mechanisms that produce gliosis in patients with obesity and propose antioxidants as an alternative to reducing neuroinflammation. METHOD: Advanced searches were performed in scientific databases: PubMed, ProQuest, EBSCO, and the Science Citation index for research on the physiopathology of gliosis in obese patients and for the possible role of antioxidants in its management. CONCLUSION: Patients with obesity can develop neuroinflammation, conditioned by various adipokines, excess lipids and glucose, which results in an increase in free radicals that must be neutralized with antioxidants to reduce gliosis and the risk of long-term neurodegeneration.

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The global pandemic caused by the SARS-CoV-2 virus began in early 2020 and is still present. The respiratory symptoms caused by COVID-19 are well established. However, neurological manifestations that may result from direct or indirect neurological damage after SARS-CoV-2 infection have been reported frequently. The main proposed pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease and indirect inflammatory/ autoimmune origin mechanisms. A growing number of studies confirm that neuroprotective measures should be maintained in COVID-19 patients. On the other hand, cannabinoids have been the subject of various studies that propose them as potentially promising drugs in chronic neurodegenerative diseases due to their powerful neuroprotective potential. In this review, we addresses the possible mechanism of action of cannabinoids as a neuroprotective treatment in patients infected by SARS-CoV-2. The endocannabinoid system is found in multiple systems within the body, including the immune system. Its activation can lead to beneficial results, such as a decrease in viral entry, a reduction of viral replication, and a reduction of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α, or IFN-c through CB2R expression induced during inflammation by SARS-CoV-2 infection in the central nervous system.

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The aging process is characterized by a gradual impairment generally caused by oxidative stress and, more specifically, sleep deprivation, which induces oxidative stress in the brain. The objective of this study was to assess the effect of three types of paradoxical sleep deprivation (PSD): 96 h of PSD (96PSD group); 192 h of PSD (192PSD group); 192 h of PSD followed by a recovery period of 20 days (192PSD + Recovery group) on an oral glucose tolerance test (OGTT), lipid peroxidation (LPO), and superoxide dismutase (SOD) and catalase (CAT) activities in the liver and pancreas of young (3-month-old) and adult (14-month-old) rats. The 96PSD and 192PSD groups of young rats showed lower glucose levels on the OGTT than the control group. In the adult rats, only the 96PSD group had lower glucose levels than the control group. However, the areas under the curve for the young and adult 192 and 192PSD + Recovery groups showed significant differences. Both LPO and SOD increased in the 192PSD and 192PSD + Recovery groups, but CAT decreased in the liver of young rats in the 192PSD group. Regarding the pancreas, LPO and SOD levels increased after 96 h of PSD. In adult animals, CAT decreased in the liver after 96 and 192 h of PSD, while LPO and SOD increased in the pancreas of the 192PSD and PSD + Recovery groups. Differences in the SOD and CAT activities in the liver and SOD activities in the pancreas were also observed between the young and adult rats and maintained across all the PSD groups. In conclusion, PSD induced differential responses that appeared to depend on the duration of the induced condition, the animals' age, and the tissue analyzed. It was found that adult rats were more susceptible to the effects of PSD than young rats.

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BACKGROUND: Botulinum toxin type A (BoNT-A) is widely employed for cosmetic purposes and in the treatment of certain diseases such as strabismus, hemifacial spasm and focal dystonia among others. BoNT-A effect mainly acts at the muscular level by inhibiting the release of acetylcholine at presynaptic levels consequently blocking the action potential in the neuromuscular junction. Despite the great progress in approval and pharmaceutical usage, improvement in displacing BoNT-A to other pathologies has remained very limited. Patients under diagnosis of several types of cancer experience pain in a myriad of ways; it can be experienced as hyperalgesia or allodynia, and the severity of the pain depends, to some degree, on the place where the tumor is located. Pain relief in patients diagnosed with cancer is not always optimal, and as the disease progresses, transition to more aggressive drugs, like opioids is sometimes unavoidable. In recent years BoNT-A employment in cancer has been explored, as well as an antinociceptive drug; experiments in neuropathic, inflammatory and acute pain have been carried out in animal models and humans. Although its mechanism has not been fully known, evidence has shown that BoNT-A inhibits the secretion of pain mediators (substance P, Glutamate, and calcitonin gene related protein) from the nerve endings and dorsal root ganglion, impacting directly on the nociceptive transmission through the anterolateral and trigeminothalamic systems. AIM: The study aimed to collect available literature regarding molecular, physiological and neurobiological evidence of BoNT-A in cancer patients suffering from acute, neuropathic and inflammatory pain in order to identify possible mechanisms of action in which the BoNT-A could impact positively in pain treatment. CONCLUSION: BoNT-A could be an important neo-adjuvant and coadjuvant in the treatment of several types of cancer, to diminish pro-tumor activity and secondary pain.

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Abstract Introduction Systemic administration of pentylenetetrazole (PTZ) causes brain damage (BD), and triggers a series of morphological and neurochemical changes, which in turn bring about behavioral, cognitive, and motor deficits. Serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels are controlled by various brain structures and these levels are related to motor activity; however, the concentration of these neurotransmitters during the postictal process remains unknown. Objective We investigated the concentration of 5-HT, NA and DA in the hippocampus, cerebellum, and cortex on motor deficit during the postictal stage. Method Eighteen male Wistar rats (300 g) assigned to two groups: control (n = 9, saline solution) and experimental (n = 9, PTZ) were used. Myoclonic shakes were counted and motor behavior assessments were recorded during three hours post PTZ injection (90 mg/kg). The cortex, cerebellum, and hippocampus of each rat were dissected to determine the 5-HT, DA, and NA concentration by high performance liquid chromatography. Results PTZ induced a significant increase in total 5-HT and DA levels in the hippocampus and cortex; in the cerebellum there was a significant increase in the concentration of 5-HT and NA. The presence of myoclonic shakes as well as a marked motor deficit in the experimental group were significantly different in comparison to the control. Discussion and conclusion 5-HT modifies the concentration of other monoamines directly involved in motor aspects such as NA and DA in the hippocampus, cerebellum, and cortex during the postictal process.

Resumen Introducción La administración sistémica de pentilentetrazol (PTZ) causa daño cerebral y desencadena una serie de cambios morfológicos y neuroquímicos que a su vez provocan déficits conductuales, cognitivos y motores. Los niveles de serotonina (5-HT), dopamina (DA) y noradrenalina (NA) son modulados por varias estructuras cerebrales y sus concentraciones se relacionan con la actividad motora; sin embargo, se desconoce la concentración de estos neurotransmisores durante el proceso postictal. Objetivo Evaluar la manera en que la concentración de 5-HT, NA y DA en el hipocampo, el cerebelo y la corteza influye en el déficit motor durante la etapa postictal. Método Se utilizaron 18 ratas macho Wistar (300 g), divididas en dos grupos: control (n = 9, solución salina) y experimental (n = 9, PTZ). Se registraron las sacudidas mioclónicas y se evaluó el comportamiento motor durante tres horas después de la inyección de PTZ (90 mg/kg). Se extrajeron la corteza, el cerebelo y el hipocampo de cada rata para determinar la concentración de 5-HT, DA y NA mediante cromatografía líquida de alta resolución. Resultados La administración de PTZ indujo un aumento significativo en los niveles totales de 5-HT y DA en el hipocampo y la corteza; en el cerebelo hubo un aumento significativo en la concentración de 5-HT y NA. Se encontró una diferencia significativa entre el grupo experimental y control con respecto a las sacudidas mioclónicas; asimismo, los animales del grupo experimental mostraron un marcado déficit motor. Discusión y conclusión La 5-HT modula la concentración de otras monoaminas involucradas directamente en aspectos motores tal como NA y DA en el hipocampo, el cerebelo y la corteza durante el proceso postictal.

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BACKGROUND: Levetiracetam (LEV) is a novel anticonvulsant with proven antinociceptive properties. However, the antinociceptive and pronociceptive effect of this drug has not yet been fully elucidated in a tonic pain model. METHODS: Thirty-six male rats (Wistar) were randomized into six groups and underwent the formalin test as follows: rats in the control group were administered 50µL of 1% formalin in the paw; sham-group rats were administered 50µL of saline in the paw to mimick the application of formalin; the four experimental groups were administered LEV intragastrically (ig) (50, 100, 200 and 300mg/kg), and 40min later 50µL of 1% formalin was injected in the paw. RESULTS: LEV exhibited antinociceptive effect in the 300mg/kg LEV group (p<0.05) and a pronociceptive effect in the 100mg/kg LEV group (p<0.05) and in the 50mg/kg LEV group (p<0.001). CONCLUSIONS: The antinociceptive and pronociceptive effect of LEV in a tonic pain model is dose-dependent.

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BACKGROUND: The aim of this review was to identify the mechanisms by which serotonin receptors involved at the central level are able to modulate the nociceptive response. Pain is a defense mechanism of the body that entails physiological, anatomical, neurochemical, and psychological changes, and is defined as an unpleasant sensory and emotional experience with potential risk of tissue damage, comprising the leading cause of appointments with Physicians worldwide. Treatment for this symptom has generated several neuropharmacological lines of research, due to the different types of pain and the various drugs employed to treat this condition. Serotonin [5- HydroxyTryptamine (5-HT)] is a neurotransmitter with seven families (5-HT1-5-HT7) and approximately 15 receptor subtypes. Serotonin modulates neuronal activity; however, this neurotransmitter is related with a number of physiological processes, such as cardiovascular function, gastric motility, renal function, etc. On the other hand, several researches reported that serotonin modulates nociceptive response through 5-HT1, 5-HT2, 5-HT3, and 5-HT7 receptors in the Central Nervous System (CNS). METHOD: In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation Index for studies evaluating the effects of 5-HT1, 5-HT2, 5-HT3, and 5-HT7 receptors in the CNS on the modulation of different types of pain. CONCLUSION: We concluded that 5-HT1, 5-HT2, 5-HT3, and 5-HT7 receptors in the CNS modulate the pain, but this depends on the distribution of the receptors, dose of agonists or antagonists, administration route, pain type and duration in order to inhibit, excite, or even maintain the nociceptive response.

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