Examinando por Autor "Bagues, Ana"

Mostrando 1 - 15 de 15

Behavior and electrophysiology studies of the peripheral neuropathy induced by individual and co-administration of paclitaxel and oxaliplatin in rat
(Elsevier, 2021) Paniagia, Nancy; Sánchez-Robles, Eva Mª; Bagues, Ana; Martín-Fontelles, Mª Isabel; Goicoechea, Carlos; Girón, Rocío
Aims: Antitumor agents, as taxanes and platinum compounds, induce peripheral neuropathies which can hamper their use for cancer treatment. The study of chemotherapy-induced neuropathies in humans is difficult because of ethical reasons, differences among administration protocols and intrinsic characteristics of patients. The aim of the present study is to compare the neuropathic signs induced by individual or combined administration of paclitaxel and oxaliplatin. Main methods: Oxaliplatin and paclitaxel were administered individually and combined to induce peripheral neuropathy in rats, sensory neuropathic signs were assessed in the hind limbs and orofacial area. The in vitro skin-saphenous nerve preparation was used to record the axonal activity of Aδ sensory neurons. Key findings: Animals treated with the combination developed mechanical allodynia in the paws and muscular hyperalgesia in the orofacial area, which was similar to that in animals treated with monotherapy, the latter also developed cold allodynia in the paws. Aδ-fibers of the rats treated with the combination were hyperexcited and presented hypersensitivity to pressure stimulation of the innervated skin, also similar to that recorded in the fibers of the animals treated with monotherapy. Significance: Our work objectively demonstrates that the combination of a platinum compound with a taxane does not worsen the development of sensorial neuropathies in rats, which is an interesting data to take into account when the combination of antitumor drugs is necessary. Co-administration of antitumor drugs is more effective in cancer treatment without increasing the risk of the disabling neuropathic side effects.
Cannabinoid Agonists
(Elsevier, 2015) Bagues, Ana; Goicoechea, Carlos
Cannabis has been used by humans since ancient history, but it was not until the 1960s, with the isolation of Δ9-tetrahydrocannabinol (Δ9-THC), that research with cannabinoids took off. One of the most important findings was the discovery of the endocannabinoid system; this system is formed by the cannabinoid receptors, endogenous ligands of these receptors, and enzymes and proteins that regulate ligand concentration. Components of the endocannabinoid system can be found in most parts of the organism and have different functions, but primarily it is a system that maintains homeostasis. Apart from the endocannabinoids, exogenous substances can bind to these receptors. These can be cannabinoid agonists found in the Cannabis sativa plant, such as Δ9-THC, which is the substance responsible for the psychoactive effects of cannabis, or synthetic cannabinoids, as of this writing available only for research purposes (but also used as substances of abuse). This chapter mainly focuses on endocannabinoids, as other agonists are explained in other chapters.
Cannabinoid drugs against chemotherapy-induced adverse effects: focus on nausea/vomiting, peripheral neuropathy and chemofog in animal models.
(Wolters Kluwer Health, 2022-04) Bagues, Ana; López-Tofiño, Yolanda; Llorente-Berzal, Álvaro; Abalo, Raquel
Although new drugs are being developed for cancer treatment, classical chemotherapeutic agents are still front-line therapies, despite their frequent association with severe side effects that can hamper their use. Cannabinoids may prevent or palliate some of these side effects. The aim of the present study is to review the basic research which has been conducted evaluating the effects of cannabinoid drugs in the treatment of three important side effects induced by classical chemotherapeutic agents: nausea and vomiting, neuropathic pain and cognitive impairment. Several published studies have demonstrated that cannabinoids are useful in preventing and reducing the nausea, vomits and neuropathy induced by different chemotherapy regimens, though other side effects can occur, such as a reduction of gastrointestinal motility, along with psychotropic effects when using centrally-acting cannabinoids. Thus, peripherally-acting cannabinoids and new pharmacological options are being investigated, such as allosteric or biased agonists. Additionally, due to the increase in the survival of cancer patients, there are emerging data that demonstrate an important cognitive deterioration due to chemotherapy, and because the cannabinoid drugs have a neuroprotective effect, they could be useful in preventing chemotherapy-induced cognitive impairment (as demonstrated through studies in other neurological disorders), but this has not yet been tested. Thus, although cannabinoids seem a promising therapeutic approach in the treatment of different side effects induced by chemotherapeutic agents, future research will be necessary to find pharmacological options with a safer profile. Moreover, a new line of research awaits to be opened to elucidate their possible usefulness in preventing cognitive impairment.
Cannabinoids and muscular pain. Effectiveness of the local administration in rat
(Wiley, 2012) Sanchez, Eva Mª; Bagues, Ana; Martín-Fontelles, Mª Isabel
Background: Pain associated with musculoskeletal disorders can be difficult to control and the incorporation of new approaches for its treatment is an interesting challenge. Activation of cannabinoid (CB) receptors decreases nociceptive transmission in acute, inflammatory and neuropathic pain states; however, although the use of cannabis derivatives has been recently accepted as a useful alternative for the treatment of spasticity and pain in patients with multiple sclerosis, the effects of CB receptor agonists in muscular pain have hardly been studied. Methods: Here, we characterized the antinociceptive effect of non selective and selective CB agonists by systemic and local administration, in two muscular models of pain, masseter and gastrocnemius, induced by hypertonic saline (HS) injection. Drugs used were: the non-selective agonist WIN 55,212-2 and two selective agonists, ACEA (CB 1) and JWH 015 (CB 2); AM 251 (CB 1) and AM 630 (CB 2) were used as selective antagonists. Results: In the masseter pain model, both systemic (intraperitoneal) and local (intramuscular) administration of CB 1 and CB 2 agonists reduced the nociceptive behaviour induced by HS, whereas in the gastrocnemius model the local administration was more effective than systemic. Conclusions: Our results provide evidence that both, CB 1 and CB 2 receptors can contribute to muscular antinociception and, interestingly, suggest that the local administration of CB agonists could be a new and useful pharmacological strategy in the treatment of muscular pain, avoiding adverse effects induced by systemic administration.
Cannabinoids to Fight Chemotherapy-Induced Adverse Effects
(Springer, 2023) Bagues, Ana; Benítez, David; Abalo, Raquel
One of the main causes of death around the world is cancer. Although the development of antitumor drugs has increased life expectancy in these patients during the past decades, chemotherapy is associated to acute and long-lasting impactful side effects. The endocannabinoid system is formed by the cannabinoid receptors CB1 and CB2, the endogenous agonists of these receptors, and all the enzymes necessary for the metabolism of the endocannabinoids. The wide distribution of the endocannabinoid system and its involvement in the modulation of a wide range of biological processes highlight the great therapeutic potential of cannabis and cannabinoids in many diseases, including gastrointestinal alterations, pain, cachexia, or cancer. To date, only a few cannabinoid agonists have been approved for different pathologies, although in relation to cancer, only oral capsules and solutions based on synthetic analogues of Δ9-tetrahydrocannabinol have been approved for the treatment of chemotherapy-induced nausea and vomiting. Despite the vast positive results obtained from animal studies regarding the usefulness of cannabinoids to reduce other symptoms related to cancer and its treatment, such as neuropathic pain or cachexia, conflicting evidence exists in the clinical setting, due, mainly, to the lack of more high-quality clinical studies. Moreover, the psychotropic effects and immune suppression mediated by CB1 and CB2 agonists, respectively, arise safety concerns that need to be considered. In conclusion, although strategies aimed at modulating the endocannabinoid system can play a pivotal role in the treatment of different side effects associated to cancer chemotherapy, future studies will be needed to confirm their effectiveness and safety in the clinical setting.
Characterization of the nociceptive effect of carrageenan: Masseter versus gastrocnemius
(Wiley, 2017) Bagues, Ana; Martín-Fontelles, Mª Isabel; Esteban-Hernández, Jesús; Sánchez-Robles, Eva Mª
Introduction: To better understand the pathophysiology of chronic muscle pain, there are multiple animal models that mimic different acute/chronic pain conditions, such as carrageenan injection. Our previous studies demonstrated differences between muscles of different innervation in acute pain. In this study we characterized the effect of carrageenan in 2 muscles: masseter (trigeminal innervation) and gastrocnemius (spinal innervation). Methods: Carrageenan (3%, 6%, and 9%) was injected into the masseter and gastrocnemius of rats. Mechanical, heat, and chemical nociceptive thresholds were measured for 14 days. Results: Carrageenan did not induce mechanical allodynia or thermal hypersensitivity in either muscle. Instead, it induced a short-lasting mechanical hyperalgesia, greater in the masseter than in the gastrocnemius. Conclusion: Carrageenan injected into the masseter and gastrocnemius induces a short-lasting hyperalgesia. These results could indicate a higher susceptibility of orofacial muscles to this type of insult and, consequently, a difference between trigeminal and spinal innervation. Muscle Nerve 56: 804-813, 2017.
Contributions of peripheral and central opioid receptors to antinociception in rat muscle pain models
(ScienceDirect, 2010) Sánchez, Eva; Bagues, Ana; Martin, Mª Isabel
Administration of hypertonic saline (HS) is an accepted model to study muscular pain. HS-induced nociceptive responses were tested in masseter, already described, and in two new pain models of spinally innervated muscles (gastrocnemius and triceps) developed in rats at our laboratory. HS administration in the masseter induced vigorous hindpaw shaking and in the gastrocnemius or triceps, paw withdrawal or flexing. Participation of the central and peripheral opioid receptors in HS-induced pain is compared in these muscles: masseter, innervated by trigeminal nerve, and gastrocnemius and triceps by spinal nerves. Morphine and loperamide were used to reveal peripheral and central components of opioid analgesia. Both agonists reduced HS-induced nociceptive behaviours in the masseter and were antagonised by the opioid antagonist naloxone and by naloxone methiodide, an opioid receptor antagonist that poorly penetrates the blood–brain barrier. Unexpectedly, in the gastrocnemius and triceps, morphine, but not loperamide, decreased the nociceptive behaviour and this effect was only reversed by naloxone. So, peripheral opioid receptors seem to participate in HS-induced masseter pain, whereas only central opioid receptors reduced the nociception in gastrocnemius and triceps. Our results suggest that the use of peripheral opioids can be more advantageous than central opioids for treatment of orofacial muscular pain.
Effects of two different acute and subchronic stressors on gastrointestinal transit in the rat: A radiographic analysis
(Wiley, 2021) Bagues, Ana; Lopez-Tofiño, Yolanda; Galvez-Robleño, Carlos; Abalo, Raquel
Background: The reaction to stress is an adaptive response necessary for survival. When stressors are repeated, the organism adapts, although these adaptive responses can become dysregulated and result in disease, causing gastrointestinal (GI) disorders. Radiographic methods allow the non-invasive study of how a given factor affects GI transit in the same animal at different time points. These methods have never been applied to study the consequences of stress on GI motor function and their dependency on time and stimulus. Therefore, our aim was to characterize, using radiographic techniques, the effect on GI transit of cold-restraint (CR) and forced swim (FS) stress applied acutely and subchronically in the rat. Methods: Male Wistar rats (260–330 g) were submitted to FS or CR stress, during 1 (acute) or 4 (subchronic) consecutive days. To study GI transit, radiographic methods were used. Radiographs were taken 0–24 h after barium intragastric administration on the 1st or 4th day of stress, which was applied 1 h after contrast. Results: Acute FS or CR slowed down gastric and small intestinal emptying but had opposite effects in the caecum: CR tended to accelerate barium transit and feces formation while FS tended to slow these parameters down. When the stimuli were applied subchronically, GI transit was not completely normalized in most of the studied parameters. Conclusion and Inferences: Mild stress alters GI transit differently depending on the nature of the stressor and its duration. Exposure to mild stressors should be considered as contributing factors to different functional GI disorders.
Efficacy of botulinum toxin type A in the management of masticatory myofascial pain: A retrospective clinical study
(Elsevier, 2021) de la Hoz, José Luis; de Pedro, Miguel; Martín-Fontelles, Mª Isabel; Mesa, Juan; Chivato, Tomás; Bagues, Ana
Background: Muscular pain is the main cause of disability worldwide. Myofascial pain of orofacial origin is a frequent condition, the treatment of which is not always accomplished with traditional treatment. Botulinum toxin type A (BTA) is being studied for the treatment of this type of pain with contradicting results. Thus, the objective of this study was to assess the efficacy of BTA in the therapeutic management of masticatory myofascial pain (MFP). Case description: A retrospective study of 100 patients with a diagnosis of MFP was conducted. The control group (50 patients) received conventional treatment (prescription of a muscle relaxant and craniocervical physical therapy). The BTA group (50 patients) received this same treatment and the infiltration of 100 units of BTA in the masticatory musculature. Subjective and objective pain ratings and range of mandibular movements were recorded before and after the treatment. No differences were found between groups in the baseline values. Statistically significant improvements were found in both groups compared with baseline values in all studied parameters. Moreover, BTA improved the subjective pain ratings compared with the control group. The administration of BTA added to the conventional treatment does not seem to improve objective pain ratings and functional measurements, but it improves the subjective pain ratings. Practical implications: The addition of BTA could be beneficial in the treatment of MFP in addition to conventional treatment, but further studies are needed to elucidate the mechanisms underlying this positive effect.
Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain
(Elsevier, 2014) Bagues, Ana; Martín, Mª Isabel; Sánchez-Robles, Eva Mª
Cannabinoid (CB) receptors have emerged as an attractive therapeutic target for pain management in recent years and the interest in the use of cannabinoids is gradually increasing, particularly in patients where conventional treatments fail. Muscle pain is a major clinical problem and new pharmacological approaches are being studied. Recently, we have demonstrated that cannabinoid synthetic agonists are useful to reduce muscular pain in two animal models, where the local administration is effective. Now, we want to know if tetrahydrocannabinol (THC), a cannabinoid natural derivative with therapeutic use in humans, is also effective in reducing acute muscle pain. The antinociceptive effect of THC by systemic (i.p.) and local (i.m.) administration was tested in two animal models of acute muscle pain, rat masseter and gastrocnemius, induced by hypertonic saline (HS) injection. The drugs used were the non-selective agonist THC and two selective cannabinoid antagonists, AM251 (CB1) and AM630 (CB2). THC, i.p. and i.m. administered, reduced the nociceptive behaviours induced by HS in both muscular pain models. The antinociceptive effect induced by the systemic administration of THC was mediated by CB1 receptors in the masseter muscle whereas in gastrocnemius both CB1 and CB2 receptors participated. When THC was administered locally, only CB2 receptors were involved in the antinociceptive effect in both muscles. This study suggests that THC could be a future pharmacological option in the treatment of muscle pain. The local administration of THC could be an interesting option to treat this type of pain avoiding the central adverse effects.
Maternal separation affects the electrophysiological properties of Aδ-fibres and nociceptive behaviours in male and female mice
(2020) Paniagia, Nancy; Girón, Rocío; Goicoechea, Carlos; Martín-Fontelles, Mª Isabel; Bagues, Ana
Aim: Early life adverse effects have been associated with an increased risk of suffering pain syndromes in adulthood. Although animal models are of great importance to study modifications of pain sensitivity, up to date the results obtained are contradicting due to the varied methodologies used. Therefore, the aim of the present study was to characterise, as a whole, possible modifications in visceral and somatic nociceptive responses in male and female ICR mice, submitted to two different protocols of maternal separation (MS), and possible modifications in the electrophysiological properties of peripheral nociceptive Aδ-primary afferents. Main methods: Male and female mice were submitted to 3 or 4-8 hr of daily MS from postnatal day (PND) 2-17 and early weaned. On PND 67 von Frey, hot plate and writhing tests were performed. Afterwards electrophysiological recordings were carried out, using the in vitro skin-saphenous nerve preparation in males. Key findings: The short separation protocol of MS did not modify nociceptive sensitivity; but when mice were separated from their dams for the long separation, mechanical pain thresholds were modified in male and female mice and visceral nociception was increased in female mice. Electrophysiological recordings showed that cutaneous Aδ-fibres were sensitised and their mechanotransduction properties were altered in both MS protocols. Significance: Although MS increases the activity and the mechanosensitivity of cutaneous Aδ-afferent fibres at both short and long periods of separation, only the longer interval of time induces nociceptive sensitivity alterations during adulthood. These results highlight the possible influence of a stress free environment during childhood to reduce nociceptive alterations in adulthood.
Mechanisms of Chemotherapy-Induced Neurotoxicity.
(Frontiers, 2022) Was, Halina; Borkowska, Agata; Bagues, Ana; Longlong, Tu; Liu, Julia; Lu, Zengbing; Rudd, John A; Nurgali
Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients' quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients' quality of life.
Mu-Opioid Receptors in Ganglia, But Not in Muscle, Mediate Peripheral Analgesia in Rat Muscle Pain
(2018) Bagues, Ana
Background: Previous studies have demonstrated the participation of peripheral μ-opioid receptors (MOR) in the antinociceptive effect of systemically administered morphine and loperamide in an orofacial muscle pain model, induced by hypertonic saline, but not in a spinally innervated one, in rats. In this study, we determine whether this peripheral antinociceptive effect is due to the activation of MOR localized in the muscle, ganglia, or both. Methods: To determine the local antinociceptive effect of morphine and loperamide, 2 models of acute muscle pain (trigeminal and spinal) were used. Also, to study the MOR expression, protein quantification was performed in the trigeminal and spinal ganglia, and in the muscles. Results: The behavioral results show that the intramuscular injection of morphine and loperamide did not exert an antinociceptive effect in either muscle (morphine: P = .63, loperamide: P = .9). On the other hand, MOR expression was found in the ganglia but not in the muscles. This expression was on average 44% higher (95% confidence interval, 33.3-53.9) in the trigeminal ganglia than in the spinal one. Conclusions: The peripheral antinociceptive effect of systemically administered opioids may be due to the activation of MOR in ganglia. The greater expression of MOR in trigeminal ganglia could explain the higher antinociceptive effect of opioids in orofacial muscle pain than in spinal muscle pain. Therefore, peripheral opioids could represent a promising approach for the treatment of orofacial pain.
New Pieces for an Old Puzzle: Approaching Parkinson’s Disease from Translatable Animal Models, Gut Microbiota Modulation, and Lipidomics
(2023) Ortega Moreno, Lorena; Bagues, Ana; Martínez, Vicente; Abalo, Raquel
Parkinson’s disease (PD) is a severe neurodegenerative disease characterized by disabling motor alterations that are diagnosed at a relatively late stage in its development, and non-motor symptoms, including those affecting the gastrointestinal tract (mainly constipation), which start much earlier than the motor symptoms. Remarkably, current treatments only reduce motor symptoms, not without important drawbacks (relatively low efficiency and impactful side effects). Thus, new approaches are needed to halt PD progression and, possibly, to prevent its development, including new therapeutic strategies that target PD etiopathogeny and new biomarkers. Our aim was to review some of these new approaches. Although PD is complex and heterogeneous, compelling evidence suggests it might have a gastrointestinal origin, at least in a significant number of patients, and findings in recently developed animal models strongly support this hypothesis. Furthermore, the modulation of the gut microbiome, mainly through probiotics, is being tested to improve motor and non-motor symptoms and even to prevent PD. Finally, lipidomics has emerged as a useful tool to identify lipid biomarkers that may help analyze PD progression and treatment efficacy in a personalized manner, although, as of today, it has only scarcely been applied to monitor gut motility, dysbiosis, and probiotic effects in PD. Altogether, these new pieces should be helpful in solving the old puzzle of PD.
Short-term stress significantly decreases morphine analgesia in trigeminal but not in spinal innervated areas in rats
(Elsevier, 2022) Bagues, Ana; Girón, Rocío; Abalo, Raquel; Goicoechea, Carlos; Martín-Fontelles, María Isabel; Sánchez-Robles, Eva María
Plenty information exists regarding the effects of chronic stress, although few data exist on the effects of shortlasting stressors, which would mimic daily challenges. Differences in craniofacial and spinal nociception have been observed, thus those observations obtained in spinally innervated areas cannot be directly applied to the orofacial region. Although, opioids are considered amongst the most effective analgesics, their use is sometimes hampered by the constipation they induce. Thus, our aims were to study if a short-lasting stressor, forced swim stress (FSS), modifies nociception, morphine antinociception and constipation in rats. Animals were submitted to 10–20 min of FSS for three days, nociception and gastrointestinal transit were studied 24 h after the last swimming session. Nociception and morphine (0.6–5 mg/kg) antinociception were evaluated in the formalin and hypertonic saline tests in the orofacial area and limbs. Morphine-induced modifications in the GI transit were studied through radiographic techniques. Naloxone was administered, before each swimming session, to analyse the involvement of the endogenous opioid system on the effect of stress. Overall, stress did not alter nociception, although interestingly it reduced the effect of morphine in the orofacial tests and in the inflammatory phase of the formalin tests. Naloxone antagonized the effect of stress and normalized the effect of morphine. Stress did not modify the constipation induced by morphine. Opioid treatment may be less effective under a stressful situation, whilst adverse effects, such as constipation, are maintained. The prevention of stress may improve the level of opioid analgesia.