RESUMEN
BACKGROUND: Peripheral neuropathy (PN) constitutes a dose-limiting side effect of oxaliplatin chemotherapy that often compromises the efficacy of antineoplastic treatments. Sensory neurons damage in dorsal root ganglia (DRG) are the cellular substrate of PN complex molecular origin. Dehydropeptidase-1 (DPEP1) inhibitors have shown to avoid platin-induced nephrotoxicity without compromising its anticancer efficiency. The objective of this study was to describe DPEP1 expression in rat DRG in health and in early stages of oxaliplatin toxicity. To this end, we produced and characterized anti-DPEP1 polyclonal antibodies and used them to define the expression, and cellular and subcellular localization of DPEP1 by immunohistochemical confocal microscopy studies in healthy controls and short term (six days) oxaliplatin treated rats. RESULTS: DPEP1 is expressed mostly in neurons and in glia, and to a lesser extent in endothelial cells. Rats undergoing oxaliplatin treatment developed allodynia. TNF-ð¼ expression in DRG revealed a pattern of focal and at different intensity levels of neural cell inflammatory damage, accompanied by slight variations in DPEP1 expression in endothelial cells and in nuclei of neurons. CONCLUSIONS: DPEP1 is expressed in neurons, glia and endothelial cells of DRG. Oxaliplatin caused allodynia in rats and increased TNF-α expression in DRG neurons. The expression of DPEP1 in neurons and other cells of DRG suggest this protein as a novel strategic molecular target in the prevention of oxaliplatin-induced acute neurotoxicity.
Asunto(s)
Antineoplásicos , Ganglios Espinales , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico , Animales , Oxaliplatino/toxicidad , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/prevención & control , Enfermedades del Sistema Nervioso Periférico/patología , Masculino , Antineoplásicos/toxicidad , Ratas , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Hiperalgesia/prevención & control , Factor de Necrosis Tumoral alfa/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Ratas Sprague-Dawley , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Inflamación/metabolismo , Inflamación/inducido químicamenteRESUMEN
Our previous in vitro studies showed that excitotoxicity evoked by glutamate analogue kainate (KA) significantly decreased the number of rat spinal neurons and triggered high release of glutamate leading to locomotor network block. Our current objective was to assess the role of CREB as a predictive marker of damage following chemically-induced spinal cord injury by using in vivo and in vitro models. Thus, in vivo excitotoxicity in Balb/c adult mice was induced by KA intraspinal injection, while in vitro spinal cord excitotoxicity was produced by bath-applied KA. KA application evoked significant neuronal loss, deterioration in hindlimb motor coordination and thermal allodynia. In addition, immunohistochemical analysis showed that KA application resulted in decreased number of CREB positive nuclei in the ventral horn and in dorsal layers III-IV. Our data suggests that excitotoxic-induced neuronal loss may be potentially predicted by altered CREB nuclear translocation.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Ácido Kaínico , Ratones Endogámicos BALB C , Nocicepción , Médula Espinal , Animales , Ácido Kaínico/farmacología , Ratones , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Nocicepción/efectos de los fármacos , Masculino , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/toxicidad , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/inducido químicamente , Locomoción/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/efectos de los fármacos , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
Morphine is an important pain reliever employed in pain management, its extended utilize is hindered by the onset of analgesic tolerance and oxidative stress. Long-term morphine administration causes elevated production of reactive oxygen species (ROS), disrupting mitochondrial function and inducing oxidation. Sirtuin 3 (SIRT3), a mitochondrial protein, is essential in modulating ROS levels by regulating mitochondrial antioxidant enzymes as manganese superoxide dismutase (MnSOD). Our investigation focused on the impact of SIRT3 on hyperalgesia and morphine tolerance in mice, as evaluating the antioxidant effect of the polyphenolic fraction of bergamot (BPF). Mice were administered morphine twice daily for four consecutive days (20 mg/kg). On the fifth day, mice received an acute dose of morphine (3 mg/kg), either alone or in conjunction with BPF or Mn (III)tetrakis (4-benzoic acid) porphyrin (MnTBAP). We evaluated levels of malondialdehyde (MDA), nitration, and the activity of SIRT3, MnSOD, glutamine synthetase (GS), and glutamate 1 transporter (GLT1) in the spinal cord. Our findings demonstrate that administering repeated doses of morphine led to the development of antinociceptive tolerance in mice, accompanied by increased superoxide production, nitration, and inactivation of mitochondrial SIRT3, MnSOD, GS, and GLT1. The combined administration of morphine with either BPF or MnTBAP prevented these effects.
Asunto(s)
Tolerancia a Medicamentos , Hiperalgesia , Mitocondrias , Morfina , Estrés Oxidativo , Polifenoles , Sirtuina 3 , Animales , Morfina/farmacología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Masculino , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Polifenoles/farmacología , Sirtuina 3/metabolismo , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Antioxidantes/farmacología , Analgésicos Opioides/farmacología , Malondialdehído/metabolismo , Glutamato-Amoníaco Ligasa/metabolismo , Metaloporfirinas/farmacologíaRESUMEN
The majority of somatosensory DRG neurons express GABAA receptors (GABAAR) and depolarise in response to its activation based on the high intracellular chloride concentration maintained by the Na-K-Cl cotransporter type 1 (NKCC1). The translation of this response to peripheral nerve terminals in people is so far unclear. We show here that GABA (EC50 = 16.67µM) acting via GABAAR produces an influx of extracellular calcium in approximately 20% (336/1720) of isolated mouse DRG neurons. In contrast, upon injection into forearm skin of healthy volunteers GABA (1mM, 100µl) did not induce any overt sensations nor a specific flare response and did not sensitize C-nociceptors to slow depolarizing electrical sinusoidal stimuli. Block of the inward chloride transporter NKCC1 by furosemide (1mg/100µl) did not reduce electrically evoked pain ratings nor did repetitive GABA stimulation in combination with an inhibited NKCC1 driven chloride replenishment by furosemide. Finally, we generated a sustained period of C-fiber firing by iontophoretically delivering codeine or histamine to induce tonic itch. Neither the intensity nor the duration of histamine or codeine itch was affected by prior injection of furosemide. We conclude that although GABA can evoke calcium transients in a proportion of isolated mouse DRG neurons, it does not induce or modify pain or itch ratings in healthy human skin even when chloride gradients are altered by inhibition of the sodium coupled NKCC1 transporter.
Asunto(s)
Furosemida , Ganglios Espinales , Voluntarios Sanos , Hiperalgesia , Miembro 2 de la Familia de Transportadores de Soluto 12 , Ácido gamma-Aminobutírico , Humanos , Animales , Ratones , Ácido gamma-Aminobutírico/metabolismo , Masculino , Adulto , Furosemida/farmacología , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Hiperalgesia/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Femenino , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Dolor Agudo/metabolismo , Dolor Agudo/fisiopatología , Calcio/metabolismo , Receptores de GABA-A/metabolismo , Prurito/inducido químicamente , Prurito/metabolismo , Prurito/fisiopatología , Adulto JovenRESUMEN
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic bladder inflammation characterized by the main symptoms of urinary frequency, urgency, and pelvic pain. The hypersensitivity of bladder afferent neurons is considered a significant pathophysiologic mechanism in IC/PBS. Serotonin (5-HT, 5-hydroxytryptamine) receptors are known to be involved in the regulation of the micturition reflex and hyperalgesia, but the effect of 5-HT receptors on cystitis remains unknown. In this study, a rat model of interstitial cystitis induced by intraperitoneal injection of cyclophosphamide (CYP) was used to investigate the role of 5-HT receptors on cystitis. The histology and urodynamics exhibited chronic cystitis and overactive bladder in CYP-treated rats. Notably, among 5-HT1A, 5-HT2A and 5-HT7 receptors, the expression of 5-HT2A receptor was significantly increased in bladder afferent neurons in CYP-treated rats. Intrathecal administration of the 5-HT2A receptor antagonist M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis rats. Neuronal calcium imaging of bladder afferent neurons revealed increased calcium influx induced by the 5-HT2A receptor agonist or capsaicin in cystitis rats, which could be inhibited by M100907. Moreover, RNA sequencing indicated that differentially expressed genes were enriched in inflammation-related pathways and cellular calcium homeostasis. These findings suggest that the 5-HT2A receptor is involved in the hypersensitivity of bladder afferent neurons in CYP-induced cystitis, and M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis by inhibiting neuronal hypersensitivity in the afferent pathways. The 5-HT2A receptor may be a potential therapeutic target for the treatment of IC/BPS.
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Ciclofosfamida , Cistitis , Neuronas Aferentes , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Vejiga Urinaria , Animales , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/inervación , Vejiga Urinaria/patología , Vejiga Urinaria/metabolismo , Neuronas Aferentes/metabolismo , Neuronas Aferentes/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Ratas , Cistitis/inducido químicamente , Cistitis/metabolismo , Cistitis/patología , Femenino , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Cistitis Intersticial/inducido químicamente , Cistitis Intersticial/metabolismo , Cistitis Intersticial/tratamiento farmacológico , Cistitis Intersticial/patología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Vejiga Urinaria Hiperactiva/inducido químicamente , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria Hiperactiva/fisiopatología , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
RATIONALE: Diabetic neuropathy is a prevalent and debilitating complication of diabetes, necessitating effective pain management strategies. While pharmacological treatments, including opioids, are commonly employed, they pose significant challenges due to the risk of developing opioid-induced hyperalgesia (OIH). This case report aims to illustrate the efficacy of a comprehensive, multidisciplinary approach in managing painful diabetic neuropathy complicated by OIH. PATIENT CONCERNS: A 64-year-old male patient presented to the Pain Treatment Clinic with severe lower limb pain due to diabetic polyneuropathy. He had a history of multiple comorbidities. DIAGNOSES: The patient's condition and physical examination suggested the presence of opioid-induced hyperalgesia (OIH). Despite the increased dose of opioids, the patient did not report significant constipation or breathing difficulties but experienced drowsiness and dry mouth. A diagnosis of opioid and benzodiazepine dependence was made. INTERVENTIONS: The treatment plan involved the initiation of pregabalin and duloxetine, gradual reduction of opioid use, and psychiatric support for addiction management. OUTCOMES: Over 12 months, the patient experienced significant pain reduction and minimal adverse effects. LESSONS: Effective management of OIH involves gradual opioid tapering and a multimodal therapeutic approach. However, the optimal treatment strategies and the frequency of OIH occurrence remain areas of uncertainty, relying heavily on clinical expertise and individualized patient care. Further research is needed to refine these treatment strategies and improve patient outcomes.
Asunto(s)
Analgésicos Opioides , Neuropatías Diabéticas , Hiperalgesia , Humanos , Masculino , Persona de Mediana Edad , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/terapia , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Manejo del Dolor/métodos , Clorhidrato de Duloxetina/uso terapéutico , Pregabalina/uso terapéutico , Pregabalina/efectos adversos , Terapia CombinadaRESUMEN
BACKGROUND: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice. METHODS: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR. RESULTS: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice. CONCLUSIONS: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.
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Modelos Animales de Enfermedad , Ratones Noqueados , Trastornos Migrañosos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Receptores de Tipo II del Péptido Intestinal Vasoactivo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo , Animales , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/genética , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/genética , Ratones , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/fisiopatología , Hiperalgesia/fisiopatología , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Masculino , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Ratones Endogámicos C57BL , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/genética , Miembro Posterior/fisiopatologíaRESUMEN
AIMS: Paclitaxel (PTX) is extensively utilized in the management of diverse solid tumors, frequently resulting in paclitaxel-induced peripheral neuropathy (PIPN). The present study aimed to investigate sex differences in the behavioral manifestations and underlying pathogenesis of PIPN and search for clinically efficacious interventions. METHODS: Male and female C57BL/6 mice (5-6 weeks and 12 months, weighing 18-30 g) were intraperitoneally (i.p.) administered paclitaxel diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections. Von Frey and hot plate tests were performed before and after administration to confirm the successful establishment of the PIPN model and also to evaluate the pain of PIPN and the analgesic effect of PD-L1. On day 14 after PTX administration, PD-L1 protein (10 ng/pc) was injected into the PIPN via the intrathecal (i.t.) route. To knock down TRPV1 in the spinal cord, adeno-associated virus 9 (AAV9)-Trpv1-RNAi (5 µL, 1 × 1013 vg/mL) was slowly injected via the i.t. route. Four weeks after AAV9 delivery, the downregulation of TRPV1 expression was verified by immunofluorescence staining and Western blotting. The levels of PD-L1, TRPV1 and CGRP were measured via Western blotting, RT-PCR, and immunofluorescence staining. The levels of TNF-α and IL-1ß were measured via RT-PCR. RESULTS: TRPV1 and CGRP protein and mRNA levels were higher in the spinal cords of control female mice than in those of control male mice. PTX-induced nociceptive behaviors in female PIPN mice were greater than those in male PIPN mice, as indicated by increased expression of TRPV1 and CGRP. The analgesic effects of PD-L1 on mechanical hyperalgesia and thermal sensitivity were significantly greater in female mice than in male mice, with calculated relative therapeutic levels increasing by approximately 2.717-fold and 2.303-fold, respectively. PD-L1 and CGRP were partly co-localized with TRPV1 in the dorsal horn of the mouse spinal cord. The analgesic effect of PD-L1 in PIPN mice was observed to be mediated through the downregulation of TRPV1 and CGRP expression following AAV9-mediated spinal cord specific decreased TRPV1 expression. CONCLUSIONS: PTX-induced nociceptive behaviors and the analgesic effect of PD-L1 in PIPN mice were sexually dimorphic, highlighting the significance of incorporating sex as a crucial biological factor in forthcoming mechanistic studies of PIPN and providing insights for potential sex-specific therapeutic approaches.
Asunto(s)
Antígeno B7-H1 , Péptido Relacionado con Gen de Calcitonina , Ratones Endogámicos C57BL , Paclitaxel , Enfermedades del Sistema Nervioso Periférico , Caracteres Sexuales , Canales Catiónicos TRPV , Animales , Paclitaxel/toxicidad , Masculino , Femenino , Ratones , Péptido Relacionado con Gen de Calcitonina/metabolismo , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Antineoplásicos Fitogénicos/toxicidad , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismoRESUMEN
Irritant contact dermatitis (ICD) is a nonspecific skin inflammation caused by irritants, leading to itch and pain. We tested whether differential responses to histamine-dependent and -independent pruritogens can be evoked in ICD induced by sodium lauryl sulfate (SLS). An ICD mouse model was established with 5% SLS in acetone versus a vehicle topically applied for 24 h to the cheek. Site-directed itch- and pain-like behaviors, occurring spontaneously and in response to mechanical, thermal, and chemical stimuli (histamine, ß-alanine, BAM8-22, and bradykinin) applied to the cheek, were recorded before (day 0) and after irritant removal (days 1, 2, 3, and 4). Skin inflammation was assessed through visual scoring, ultrasound, and measurements of skin thickness. SLS-treated mice exhibited hyperalgesia-like behavior in response to mechanical and heat stimuli on day 1 compared to the controls. SLS mice exhibited more spontaneous wipes (pain) but not scratching bouts (itch) on day 1. Pruritogen injections caused more scratching but not wiping in SLS-treated mice compared to the controls. Only bradykinin increased wiping behavior compared to saline. SLS-treated mice developed noticeable erythema, scaling, and increased skin thickness on days 1 and 2. SLS induced cutaneous inflammation and behavioral signs of spontaneous pain and itching, hyperalgesia to mechanical and heat stimuli and a chemical algogen, and enhanced itch response to pruritogens. These sensory reactions preceded the inflammation peak and lasted up to two days.
Asunto(s)
Dermatitis Irritante , Modelos Animales de Enfermedad , Dolor , Prurito , Dodecil Sulfato de Sodio , Animales , Dodecil Sulfato de Sodio/efectos adversos , Prurito/inducido químicamente , Ratones , Dermatitis Irritante/etiología , Dermatitis Irritante/patología , Dermatitis Irritante/fisiopatología , Dolor/inducido químicamente , Dolor/fisiopatología , Masculino , Hiperalgesia/inducido químicamente , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Histamina , Irritantes/toxicidad , Bradiquinina/farmacología , Conducta Animal/efectos de los fármacosRESUMEN
OBJECTIVES: Duloxetine, the only American Society of Clinical Oncology (ASCO) treatment recommended for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors, is not effective for 40% of survivors. This study examined the ability of a duloxetine-prazosin combination to prevent the development of allodynia and hyperalgesia in a rat model of oxaliplatin-induced peripheral neuropathy (OPIN). METHODS: Female (nâ¯=â¯24) and male (nâ¯=â¯41) rats were started on duloxetine (15 mg), prazosin (2 mg), or a duloxetine-prazosin combination one week prior to administration of the chemotherapy drug, oxaliplatin, and continued the duloxetine-prazosin combination for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments over the course of the study. RESULTS: Overall percent paw withdrawal for rats that received the duloxetine-prazosin combination was significantly lower in female (p < .001 for both conditions) and male (pâ¯=â¯.029 for allodynia; p < .001 for hyperalgesia) than those that received water. No significant posttreatment differences were found for allodynia or hyperalgesia between rats treated with duloxetine and rats that received the duloxetine-prazosin combination in either sex. CONCLUSIONS: These finding provide preliminary evidence that a duloxetine-prazosin combination can prevent the posttreatment development of allodynia and hyperalgesia in both male and female rats; however, the results suggest that the duloxetine-prazosin combination is no more efficacious than duloxetine alone in preventing chronic OIPN. IMPLICATIONS FOR NURSING PRACTICE: The profession of nursing is built on clinical practice supported by scientific research. The current study addressed the clinical practice problem of prevention and management of painful OIPN, which is a priority area in oncology nursing.
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Modelos Animales de Enfermedad , Clorhidrato de Duloxetina , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico , Prazosina , Animales , Clorhidrato de Duloxetina/farmacología , Clorhidrato de Duloxetina/uso terapéutico , Ratas , Oxaliplatino/efectos adversos , Femenino , Masculino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Prazosina/farmacología , Prazosina/uso terapéutico , Antineoplásicos/efectos adversos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Hiperalgesia/prevención & control , Ratas Sprague-DawleyRESUMEN
Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.
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Ganglios Espinales , Neuralgia , Paclitaxel , Ratas Sprague-Dawley , Canales Catiónicos TRPM , Canales Catiónicos TRPV , Animales , Paclitaxel/efectos adversos , Paclitaxel/farmacología , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPV/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ratas , Neuralgia/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/inducido químicamente , Masculino , Hiperalgesia/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Capsaicina/farmacología , Capsaicina/análogos & derivados , Neuronas/metabolismo , Neuronas/efectos de los fármacosRESUMEN
Remifentanil-induced hyperalgesia (RIH) is a part of a general opioid-induced hyperalgesia (OIH) syndrome, seemingly resulting from abrupt cessation of continuous remifentanil infusion at rates equal or exceeding 0.3âmcg/kg/min. The intricate mechanisms of its development are still not completely understood. However, hyperactivation of the N -methyl d -aspartate receptor system, descending spinal facilitation and increased concentration of dynorphin (a κ-opioid ligand) are commonly proposed as possible mechanisms. Several ways of prevention and management have been suggested, such as slow withdrawal of remifentanil infusion, the addition of propofol, pretreatment with or concomitant administration of ketamine, buprenorphine, cyclooxygenase-2 inhibitors (NSAIDs), methadone, dexmedetomidine. In clinical and animal studies, these strategies exhibited varying success, and many are still being investigated.
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Analgésicos Opioides , Hiperalgesia , Piperidinas , Remifentanilo , Remifentanilo/efectos adversos , Remifentanilo/administración & dosificación , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/prevención & control , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Analgésicos Opioides/efectos adversos , Animales , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Propofol/efectos adversos , Propofol/administración & dosificaciónRESUMEN
Hyperalgesic priming is a preclinical model of the transition from acute to chronic pain characterized by a leftward shift in the dose-response curve for and marked prolongation of prostaglandin E2 (PGE2)-induced mechanical hyperalgesia, in vivo. In vitro, priming in nociceptors is characterized by a leftward shift in the concentration dependence for PGE2-induced nociceptor sensitization. In the present in vitro study we tested the hypothesis that a mu-opioid receptor (MOR) agonist opioid analgesic, morphine, can produce priming by its direct action on nociceptors. We report that treatment of nociceptors with morphine, in vitro, produces a leftward shift in the concentration dependence for PGE2-induced nociceptor sensitization. Our findings support the suggestion that opioids act directly on nociceptors to induce priming.
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Dinoprostona , Morfina , Nociceptores , Morfina/farmacología , Animales , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Dinoprostona/metabolismo , Dinoprostona/farmacología , Receptores Opioides mu/metabolismo , Analgésicos Opioides/farmacología , Masculino , Ratas , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Ratas Sprague-Dawley , Relación Dosis-Respuesta a DrogaRESUMEN
In the search for new small molecules for the therapy of neuropathic pain, we found that 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile (12) induced a robust antiallodynic effect in capsaicin-induced mechanical allodynia, a behavioural model of central sensitization, through σ1R antagonism. Furthermore, administration of compound 12 to neuropathic animals, fully reversed mechanical allodynia, increasing its mechanical threshold to levels that were not significantly different from those found in paclitaxel-vehicle treated mice or from basal levels before neuropathy was induced. Ligand 12 is thus a promising hit-compound for the therapy of neuropathic pain.
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Neuralgia , Nitrilos , Animales , Neuralgia/tratamiento farmacológico , Ratones , Masculino , Nitrilos/química , Nitrilos/farmacología , Nitrilos/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Analgésicos/farmacología , Analgésicos/química , Analgésicos/síntesis química , Analgésicos/uso terapéutico , Piridinas/química , Piridinas/farmacología , Piridinas/síntesis química , Piridinas/uso terapéutico , Receptor Sigma-1 , Capsaicina/farmacología , Capsaicina/química , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamenteRESUMEN
Pain in Parkinson's disease (PD) has been validated as one of the major non-motor dysfunctions affecting the quality of life and subsequent rehabilitation. In the present study, we investigated the role of the dopamine D3 receptor in the thalamic mediodorsal (MD) and ventromedial (VM) nuclei mediated descending control of nociception and intramuscular (i.m.) 2.5% formalin-induced persistent muscle nociception. Paw withdrawal reflexes were measured in naive rats and rats subjected to PD induced by unilateral microinjection of 6 µg 6-OHDA into the rat striatum. Formalin-induced muscle nociception in phase 1, inter-phase, and phase 2 was significantly greater in PD rats compared to naive and vehicle-treated rats (P < 0.001). PD rats exhibited bilaterally mechanical hyperalgesia and heat hypoalgesia in formalin-induced muscle nociception. Microinjection of SK609, a dopamine D3 receptor agonist, at various doses (2.5-7.5 nmol/0.5 µl) into the thalamic VM nucleus dose-dependently prolonged heat-evoked paw withdrawal latencies in both naive and PD rats. Administration of SK609 to either the MD or VM nuclei had no effect on noxious mechanically evoked paw withdrawal reflexes. Pre-treatment of the thalamic MD nucleus with SK609 significantly attenuated formalin-induced nociception, and reversed mechanical hyperalgesia, but not heat hypoalgesia. Pre-treatment of the thalamic VM nucleus with SK609 inhibited formalin-induced nociception in the late phase of phase 2 (30-75 min) and heat hypoalgesia, but not mechanical hyperalgesia (P < 0.05). It is suggested that the dopamine D3 receptors in the thalamus play an antinociceptive role in the descending modulation of nociception. Activation of D3 receptors within the thalamic MD and VM nuclei attenuates descending facilitation and enhances descending inhibition in rats during PD.
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Modelos Animales de Enfermedad , Formaldehído , Nocicepción , Ratas Sprague-Dawley , Receptores de Dopamina D3 , Animales , Ratas , Masculino , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/metabolismo , Formaldehído/toxicidad , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Tálamo/efectos de los fármacos , Tálamo/metabolismo , Dimensión del Dolor/métodos , Oxidopamina/toxicidadRESUMEN
Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED50 (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam-pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain.
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Analgésicos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Gabapentina , Inflamación , Nefopam , Neuralgia , Osteoartritis , Animales , Neuralgia/tratamiento farmacológico , Neuralgia/inducido químicamente , Nefopam/farmacología , Nefopam/uso terapéutico , Ratones , Gabapentina/farmacología , Gabapentina/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Masculino , Osteoartritis/tratamiento farmacológico , Osteoartritis/inducido químicamente , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Pregabalina/farmacología , Pregabalina/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , CarrageninaRESUMEN
BACKGROUND AND PURPOSE: We extend the characterization of the TRPM8 antagonist VBJ103 with tests of selectivity, specificity and distribution, therapeutic efficacy of systemic administration against oxaliplatin-induced cold hyperalgesia and the impact of systemic administration on core body temperature (CBT). EXPERIMENTAL APPROACH: Selectivity at human TRPA1 and TRPV1 as well as in vitro safety profiling was determined. Effects of systemic administration of VBJ103 were evaluated in a model of oxaliplatin-induced cold hyperalgesia. Both peripheral and centrally mediated effects of VBJ103 on CBT were assessed with radiotelemetry. KEY RESULTS: VBJ103 had no antagonist activity at TRPV1 and TRPA1, but low potency TRPA1 activation. The only safety liability detected was partial inhibition of the dopamine transporter (DAT). VBJ103 delivered subcutaneously dose-dependently attenuated cold hypersensitivity in oxaliplatin-treated mice at 3, 10 and 30 mg·kg-1 (n = 7, P < 0.05). VBJ103 (30 mg·kg-1) antinociception was influenced by neither the TRPA1 antagonist HC-030031 nor the DAT antagonist GBR12909. Subcutaneous administration of VBJ103 (3, 10 and 30 mg·kg-1, but not 100 or 300 mg·kg-1, n = 7) decreased CBT (2°C). Intraperitoneal (i.p.) administration of VBJ103 (3, 10 and 30 mg·kg-1) dose-dependently decreased CBT to an extent larger than that detected with subcutaneous administration. Intracerebroventricular (i.c.v.) administration (306 nmol/1 µL; n = 5) did not alter CBT. CONCLUSIONS AND IMPLICATIONS: We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a side effect that has largely prevented the translation of TRPM8 as a target.
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Hiperalgesia , Oxaliplatino , Canales Catiónicos TRPM , Animales , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/metabolismo , Masculino , Ratones , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Humanos , Oxaliplatino/administración & dosificación , Inyecciones Subcutáneas , Temperatura Corporal/efectos de los fármacos , Ratones Endogámicos C57BL , Relación Dosis-Respuesta a Droga , Células HEK293 , Síndromes Periódicos Asociados a CriopirinaRESUMEN
Cannabis sativa L. (hemp) is a herbaceous plant rich in cannabinoids with a long history of use in pain treatment. The most well-characterized cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), garnered much attention in chemotherapy-induced peripheral neuropathy (CIPN) treatment. However, few studies have investigated the biological benefits and mechanism of hemp extract on CIPN. In the present study, hemp extract (JG) rich in cannabinoids was extracted by supercritical fluid carbon dioxide extraction (SFCE). The antinociceptive efficacy was evaluated using a paclitaxel-induced peripheral neuropathy (PIPN) rat model based on behavioral tests. Further omics-based approaches were applied to explore the potential mechanisms. The results showed that JG decreased mechanical allodynia, thermal hyperalgesia, and inflammatory cytokines in PIPN rats significantly. Transcriptome analysis identified seven key genes significantly regulated by JG in PIPN model rats, mainly related to the neuroactive ligand-receptor interaction pathway, PPAR signaling pathway, and cAMP signaling pathway. In metabolomic analysis, a total of 39 significantly altered metabolites were identified, mainly correlated with pentose and glucuronate interconversions and the glycerophospholipid metabolism pathway. Gut microbiota analysis suggested that increased community Lachnoclostridium and Lachnospiraceae_UCG-006 in PIPN rats can be reversed significantly by JG. In conclusion, hemp extract exhibited antinociceptive effects on PIPN. The analgesic mechanism was probably related to the regulation of inflammation, neuroactive ligand-receptor interaction pathway, sphingolipid metabolism, etc. This study provides novel insights into the functional interactions of Cannabis sativa L. extract on PIPN.
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Analgésicos , Cannabis , Neuralgia , Paclitaxel , Extractos Vegetales , Animales , Cannabis/química , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ratas , Analgésicos/farmacología , Analgésicos/química , Paclitaxel/efectos adversos , Masculino , Metabolómica , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Cannabinoides/farmacología , MultiómicaRESUMEN
BACKGROUND: Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM. METHODS: A mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated. RESULTS: Repeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE. CONCLUSION: EE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.
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Sensibilización del Sistema Nervioso Central , Modelos Animales de Enfermedad , Hiperalgesia , Trastornos Migrañosos , Nitroglicerina , Animales , Nitroglicerina/toxicidad , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/metabolismo , Hiperalgesia/inducido químicamente , Femenino , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Sensibilización del Sistema Nervioso Central/fisiología , Ratones , Péptido Relacionado con Gen de Calcitonina/metabolismo , Ambiente , Ratones Endogámicos C57BLRESUMEN
The purpose of this study was to assess, from a behavioral, biochemical, and molecular standpoint, how exercise training affected fibromyalgia (FM) symptoms in a reserpine-induced FM model and to look into the potential involvement of the hippocampal PGC-1α/FNDC5/BDNF pathway in this process. Reserpine (1 mg kg-1) was subcutaneously injected once daily for three consecutive days and then the rats were exercised for 21 days. Mechanical allodynia was evaluated 1, 11, and 21 days after the last injection. At the end of the exercise training protocol forced swim, open field and Morris water maze tests were performed to assess depression, locomotion and cognition, respectively. Additionally, biochemical and molecular markers related to the pathogenesis of the FM and cognitive functions were measured. Reserpine exposure was associated with a decrease in locomotion, an increase in depression, an increase in mechanical allodynia, and a decrease in spatial learning and memory (p < 0.05). These behavioral abnormalities were found to be correlated with elevated blood cytokine levels, reduced serotonin levels in the prefrontal cortex, and altered PGC-1α/FNDC5/BDNF pathway in the hippocampus (p < 0.05). Interestingly, exercise training attenuated all the neuropathological changes mentioned above (p < 0.05). These results imply that exercise training restored behavioral, biochemical, and molecular changes against reserpine-induced FM-like symptoms in rats, hence mitigating the behavioral abnormalities linked to pain, depression, and cognitive functioning.