RESUMEN
BACKGROUND: Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect. METHODS: CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG). RESULTS: Oral administration of two doses of nicorandil (150 mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40 mg/kg) or naltrexone (5 mg/kg or 10 mg/kg). Two doses of nicorandil (150 mg/kg, po) reduced tumor necrosis factor-α, interleukin-1ß and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150 mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150 mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG. CONCLUSIONS: Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity.
Asunto(s)
Citocinas , Modelos Animales de Enfermedad , Ganglios Espinales , Hiperalgesia , Canales KATP , Neuralgia , Nicorandil , Nervio Ciático , Animales , Nicorandil/farmacología , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ratones , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Masculino , Citocinas/metabolismo , Canales KATP/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Gliburida/farmacología , Naltrexona/farmacología , Naltrexona/análogos & derivados , Peroxidasa/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Analgésicos/farmacologíaRESUMEN
The dynorphin peptides are the endogenous ligands for the kappa opioid receptor (KOR) and regulate food intake. Administration of dynorphin-A1-13 (DYN) in the paraventricular hypothalamic nucleus (PVN) increases palatable food intake, and this effect is blocked by co-administration of the orexin-A neuropeptide, which is co-released with DYN in PVN from neurons located in the lateral hypothalamus. While PVN administration of DYN increases palatable food intake, whether it increases food-seeking behaviors has yet to be examined. We tested the effects of DYN and norBNI (a KOR antagonist) on the seeking and consumption of sucrose using a progressive ratio (PR) and demand curve (DC) tasks. In PVN, DYN did not alter the sucrose breaking point (BP) in the PR task nor the elasticity or intensity of demand for sucrose in the DC task. Still, DYN reduced the delay in obtaining sucrose and increased licks during sucrose intake in the PR task, irrespective of the co-administration of orexin-A. In PVN, norBNI increased the delay in obtaining sucrose and reduced licks during sucrose intake in the PR task while increasing elasticity without altering intensity of demand in the DC task. However, subcutaneous norBNI reduced the BP for sucrose and increased the delay in obtaining sucrose in the PR task while reducing the elasticity of demand. Together, these data show different effects of systemic and PVN blockade of KOR on food-seeking, consummatory behaviors, and incentive motivation for sucrose and suggest that KOR activity in PVN is necessary but not sufficient to drive seeking behaviors for palatable food.
Asunto(s)
Dinorfinas , Motivación , Núcleo Hipotalámico Paraventricular , Receptores Opioides kappa , Receptores Opioides kappa/metabolismo , Dinorfinas/farmacología , Dinorfinas/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Animales , Masculino , Motivación/efectos de los fármacos , Orexinas , Ratas , Ratas Sprague-Dawley , Naltrexona/farmacología , Naltrexona/análogos & derivados , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Ingestión de Alimentos/psicología , Sacarosa , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/psicología , Antagonistas de Narcóticos/farmacologíaRESUMEN
Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked.
Asunto(s)
Dolor Crónico , Trastornos Relacionados con Opioides , Ratas , Ratones , Animales , Analgésicos Opioides/farmacología , Agonismo Inverso de Drogas , Ratas Wistar , Inflamación/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Péptidos Opioides/uso terapéutico , Naltrexona/farmacología , Naltrexona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
Painmanagement after oral surgeries is essential to enhance recovery, reduce negative outcomes and improve the experience of the patient. Naltrexone (NTX) is a non-selective opioid receptor antagonist that has been shown to modulate neuro-inflammation when employed in low to ultra-low doses. In addition, ultra-low dose naltrexone (ULDN) has been shown to potentiate opioids' analgesia and to have opioid-sparing effects. Herein it was investigated the effect of ULDN in a model of postoperative orofacial pain in rats, and it was tested the hypothesis that blockade of TLR4-signalling pathway contributes to its antinociceptive effect. Systemic NTX reduced heat hyperalgesia in female rats and heat and mechanical hyperalgesia in male rats after incision surgery. Combined treatment with NTX and morphine, both at ineffective doses, resulted in a significant reduction of heat hyperalgesia in male rats. NTX injection at the incision site failed to change heat hyperalgesia, but injection at the trigeminal ganglion (TG) or subnucleus caudalis (Sp5C) caused a significant reduction in heat hyperalgesia. At these sites, blockade of TLR4 impeded NTX effect. Lipopolysaccharide (LPS) injection in the intraoral mucosa resulted in facial heat hyperalgesia an increase in IL-1ß levels in the TG, which were reduced by systemic NTX. Stimulation of macrophages with LPS resulted in increase of nitric oxide, IL-1ß and CXCL-2 levels which were reduced by NTX. Altogether, these results provide evidence for an antinociceptive effect of ULDN in postoperative orofacial pain and suggest that blockade of TLR4 and downstream signaling pathway contribute to its effect.
Asunto(s)
Hiperalgesia , Naltrexona , Masculino , Femenino , Ratas , Animales , Naltrexona/farmacología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Receptor Toll-Like 4/metabolismo , Lipopolisacáridos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Dolor Facial/tratamiento farmacológico , Dolor Postoperatorio/tratamiento farmacológicoRESUMEN
Naltrexone is a potent opioid antagonist with good blood-brain barrier permeability, targeting different endogenous opioid receptors, particularly the mu-opioid receptor (MOR). Therefore, it represents a promising candidate for drug development against drug addiction. However, the details of the molecular interactions of naltrexone and its derivatives with MOR are not fully understood, hindering ligand-based drug discovery. In the present study, taking advantage of the high-resolution X-ray crystal structure of the murine MOR (mMOR), we constructed a homology model of the human MOR (hMOR). A solvated phospholipid bilayer was built around the hMOR and submitted to microsecond (µs) molecular dynamics (MD) simulations to obtain an optimized hMOR model. Naltrexone and its derivatives were docked into the optimized hMOR model and submitted to µs MD simulations in an aqueous membrane system. The MD simulation results were submitted to the molecular mechanics-generalized Born surface area (MMGBSA) binding free energy calculations and principal component analysis. Our results revealed that naltrexone and its derivatives showed differences in protein-ligand interactions; however, they shared contacts with residues at TM2, TM3, H6, and TM7. The binding free energy and principal component analysis revealed the structural and energetic effects responsible for the higher potency of naltrexone compared to its derivatives.
Asunto(s)
Naltrexona , Receptores Opioides mu , Animales , Humanos , Ligandos , Ratones , Simulación de Dinámica Molecular , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Receptores Opioides mu/metabolismo , AguaRESUMEN
OBJECTIVE: To evaluate the effects of combining topiramate, bupropion and naltrexone in obesity-induced rats on their weight and subcutaneous adipose tissue. METHODS: A total of 40 male Wistar rats were induced to obesity for 8 weeks and the animals were divided into 8 groups: Ctr - control, G0 - Sham, G1 - oral saline solution (1.0mL/day), G2 - topiramate (20.0mg/kg) and bupropion (5.0mg/kg), G3 - naltrexone (20.0mg/kg), G4 - topiramate (20.0mg/kg), G5 - bupropion (5.0mg/kg) and G6 - topiramate (20.0mg/kg), bupropion (5.0mg/kg) and naltrexone (20.0mg/kg). During the experiment, all animals were weighed weekly. After 30 days of treatment animals were euthanized and their skin fragments were processed and stained with hematoxylin and eosin for morphological, morphometric and biochemical analyzes. RESULTS: The only group that presented a decrease in the volume of subcutaneous adipose tissue was G3, but this decrease was not significant when compared with the other groups. The G4, the G5 and the G6 presented increased adipose tissue volume. Data showed that until the eighth week all animals increased their weight by approximately 50%. After treatment animals of all groups, except G3, increased their weight from 4% to 9% approximately. The G3 was the only group that lost weight, but this decrease was not significant. CONCLUSION: The medicines studied were not efficient in reducing weight in obese rats. However, it should be considered that 30-day treatment period is not enough to observe the stronger effects of these drugs.
Asunto(s)
Bupropión , Naltrexona , Animales , Bupropión/farmacología , Bupropión/uso terapéutico , Humanos , Masculino , Naltrexona/farmacología , Naltrexona/uso terapéutico , Obesidad/tratamiento farmacológico , Ratas , Ratas Wistar , Grasa Subcutánea , Topiramato/farmacología , Topiramato/uso terapéuticoRESUMEN
Obesogenic diets are known to induce obesity and changes in food intake in experimental animals. Obesity negatively affects the peripheral metabolism and neural aspects, such as changes in eating behavior. In obese animals, dopamine (DA) receptor levels are reduced. DA is one of the main peptides involved in the motivation and pleasure of eating. A combination of naltrexone/bupropion (NB) has shown promise in controlling metabolic alterations, but there are few studies on how they modulate dopaminergic expression. NB, in addition to reducing food intake and body weight, can modify tyrosine hydroxylase (Th) and DA receptor D2 (Drd2) levels in the mesolimbic areas of rats submitted to a high-fat diet (HF). The study evaluated the effect of NB on food intake, body weight, and expression levels of Th, Drd1a, and Drd2, in the nucleus accumbens and striatum of rats fed on HF diet. Wistar rats were grouped according to diet: standard (n = 20) and HF diet (n = 20). The food intake and body weight were analyzed. The gene expression of Th, Drd1a, and Drd2 was evaluated using real-time PCR. NB combination of 1 mg/kg and 20 mg/kg reduced food intake and body weight, increased Drd2 expression in rats on HF diet, and increased Th in rats on both experimental diets. The level of Drd1a was unchanged. We concluded that bodyweight reduction may be associated with decreased food intake in response to the increased Drd2 expression in the mesolimbic areas of rats that received an HF diet.
Asunto(s)
Bupropión , Naltrexona , Animales , Peso Corporal , Bupropión/farmacología , Dieta Alta en Grasa , Ingestión de Alimentos , Expresión Génica , Naltrexona/farmacología , Obesidad/genética , Obesidad/metabolismo , Ratas , Ratas Wistar , Receptores de Dopamina D2/genética , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The participation of the peripheral opioid and cannabinoid endogenous systems in modulating muscle pain and inflammation has not been fully explored. Thus, the aim of this study was to investigate the involvement of these endogenous systems during muscular-tissue hyperalgesia induced by inflammation. Hyperalgesia was induced by carrageenan injection into the tibialis anterior muscles of male Wistar rats. We padronized an available Randal-Sellito test adaptation to evaluate nociceptive behavior elicited by mechanical insult in muscles. Western blot analysis was performed to evaluate the expression levels of opioid and cannabinoid receptors in the dorsal root ganglia. The non-selective opioid peptide receptor antagonist (naloxone) and the selective mu opioid receptor MOP (clocinnamox) and kappa opioid receptor KOP (nor-binaltorphimine) antagonists were able to intensify carrageenan-induced muscular hyperalgesia. On the other hand, the selective delta opioid receptor (DOP) antagonist (naltrindole) did not present any effect on nociceptive behavior. Moreover, the selective inhibitor of aminopeptidases (Bestatin) provoked considerable dose-dependent analgesia when intramuscularly injected into the hyperalgesic muscle. The CB1 receptor antagonist (AM251), but not the CB2 receptor antagonist (AM630), intensified muscle hyperalgesia. All irreversible inhibitors of anandamide hydrolase (MAFP), the inhibitor for monoacylglycerol lipase (JZL184) and the anandamide reuptake inhibitor (VDM11) decreased carrageenan-induced hyperalgesia in muscular tissue. Lastly, MOP, KOP and CB1 expression levels in DRG were baseline even after muscular injection with carrageenan. The endogenous opioid and cannabinoid systems participate in peripheral muscle pain control through the activation of MOP, KOP and CB1 receptors.
Asunto(s)
Mialgia/tratamiento farmacológico , Receptores de Cannabinoides/fisiología , Receptores Opioides/fisiología , Animales , Ácidos Araquidónicos/antagonistas & inhibidores , Carragenina , Cinamatos/farmacología , Endocannabinoides/antagonistas & inhibidores , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/psicología , Masculino , Monoacilglicerol Lipasas/antagonistas & inhibidores , Derivados de la Morfina/farmacología , Mialgia/inducido químicamente , Mialgia/psicología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Dimensión del Dolor/efectos de los fármacos , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Ratas , Ratas Wistar , Receptores de Cannabinoides/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Receptores Opioides delta/efectos de los fármacos , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacosRESUMEN
Adverse experiences that occur during the early stages of life can have permanent repercussions in adulthood. Among these experiences, early weaning is one that can alter the molecular, cellular, and behavior patterns in later life. Centered on this fact, the objective of the current study was to evaluate the effect of early weaning at 15â¯days of life of Wistar rats on their feeding behavior and if the opioidergic system blockade would cause a reversal of these outcomes. Experimental groups were formed based on the weaning period of each litter. On postnatal day 15, the group D15 was weaned and, on postnatal day 30 (natural weaning), the group D30 was weaned. The rats weaned on postnatal day 15, and administered subcutaneous Naltrexone (3â¯mg/kg) were from group D15â¯+â¯NTX. Those weaned at 15â¯days of age exhibited higher depressive-like behavior, lesser reactivity time to sucrose, and higher intake of palatable food than the control group. The Naltrexone administration was observed to reverse some outcomes, such as increasing the reactivity time to sucrose and decreasing the quantity of palatable food consumed, to levels similar to those of the control group. Together, the findings of the present study are indicative of the vital role played by the opioidergic system in inducing the changes noted in the eating behavior patterns during adulthood, post early weaning.
Asunto(s)
Conducta Alimentaria , Naltrexona , Animales , Hábitos , Naltrexona/farmacología , Ratas , Ratas Wistar , DesteteRESUMEN
Naltrexone (NTX) is an opioid antagonist that inhibits cell proliferation in vivo when administered in low doses. Naltrexone in low doses can reduce tumor growth by interfering with cell signalling as well as by modifying the immune system. It acts as an Opioid Growth Factor receptor (OGFr) antagonist and the OGF-OGFr axis is an inhibitory biological pathway present in human cancer cells and tissues, being a target for the treatment with naltrexone low-dose (LDN). Clinical trials have proposed a unique mechanism(s) allowing LDN to affect tumors. LDN shows promising results for people with primary cancer of the bladder, breast, liver, lung, lymph nodes, colon and rectum. This short review provides further evidence to support the role of LDN as an anticancer agent.
Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Proliferación Celular , Humanos , Naltrexona/farmacología , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
The development of analgesic drugs is still a necessity due to the inefficiency of the current treatments for some pathological conditions and also due to the adverse effects produced by these drugs. The aim of this study was to deepen the pharmacological study of two new hybrids NSAIDs tetrahydropyran derivatives, regarding their antinociceptive effects on acute pain in mice. Male swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail-flick, open-field, glutamate- and capsaicin-induced paw licking tests, and in vitro Cox inhibition assay, besides the acute toxicological evaluation. The compounds had an effect on the acetic acid-induced abdominal writhing, formalin (both phases), and tail-flick tests. In the study of the mechanism of action was observed reversion of the antinociceptive effect of the compounds from the previous administration of naloxone, L-NAME (L-nitro-arginine methyl ester), ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), glibenclamide, and nor-binaltorphimine, by the intrathecal and intraperitoneal routes. The prior administration of MK-801 suggests that the modulation of NMDA receptor contributes to the antinociceptive effect of compounds. In summary, hybrid compounds presented central antinociceptive effect, demonstrating participation of the NO-cGMP-K+ ATP pathway, κ-opioid, and NMDA receptors. In addition, the compounds showed inhibition of cyclo-oxygenase enzymes and adverse effects were not observed with dose 300 times greater than the dose used experimentally.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Adenosina Trifosfato/metabolismo , Analgésicos Opioides/farmacología , Animales , GMP Cíclico/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Maleato de Dizocilpina/farmacología , Formaldehído/farmacología , Gliburida/farmacología , Humanos , Masculino , Ratones , NG-Nitroarginina Metil Éster/farmacología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Dimensión del Dolor/métodos , Canales de Potasio/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Ayahuasca is a hallucinogenic infusion used in religious rituals that has serotoninergic properties and may be a potential therapeutic option for drug addiction. In this study, Wistar rats had intermittent access to ethanol for 8 weeks, receiving water (control), naltrexone (NTX, 2 mg/kg body weight [bw] intraperitoneally [i.p.]) or ayahuasca (Aya) at 0.5x, 1x, or 2x the ritual dose in the final 5 days. A naïve group had access only to water. Ethanol intake was estimated throughout the experiment, and cFos expression was evaluated in medial orbital cortex (MO), ventral orbital cortex (VO), lateral orbital cortex (LO), nucleus accumbens (NAc), and striatum. Treatment with either NTX or Aya (oral) did not decrease ethanol intake compared to the baseline level (5th to 7th week), but the NTX group intake was significantly lower than controls (p < 0.05). Ethanol significantly increased cFos expression in the MO region for control (p < 0.0001), NTX (p < 0.05), Aya1 (p < 0.001), and Aya2 (p < 0.0001) groups. This increase was also observed in the VO for the Aya1 group (p = 0.035), in the LO for the Aya2 group (p < 0.01), and in NAc for NTX and ayahuasca groups (p < 0.005). Furthermore, NTX and Aya0.5 treatment decreased cFos expression compared to controls in the MO region (p < 0.05 and p < 0.01, respectively), but only the ayahuasca group reached levels not significantly different from the naïve group. Studies using other protocols and dose regime are necessary to better investigate the impact of ayahuasca on alcohol intake by rats to support the observations in humans. Additionally, the role of ayahuasca in mediating cFos expression in other selected brain regions and its relationship with the serotoninergic/dopaminergic systems and drug addiction need further investigation.
Asunto(s)
Banisteriopsis , Encéfalo/efectos de los fármacos , Etanol/administración & dosificación , Alucinógenos/farmacología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Consumo de Bebidas Alcohólicas , Animales , Cuerpo Estriado/efectos de los fármacos , Masculino , Modelos Animales , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Agua/administración & dosificaciónRESUMEN
Ketamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective µ- and δ-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not κ-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced ß-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for µ- and δ-opioid receptors and for the endogenous opioid ß-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.
Asunto(s)
Analgésicos/uso terapéutico , Ketamina/uso terapéutico , Dolor/tratamiento farmacológico , Receptores Opioides delta , Receptores Opioides mu , Analgésicos/farmacología , Animales , Cinamatos/farmacología , Dinoprostona , Ketamina/farmacología , Masculino , Ratones , Derivados de la Morfina/farmacología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/inducido químicamente , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidoresRESUMEN
BACKGROUND: Gamma-aminobutyric acid (GABA)ergic and opioid systems play a crucial role in the neural modulation of innate fear organised by the inferior colliculus (IC). In addition, the IC is rich in GABAergic fibres and opioid neurons, which are also connected to other mesencephalic structures, such as the superior colliculus and the substantia nigra. However, the contribution of distinct opioid receptors (ORs) in the IC during the elaboration and expression of innate fear and panic-like responses is unclear. The purpose of the present work was to investigate a possible integrated action exerted by ORs and the GABAA receptor-mediated system in the IC on panic-like responses. METHODS: The effect of the blockade of either µ1- or κ-ORs in the IC was evaluated in the unconditioned fear-induced responses elicited by GABAA antagonism with bicuculline. Microinjections of naloxonazine, a µ1-OR antagonist, or nor-binaltorphimine (nor-BNI), a κ-OR antagonist, were made into the IC, followed by intramesencephalic administration of the GABAA-receptor antagonist bicuculline. The defensive behaviours elicited by the treatments in the IC were quantitatively analysed, recording the number of escapes expressed as running (crossing), jumps, and rotations, over a 30-min period in a circular arena. The exploratory behaviour of rearing was also recorded. RESULTS: GABAA-receptor blockade with bicuculline in the IC increased defensive behaviours. However, pretreatment of the IC with higher doses (5 µg) of naloxonazine or nor-BNI followed by bicuculline resulted in a significant decrease in unconditioned fear-induced responses. CONCLUSIONS: These findings suggest a role played by µ1- and κ-OR-containing connexions and GABAA receptor-mediated neurotransmission on the organisation of panic attack-related responses elaborated by the IC neurons.
Asunto(s)
Conducta Animal/efectos de los fármacos , Colículos Inferiores/efectos de los fármacos , Mesencéfalo/efectos de los fármacos , Antagonistas de Narcóticos/farmacología , Pánico/efectos de los fármacos , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidores , Animales , Bicuculina/farmacología , Conducta Exploratoria/efectos de los fármacos , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Naloxona/análogos & derivados , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Neuronas/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Metformin, an AMP-activated protein kinase (AMPK) activator, is an oral hypoglycemic drug widely used to treat patients with type 2 diabetes. As AMPK plays a role in the nociceptive processing, investigating the effects induced by metformin in experimental models of pain is warranted. In the present study, we further evaluated the effects induced by metformin in models of nociceptive and neuropathic pain and investigated mechanisms that could mediate such effects. Metformin was administered per os (p.o.) in mice. Nociceptive response induced by heat (hot-plate) and mechanical allodynia induced by chronic constriction injury (CCI) were used as pain models. Naltrexone (intraperitoneal) and glibenclamide (p.o.) were used to investigate mechanisms mediating metformin effects. A single administration of metformin (500 or 1000â¯mg/kg) inhibited the nociceptive response in the hot-plate model. Single and repeated administration of metformin (250, 500 or 1000â¯mg/kg) inhibited the mechanical allodynia induced by CCI. Metformin (250, 500 or 1000â¯mg/kg) did not affect the time mice spent in the rota-rod apparatus. The activity of metformin (1000â¯mg/kg) in both pain models was attenuated by naltrexone (10â¯mg/kg), but not by glibenclamide. Concluding, metformin exhibited activity in models of nociceptive and neuropathic pain. In the model of neuropathic pain, preventive and therapeutic effects were observed. Activation of opioidergic pathways partially mediates metformin antinociceptive activity. Altogether, the results indicate that metformin should be further investigated aiming its repositioning in the treatment of patients with different painful conditions.
Asunto(s)
Analgésicos/farmacología , Metformina/farmacología , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Nocicepción/efectos de los fármacos , Receptores Opioides/metabolismo , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Femenino , Gliburida/farmacología , Hiperalgesia/tratamiento farmacológico , Metformina/uso terapéutico , Ratones , Naltrexona/farmacología , Neuralgia/fisiopatología , Desempeño Psicomotor/efectos de los fármacosRESUMEN
Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that has shown an antinociceptive effect in multiple pain models, such as inflammatory and neuropathic pain by chronic constriction injury in rats; however, its mechanism of action is still not well-understood. Reports suggest that DHA activates opioid signaling, but there is no information on this from a model of neuropathic pain. As a result, the aims of this study were (1) to determine the antihyperalgesic and antiallodynic effect of peripheral DHA administration, and (2) to evaluate the participation of the opioid receptors in the antihyperalgesic effect of DHA on streptozotocin-induced neuropathic pain in the rat. Female Wistar rats were injected with streptozotocin (50â¯mg/kg, i.p.) to induce hyperglycemia. The formalin, Hargreaves, and von Frey filaments tests were used to assess the nociceptive activity. Intraplantar administration of DHA (100-1000⯵g/paw) or gabapentin (562-1778⯵g/paw) decreased formalin-evoked hyperalgesia in diabetic rats, in a dose-dependent manner. Furthermore, DHA (562⯵g/paw) and gabapentin (1000⯵g/paw) reduced thermal hyperalgesia and allodynia. Local peripheral administration of naloxone (non-selective opioid receptor antagonist; 100⯵g/paw), naltrindole (selective δ receptor antagonist; 1⯵g/paw), and CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, µ receptor antagonist; 20⯵g/paw) prevented formalin-evoked hyperalgesia in diabetic rats but not by GNTI (guanidinonaltrindole, κ receptor antagonist;1⯵g/paw). It is suggested that peripheral DHA shows an antihyperalgesic effect in neuropathic pain in the rat. Furthermore, δ and µ receptors are involved in the antihyperalgesic peripheral effect of DHA in diabetic rats.
Asunto(s)
Analgésicos/administración & dosificación , Neuropatías Diabéticas/tratamiento farmacológico , Ácidos Docosahexaenoicos/administración & dosificación , Analgésicos/farmacología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Neuropatías Diabéticas/inducido químicamente , Ácidos Docosahexaenoicos/farmacología , Relación Dosis-Respuesta a Droga , Gabapentina/administración & dosificación , Gabapentina/farmacología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Ratas , Ratas Wistar , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidores , Receptores sigma/antagonistas & inhibidores , EstreptozocinaRESUMEN
The objective of this study was to evaluate the effect of low-dose naltrexone (LDN) as a carboplatin chemotherapy-associated drug in female dogs with mammary carcinoma in benign mixed tumors (MC-BMT) after mastectomy and to assess its association with quality of life and survival rates. Sixty female dogs were included in this study, all of which had histopathological diagnosis of MC-BMT and were divided into three groups: G1 (control), consisting of animals submitted only to mastectomy with or without regional metastasis; G2, composed of treated animals that did not present with metastasis; and G3, treated dogs that presented with metastasis. G2 and G3 were also subdivided according to the treatment administered: chemotherapy alone (MC-BMT(-) C/MC-BMT(+) C) or LDN and chemotherapy (MC-BMT(-) C+LDN/MC-BMT(+) C+LDN). All animals were subjected to clinical evaluation, mastectomy, peripheral blood lymphocyte immunophenotyping, beta-endorphin and met-enkephalin quantification, and evaluation of survival rates and quality of life scores. The results showed higher serum concentrations of beta-endorphin and met-enkephalin, fewer chemotherapy-related side effects, and better quality of life and survival rates in the LDN-treated groups than in LDN-untreated groups (P < 0.05). Evaluation of clinical and pathological parameters indicated a significant association between the use of LDN and both prolonged survival and enhanced quality of life. These results indicate that LDN is a viable chemotherapy-associated treatment in female dogs with MC-BMT, maintaining their quality of life and prolonging survival rates.
Asunto(s)
Carboplatino/administración & dosificación , Carboplatino/farmacología , Linfocitos/metabolismo , Neoplasias Mamarias Animales/tratamiento farmacológico , Naltrexona/administración & dosificación , Animales , Perros , Sinergismo Farmacológico , Encefalina Metionina/metabolismo , Femenino , Inmunofenotipificación , Neoplasias Mamarias Animales/inmunología , Neoplasias Mamarias Animales/cirugía , Mastectomía/veterinaria , Naltrexona/farmacología , Metástasis de la Neoplasia , Calidad de Vida , Análisis de Supervivencia , Resultado del Tratamiento , betaendorfina/metabolismoRESUMEN
BACKGROUND: Conditioned stimuli (CS) that predict reward delivery acquire the ability to induce phasic dopamine release in the nucleus accumbens (NAc). This dopamine release may facilitate conditioned approach behavior, which often manifests as approach to the site of reward delivery (called "goal-tracking") or to the CS itself (called "sign-tracking"). Previous research has linked sign-tracking in particular to impulsivity and drug self-administration, and addictive drugs may promote the expression of sign-tracking. Ethanol (EtOH) acutely promotes phasic release of dopamine in the accumbens, but it is unknown whether an alcoholic reward alters dopamine release to a CS. We hypothesized that Pavlovian conditioning with an alcoholic reward would increase dopamine release triggered by the CS and subsequent sign-tracking behavior. Moreover, we predicted that chronic intermittent EtOH (CIE) exposure would promote sign-tracking while acute administration of naltrexone (NTX) would reduce it. METHODS: Rats received 14 doses of EtOH (3 to 5 g/kg, intragastric) or water followed by 6 days of Pavlovian conditioning training. Rewards were a chocolate solution with or without 10% (w/v) alcohol. We used fast-scan cyclic voltammetry to measure phasic dopamine release in the NAc core in response to the CS and the rewards. We also determined the effect of NTX (1 mg/kg, subcutaneous) on conditioned approach. RESULTS: Both CIE and alcoholic reward, individually but not together, associated with greater dopamine to the CS than control conditions. However, this increase in dopamine release was not linked to greater sign-tracking, as both CIE and alcoholic reward shifted conditioned approach from sign-tracking behavior to goal-tracking behavior. However, they both also increased sensitivity to NTX, which reduced goal-tracking behavior. CONCLUSIONS: While a history of EtOH exposure or alcoholic reward enhanced dopamine release to a CS, they did not promote sign-tracking under the current conditions. These findings are consistent with the interpretation that EtOH can stimulate conditioned approach, but indicate that the conditioned response may manifest as goal-tracking.
Asunto(s)
Condicionamiento Clásico/efectos de los fármacos , Dopamina/metabolismo , Etanol/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Recompensa , Animales , Señales (Psicología) , Técnicas Electroquímicas , Etanol/antagonistas & inhibidores , Masculino , Naltrexona/farmacología , RatasRESUMEN
The main κ opioid receptors (κORs) subtypes already described (κ1ORs and κ2ORs) are expressed in brain regions involved in aversive memory consolidation, including the dorsal hippocampus (DH). However, the role of DH κORs in consolidation of aversive memories with varied intensity and specificity is still uncertain. The present study aimed to investigate this question using pharmacological agents in rats subjected to a weak, moderate or strong contextual aversive conditioning (CAC) protocol. Antagonizing DH κORs with nor-binaltorphimine (nor-BNI), immediately after, but not 6â¯h later, a moderate CAC leads to intensified freezing behavior in the re-exposure to the paired context. Thus, indicating that DH κORs have an inhibitory role in the consolidation of an aversive memory. Increased DH κORs expression 1â¯h and 3â¯h after the moderate CAC was also observed. This up-regulation was absent in animals only exposed to the shock or to the context, indicating that this phenomenon requires a shock-context pairing to occur. Intra-DH nor-BNI infusion induced no changes following a weak CAC, but it was able to potentiate the expression of freezing behavior in novel and unpaired context after a strong CAC, indicating that DH κORs also modulate the consolidation of a more intense and generalized memory. Moreover, infusing the κ2ORs agonist GR 89696, but not the κ1ORs agonist U-69593, into the DH reduced the conditioned freezing expression. Nor-BNI pretreatment in a sub-effective dose prevented the κ2ORs agonist effects. Altogether, the present findings provide convergent evidence that κORs activation negatively modulates contextual aversive memory consolidation in rat dorsal hippocampus.
Asunto(s)
Reacción de Prevención/fisiología , Hipocampo/metabolismo , Consolidación de la Memoria/fisiología , Receptores Opioides kappa/metabolismo , Analgésicos Opioides/farmacología , Animales , Asociación , Reacción de Prevención/efectos de los fármacos , Bencenoacetamidas/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Electrochoque , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Hipocampo/efectos de los fármacos , Masculino , Consolidación de la Memoria/efectos de los fármacos , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Piperazinas/farmacología , Psicotrópicos/farmacología , Pirrolidinas/farmacología , Distribución Aleatoria , Ratas Wistar , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidoresRESUMEN
PURPOSE: Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. METHODS: The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE2 (2 µg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model. RESULTS: The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 µg), naltrindole (60 µg) and nor-binaltorfimina (200 µg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 µg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng). CONCLUSIONS: These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes.