RESUMO
It has been proposed that neurotrophin-3 acts in a manner that is opposed to nerve growth factor, especially in the modulation of heat hyperalgesia. Injury to the constriction of the infraorbital nerve (CION) is a well-established model of trigeminal neuropathic pain that leads to robust heat, cold, and mechanical hyperalgesia. Here, we assessed the effect of local neurotrophin-3 treatment on CION-induced hyperalgesia, and we examined some mechanisms related to the effect of neurotrophin-3. Neurotrophin-3 (1 µg/50 µl) injected into the upper lip of CION rats caused a significant and long-lasting reduction of CION-induced heat hyperalgesia, but failed to affect cold and mechanical hyperalgesia. Increased levels of neurotrophin-3 were detected in the injured nerve at the time point that represents the peak of heat hyperalgesia. The anti-hyperalgesic effect of neurotrophin-3 was markedly reduced in the presence of an antagonist of TrkA receptors (K-252a, 1 µg/50 µl). Moreover, association of lower doses of neurotrophin-3 with an antibody anti-nerve growth factor resulted in a synergistic anti-hyperalgesic effect in CION rats. Local injection of nerve growth factor (3 µg/50 µl) or the TRPV1 agonist capsaicin (1 µg/50 µl), but not neurotrophin-3 injection (1 µg/50 µl), resulted in long-lasting facial heat hyperalgesia, which was both significantly reduced by previous neurotrophin-3 local treatment. In conclusion, we suggest that neurotrophin-3 is a potent modulator of facial heat hyperalgesia, which may exert an inhibitory influence on the trkA pathway. Neurotrophin-3 treatment may represent a promising approach, especially in pain conditions associated with increased levels of nerve growth factor.
Assuntos
Hiperalgesia/tratamento farmacológico , Fator de Crescimento Neural/metabolismo , Neurotrofina 3/administração & dosagem , Animais , Capsaicina/farmacologia , Dor Facial/tratamento farmacológico , Dor Facial/metabolismo , Temperatura Alta , Hiperalgesia/metabolismo , Masculino , Ratos , Ratos Wistar , Receptor trkA/metabolismo , Neuralgia do Trigêmeo/tratamento farmacológico , Neuralgia do Trigêmeo/metabolismoRESUMO
OBJECTIVE: To improve understanding of the pathophysiology of cancer-induced facial nociception, by evaluating the contribution of peripheral endothelin receptors in tumor-induced facial heat hyperalgesia, increased spontaneous grooming, as well as ongoing nociception in a rat model of facial cancer. DESIGN: The study was conducted using 396 rats. Facial cancer was induced by inoculating a suspension of Walker-256 cells into the rats' right vibrissal pad. Facial heat hyperalgesia and spontaneous grooming were assessed on day 6, while the conditioned place preference (CPP) test was performed on days 3-6 after tumor cells inoculation. Rats received local injections of the non-peptidic dual ETA/ETB endothelin receptors antagonist, bosentan (10 and 30 µg/50 µL), single or combined injections of peptidic ETA and ETB endothelin receptors antagonists (BQ-123 and BQ-788, at 20 ug/50 µL, each), or of lidocaine (1 mg/50 µl) and morphine (30 µg/50 µL). RESULTS: Bosentan, lidocaine and morphine local treatment all attenuated tumor-induced heat hyperalgesia (p < 0.05) and spontaneous facial grooming (p < 0.05). However, BQ-123 and BQ-788 did not modify tumor-induced heat hyperalgesia or the spontaneous facial grooming (p > 0.05). Whether this difference in effectiveness is due to receptor affinity or to pharmacokinetic factors still needs to be explored. Local injection of bosentan, lidocaine or morphine failed to control ongoing nociception, as evidenced by the absence of CPP in tumor-bearing rats (p > 0.05). CONCLUSION: Endothelins, acting through peripheral ETA and ETB receptors, may play a significant role on the development of heat hyperalgesia and increased spontaneous grooming associated to facial cancer in rats.
Assuntos
Dor do Câncer/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/farmacologia , Neoplasias Faciais/fisiopatologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Receptores de Endotelina/metabolismo , Animais , Bosentana/farmacologia , Modelos Animais de Doenças , Temperatura Alta , Lidocaína/farmacologia , Masculino , Morfina/farmacologia , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , RatosRESUMO
Pain reported by patients with head and neck cancer is characterized as persistent pain with mechanical allodynia. Pain management is inadequate for many patients, highlighting the need for improved therapies. We examined the hypothesis that the mixed endothelin ETA and ETB receptor antagonist, bosentan, reduces tumor-induced ongoing pain and evoked hypersensitivity in a rat model of facial cancer pain. Facial cancer was induced by inoculating a suspension of Walker-256 cells into the rat's right vibrissal pad. Tumor-bearing rats developed heat and tactile hypersensitivity along with increased spontaneous grooming behavior. Systemic morphine (2.5mg/kg, s.c.) blocked tumor-induced thermal and tactile hypersensitivity, with a lower dose (0.625mg/kg, s.c.) effective only against thermal hypersensitivity. Systemic bosentan blocked tumor-induced thermal hypersensitivity only at a high (300mg/kg, p.o.) dose, but failed to modify tactile hypersensitivity. Co-administration of the low doses of bosentan and morphine resulted in improved reduction of the tumor-induced heat and tactile hypersensitivity compared to either dose alone. Bosentan (100mg/kg, p.o.) reduced spontaneous grooming and induced conditioned place preference (CPP) selectively in tumor-bearing rats, suggesting that bosentan reduces tumor-induced ongoing pain at a lower dose than required to block tumor-induced hypersensitivity. This study provides evidence that endothelins may mediate tumor-induced ongoing pain and thermal hypersensitivity. In addition, bosentan enhanced morphine's effects on blocking tumor-induced heat and tactile hypersensitivity indicating that endothelin antagonists may be beneficial therapeutic targets that can be used to manage cancer-induced facial pain with opioid-sparing effects.
Assuntos
Dor do Câncer/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/farmacologia , Neoplasias Faciais/complicações , Hiperalgesia/tratamento farmacológico , Receptores de Endotelina/metabolismo , Animais , Bosentana , Dor do Câncer/complicações , Dor do Câncer/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/uso terapêutico , Neoplasias Faciais/patologia , Masculino , Morfina/farmacologia , Morfina/uso terapêutico , Ratos , Ratos Wistar , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
OBJECTIVE: Pronociceptive responses to endothelins in the trigeminal system seem to be mediated by ETA and ETB receptors, which have been shown to be expressed in neurons of the trigeminal ganglion of humans and rats. The present study aimed to evaluate the ability of endothelin-1 (ET-1) to induce facial heat hyperalgesia in female rats, the contribution of ETA and ETB receptors to this response, as well as the mechanisms underlying heat hyperalgesia induced by ET-1. DESIGN: ET-1 (100pmol/50µL) was injected into the upper lip and heat hyperalgesia was evaluated for up to 6h. Facial heat hyperalgesia induced by ET-1 was assessed in rats pre-treated locally with BQ-123 or BQ-788 (selective ETA and ETB receptor antagonists, respectively, 30nmol/50µL); BCTC (TRPV1 receptor antagonist; 300µg/50µL); anti-NGF (3µg/50µL); K252a (TrkA inhibitor, 1µg/50µL); or in rats that received intraganglionar resiniferatoxin injection (RTX, 200ng/10µL) to promote C-fibers ablation. RESULTS: ET-1 induced facial heat hyperalgesia that persisted up to 6h and was prevented by BQ-123, BQ-788 or by intraganglionar RTX injection. Likewise, local pre-treatment with BCTC abolished ET-1 induced facial heat hyperalgesia up to 3h. Local pre-treatment with anti-NGF or K252a was effective to prevent ET-1 induced heat hyperalgesia. CONCLUSIONS: In conclusion, ET-1 is able to induce heat hyperagelsia in trigeminal primary afferents of female rats, which is mediated by ETA and ETB receptors. Activation of TRPV1 receptors and NGF-signaling pathways may contribute to heat hyperalgesia induced by ET-1.
Assuntos
Endotelina-1/farmacologia , Face , Hiperalgesia/induzido quimicamente , Gânglio Trigeminal/metabolismo , Animais , Carbazóis/farmacologia , Diterpenos/farmacologia , Feminino , Temperatura Alta , Hiperalgesia/prevenção & controle , Alcaloides Indólicos/farmacologia , Fator de Crescimento Neural/antagonistas & inibidores , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Pirazinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos WistarRESUMO
Pain and anxiety are common symptoms in head and neck cancer patients. The anticonvulsant pregabalin has therapeutic indication for the treatment of pain and anxiety, and may represent a useful drug for both conditions. Thus, the aim of this study was to investigate the relationship between pain and anxiety in rats with facial carcinoma, as the influence of pregabalin treatment in both aspects. Facial carcinoma was induced by subcutaneous inoculation of Walker-256 tumor cells in the vibrissa pad of Wistar rats. On day 6 after inoculation spontaneous facial grooming and conditioned place preference were assessed as non-evoked pain measurements and facial mechanical hyperalgesia were assessed 3 and 6 days after tumor cells inoculation. Moreover, anxiety-like behavior was evaluated on the elevated plus maze and light-dark transition tests at the same time points. The effect of pregabalin treatment (30 mg/kg, p.o.) was evaluated in all tests. Our results demonstrated that pregabalin treatment reduced the spontaneous facial grooming and induced conditioned place preference 6 days post tumor inoculation. Tumor-bearing rats developed mechanical hyperalgesia starting 3 days post tumor induction, which was also significant on day 6, but the anxiety-like behavior was detected only in tumor-bearing rats that developed mechanical hyperalgesia and only six days after tumor cells inoculation. Both, the mechanical hyperalgesia and the anxiety-like behavior related to the tumor were significantly reduced by pregabalin treatment on day 6. Pregabalin treatment resulted in antinociceptive and anxiolytic-like effects on facial tumor-bearing rats and may represent a promising therapeutic option for cancer patients.
Assuntos
Analgésicos/farmacologia , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Neoplasias Faciais/tratamento farmacológico , Dor Facial/tratamento farmacológico , Pregabalina/farmacologia , Animais , Ansiedade/fisiopatologia , Dor do Câncer/tratamento farmacológico , Dor do Câncer/fisiopatologia , Linhagem Celular Tumoral , Condicionamento Psicológico/efeitos dos fármacos , Neoplasias Faciais/fisiopatologia , Neoplasias Faciais/psicologia , Dor Facial/fisiopatologia , Asseio Animal/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Transplante de Neoplasias , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/fisiopatologia , Ratos Wistar , Comportamento Espacial/efeitos dos fármacos , Tato , VibrissasRESUMO
Substance P (SP) is involved in fever that is induced by lipopolysaccharide (LPS) but not by interleukin-1ß or macrophage inflammatory protein-1α. Intracerebroventricular (i.c.v.) administration of the neurokinin-1 (NK1) receptor antagonist SR140333B in rats reduced fever that was induced by an i.c.v. injection of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2), corticotropin-releasing factor (CRF), endothelin-1 (ET-1), and morphine (MOR). Furthermore, an i.c.v. injection of SP induced a febrile response that was inhibited by indomethacin concomitant with an increase in PGE2 levels in cerebrospinal fluid. Lipopolysaccharide and PGE2 caused higher expression and internalization of NK1 receptors in the hypothalamus which were prevented by SR140333B. These data suggest that SP is an important mediator of fever, in which it induces a prostaglandin-dependent response and is released after TNF-α, IL-6, PGE2, CRF, endogenous opioids, and ET-1.
Assuntos
Dinoprostona/líquido cefalorraquidiano , Febre/induzido quimicamente , Febre/prevenção & controle , Pirogênios , Substância P/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Temperatura Corporal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Indometacina/farmacologia , Interleucina-6/administração & dosagem , Interleucina-6/metabolismo , Masculino , Morfina/farmacologia , Polissacarídeos/toxicidade , Ratos , Ratos Wistar , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Fatores de Tempo , Tropanos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Pain and anxiety are commonly experienced by cancer patients and both significantly impair their quality of life. Some authors claim that there is a relationship between pain and anxiety, while others suggest that there is not a direct association. In any case, there is indeed a consensus that anxiety impairs the pain condition beyond be under diagnosed and undertreated in cancer pain patients. Herein we investigated if rats presenting heat hyperalgesia induced by orofacial cancer cell inoculation would display anxiety-like behaviors. In addition, we evaluated if pain blockade would result in alleviation of anxiety behaviors, as well as, if blockade of anxiety would result in pain relief. Orofacial cancer was induced in male Wistar rats by inoculation of Walker-256 cells into the right vibrissal pad. Heat facial hyperalgesia was assessed on day 6 after the inoculation, and on this time point rats were submitted to the elevated plus maze and the light-dark transition tests. The influence of lidocaine and midazolam on heat hyperalgesia and anxiety-like behaviors was assessed. The peak of facial heat hyperalgesia was detected 6 days after cancer cells inoculation, and at this time point, rats exhibited increased anxiety-like behaviors. Local treatment with lidocaine (2%/50µL) caused a marked reduction of heat hyperalgesia, but failed to affect the anxiety-like behaviors, while midazolam (0.5mg/kg, i.p.) treatment failed to change the heat threshold, but induced an anxiolytic-like effect. Altogether, our data demonstrated that rats with orofacial cancer present pain- and anxiety-like behaviors, but brief heat hyperalgesia relief does not affect the anxiety-like behaviors, and vice-versa, in our experimental conditions.
Assuntos
Ansiedade/tratamento farmacológico , Neoplasias Faciais/fisiopatologia , Neoplasias Faciais/psicologia , Hiperalgesia/tratamento farmacológico , Neoplasias Bucais/fisiopatologia , Neoplasias Bucais/psicologia , Analgésicos/uso terapêutico , Animais , Ansiolíticos/uso terapêutico , Ansiedade/psicologia , Linhagem Celular Tumoral , Temperatura Alta , Hiperalgesia/fisiopatologia , Hiperalgesia/psicologia , Lidocaína/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Midazolam/uso terapêutico , Transplante de Neoplasias , Ratos Wistar , Limiar SensorialRESUMO
Introduction: Trigeminal neuralgia (TN) is defined as sudden, usually unilateral, severe and brief pain episodes within the distribution of one or more branches of the trigeminal nerve. In some patients a constant background pain may persist, additionally to pain attacks, which can make difficult to differentiate the trigeminal neuralgia from other orofacial pain types. Objective: To review the classification, physiopathological aspects, epidemiologic data and pharmacological options to control pain related to trigeminal neuralgia. Literature review: One of the proposed etiologies for this condition is a localcircumscribed demyelination of the trigeminal nerve resulting in neuronal hyperexcitability and generation of ephaptic coupling, which would be responsible for the pain paroxysms. Initially, the treatment of patients with these pain characteristics is based on the use of anticonvulsants, in order to attenuate the ectopic-generated pain impulses. Carbamazepine is the first-line drug, but other anticonvulsants may be employed and have shown variable efficacy in the treatment of trigeminal neuralgia. Conclusion: According to the new classification of the International Headache Society, classic trigeminal neuralgia is divided in purely paroxysmal and with concomitant persistent facial pain. The pathophysiology is unclear, but trigeminal neuralgia seems to be the consequence of vascular compression of the trigeminal nerve near the brain stem. Although TN presents a low prevalence in general population (i.e. 5-30 new patients per 100,000), trigeminal neuralgia is an important clinical concern both by pain severity and difficulty of its satisfactory control. Anticonvulsants are the medication of choice in the treatment of trigeminal neuralgia; however, their use is associated with several adverse effects and possibility of treatment refractoriness.
RESUMO
Peripheral neuropathy is a common complication of diabetes and is often accompanied by episodes of pain. There is evidence that diabetic neuropathy may affect the trigeminal nerve, altering the transmission of orofacial sensory information. Structural changes in the trigeminal ganglia may be involved in the development of these sensory alterations. Herein, we evaluate the development of orofacial sensory changes after streptozotocin-induced diabetes in rats, and their sensitivity to pregabalin and morphine treatments. Furthermore, stereological analysis of the trigeminal ganglia was performed. Diabetic rats showed similar responses to 1% formalin applied into the upper lip compared to normoglycemic rats on weeks 1, 2 and 4 after streptozotocin. Additionally, there was no difference in the facial mechanical threshold of normoglycemic and diabetic rats, on weeks 1 up to 5 after streptozotocin, while the paw mechanical threshold of diabetic rats was significantly reduced. In contrast, diabetic rats developed long-lasting orofacial heat and cold hyperalgesia. Moreover, stereological analyses revealed significant neuronal loss in the trigeminal ganglia of diabetic compared to normoglycemic rats. Pregabalin treatment (30mg/kg, p.o.) of diabetic rats resulted in marked and prolonged (up to 6h) reduction of heat and cold orofacial hyperalgesia. Likewise, morphine treatment (2.5mg/kg, s.c.) abolished orofacial heat and cold hyperalgesia, but its effect was significant only up to 1h after the administration. In conclusion, the results of the present study demonstrated that streptozotocin-treated rats developed long-lasting orofacial heat and cold hyperalgesia, which is more amenable to reduction by pregabalin than morphine.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Dor Facial/fisiopatologia , Hiperalgesia/fisiopatologia , Gânglio Trigeminal/fisiopatologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Neuropatias Diabéticas/tratamento farmacológico , Dor Facial/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Masculino , Morfina/farmacologia , Morfina/uso terapêutico , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Estimulação Física , Pregabalina , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
This study evaluated the toxic effects of two doses of inorganic lead (PbII) and tributyltin (TBT), separately and together in different exposure times (30 and 60 days) in rats. After exposure, liver, kidney, brain and blood were sampled for histopathological, hematological and enzymatic analysis. The number of peritoneal cells and lipopolysaccharide (LPS)-induced neutrophil migration after exposure was also analyzed. The liver presented necrotic areas in all exposed individuals while hematological and enzymatic parameters showed no changes. TBT, but not PbII, reduced the number of resident peritoneal macrophages. The combination of both toxicants abolished TBT effects at lower doses and even increased the number of macrophages at higher doses. The neutrophil migration was increased by lead and lead associated with TBT. These results confirm the potential hepatotoxicity of these compounds and they may have antagonistic effects on the immune cells when administered alone. The combination of toxicants induced an increased inflammatory response suggesting that lead effects may prevail over TBT reduction on macrophage number.