RESUMEN
OBJECTIVE: Hydrogen sulfide is an endogenous gaseous mediator that has been indicated to have a role in pain mechanisms. In this study, we aimed to detect brain and spinal cord hydrogen sulfide levels during different phases of tolerance and dependence to morphine and to determine the effects of inhibition of endogenous hydrogen sulfide production on the development of tolerance and dependence. METHODS: Morphine tolerance and dependence was developed by subcutaneous injection of morphine (10 mg/kg) twice daily for 12 days. Physical dependence was determined by counting the jumps for 20 min, which is a withdrawal symptom occurring after a single dose of naloxone (5 mg/kg) administered intraperitoneally (i.p.). Propargylglycine (30 mg/kg, i.p.), a cystathionine-γ-lyase inhibitor, and hydroxylamine (12.5 mg/kg, i.p.), a cystathionine-ß-synthase inhibitor, were used as hydrogen sulfide synthase inhibitors. The tail-flick and hot-plate tests were used to determine the loss of antinociceptive effects of morphine and development of tolerance. RESULTS: It was found that chronic and acute uses of both propargylglycine and hydroxylamine prevented the development of tolerance to morphine, whereas they had no effect on morphine dependence. Chronic and acute administrations of hydrogen sulfide synthase inhibitors did not exert any difference in hydrogen sulfide levels in brain and spinal cords of both morphine-tolerant and -dependent animals. CONCLUSION: It has been concluded that hydrogen sulfide synthase inhibitors may have utility in preventing morphine tolerance.
Asunto(s)
Conducta Animal/efectos de los fármacos , Tolerancia a Medicamentos , Inhibidores Enzimáticos/farmacología , Sulfuro de Hidrógeno/metabolismo , Dependencia de Morfina/prevención & control , Alquinos/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Glicina/análogos & derivados , Glicina/farmacología , Hidroxilamina/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Morfina/administración & dosificación , Narcóticos/administración & dosificaciónRESUMEN
It has been indicated that acute and chronic morphine administrations enhance nociceptin/orphanin FQ (N/OFQ) levels in the brain, which might play role in the development of tolerance to the antinociceptive effect of morphine. Accordingly, N/OFQ receptor (NOP) antagonists have been shown to prevent the development of antinociceptive tolerance to morphine. Our aim is to observe whether cannabinoids, similarly to opioids, enhance N/OFQ levels in pain-related brain regions and whether antagonism of NOP receptors attenuates the development of tolerance to the antinociceptive effect of cannabinoids. Hot plate and Tail flick tests are used to assess the antinociceptive response in Sprague-Dawley rats. N/OFQ levels are measured in cortex, amygdala, hypothalamus, periaqueductal gray, nucleus raphe magnus and locus coeruleus of rat brains using Western blotting and immunohistochemistry. Within 9 days, animals became completely tolerant to the antinociceptive effect of the cannabinoid agonist WIN 55,212-2 (2, 4, 6 mg/kg, i.p.). Chronic administration of JTC-801, a NOP receptor antagonist, at a dose that exerted no effect on its own (1 mg/kg, i.p.), attenuated development of tolerance to the antinociceptive effect of WIN 55,212-2 (4 mg/kg, i.p.). Western blotting and immunohistochemistry results showed that N/OFQ levels significantly increased in amygdala, periaqueductal gray, nucleus raphe magnus and locus coeruleus of rat brains when WIN 55,212-2 was combined with JTC-801. We hypothesize that, similar to opioids, chronic cannabinoid + NOP antagonist administration may enhance N/OFQ levels and NOP receptor antagonism prevents development of tolerance to cannabinoid antinociception.
Asunto(s)
Analgésicos/farmacología , Encéfalo/metabolismo , Cannabinoides/farmacología , Tolerancia a Medicamentos/fisiología , Antagonistas de Narcóticos/farmacología , Péptidos Opioides/metabolismo , Aminoquinolinas/farmacología , Analgésicos Opioides/farmacología , Animales , Benzamidas/farmacología , Benzoxazinas/farmacología , Encéfalo/efectos de los fármacos , Masculino , Morfina/farmacología , Morfolinas/farmacología , Naftalenos/farmacología , Dolor/tratamiento farmacológico , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Receptores Opioides/metabolismo , NociceptinaRESUMEN
Combinations of analgesics from different classes are commonly used in the management of chronic pain. The goal is to enhance pain relief together with the reduction of side effects. The present study was undertaken to examine the anti-allodynic synergy resulting from the combination of WIN 55,212-2, a cannabinoid CB1 receptor agonist, and JTC-801, a nociceptin/orphanin FQ receptor antagonist, on neuropathic pain. Mice were tested for behavioral effects before and 2-4 weeks after the surgery, in which a partial tight ligation of the sciatic nerve was made. Nerve injury-induced mechanical allodynia was assessed with Dynamic Plantar Aesthesiometer, and a hot/cold plate was used to assess cold allodynia. Both WIN 55,212-2 and JTC-801 produced dose-dependent mechanical and cold anti-allodynic effects. As shown by isobolographic analysis, WIN 55,212-2/JTC-801 combinations interacted synergistically at all three ratios studied in the mechanical allodynia assay. In conclusion, co-administration of a cannabinoid with a nociceptin/orphanin FQ receptor antagonist resulted in a synergistic interaction, which may have utility in the pharmacological treatment of neuropathic pain.
Asunto(s)
Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Péptidos Opioides/farmacología , Receptores de Cannabinoides/efectos de los fármacos , Aminoquinolinas/farmacología , Analgésicos/farmacología , Animales , Benzamidas/farmacología , Benzoxazinas/farmacología , Enfermedad Crónica , Frío , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Calor , Hiperalgesia/psicología , Ligadura , Masculino , Ratones , Ratones Endogámicos BALB C , Morfolinas/farmacología , Naftalenos/farmacología , Neuralgia/psicología , Péptidos Opioides/antagonistas & inhibidores , Dimensión del Dolor/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Ciática/tratamiento farmacológico , Ciática/patología , Receptor de Nociceptina , NociceptinaRESUMEN
The antinociceptive action of cannabinoids in acute and inflammatory pain states have been well-documented. There is also accumulating evidence suggesting that cannabinoids are effective analgesics in chronic pain conditions. WIN 55,212-2, a mixed CB1 and CB2 cannabinoid receptor agonist, has been shown to be effective against hyperalgesia and allodynia in painful peripheral mononeuropathy. Recently, in addition to their spinal and supraspinal antinociceptive action, cannabinoids have also reported to exert local analgesic effects. The aim of this study is to observe the effect of a high affinity cannabinoid, WIN 55,212-2, on tactile allodynia and thermal hyperalgesia in diabetic rats. Diabetes was produced with the injection of a single dose of streptozocin (50 mg/kg, i.p.) and this procedure resulted in neuropathic pain behaviors in the hindlimbs. Mechanical allodynia was detected by application of von Frey filaments to the plantar surface of the foot, and thermal hyperalgesia was studied using the Hargreaves' method; however, thermal hyperalgesia did not develop in diabetic rats. With its higher doses, both systemic (3 and 10 mg/kg, i.p.) and peripheral (30 microg, i.p.l.) injections of WIN 55,212-2 reduced mechanical allodynia. These results suggest that WIN 55,212-2 has an antiallodynic effect in streptozocin-induced diabetic rats and may be a promising approach in the treatment of diabetic neuropathy.
Asunto(s)
Cannabinoides/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Morfolinas/farmacología , Naftalenos/farmacología , Dimensión del Dolor/efectos de los fármacos , Tacto/efectos de los fármacos , Animales , Benzoxazinas , Cannabinoides/uso terapéutico , Relación Dosis-Respuesta a Droga , Masculino , Morfolinas/uso terapéutico , Naftalenos/uso terapéutico , Dimensión del Dolor/métodos , Ratas , Ratas Wistar , Tacto/fisiologíaRESUMEN
Recent evidence suggests that agmatine, an endogenous polyamine metabolite, might be an important neurotransmitter in central nervous system and has potential as a treatment of pain. The aim of our study was to evaluate the effect of agmatine on allodynia in two experimental neuropathic pain models, the spinal nerve ligation (SNL) model and the streptozocin (STZ)-induced diabetic neuropathy in rats, and to determine if the N-methyl-D-aspartate (NMDA) receptor antagonists and the nitric oxide synthase (NOS) inhibitors influence this effect of agmatine. Nerve injury was produced by tight ligation of the left L5 and L6 spinal nerves, and diabetic neuropathy is induced with the injection of a single dose of STZ; these procedures resulted in tactile allodynia in the hindpaw. Tactile allodynia was detected by application of von Frey filaments to the plantar surface of the foot. Agmatine reduced mechanical allodynia with its higher doses. Dizocilpine maleate (MK-801), a NMDA receptor antagonist, and the NOS inhibitors, N(G)-nitro-L-arginine methyl ester and 7-nitroindazole, did not influence the antiallodynic effect of agmatine. These results suggest that agmatine has an antiallodynic effect in both spinal nerve ligation and diabetic models and may be a promising drug in the treatment of neuropathic pain.
Asunto(s)
Amantadina/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Dolor/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/complicaciones , Animales , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/complicaciones , Femenino , Ligadura , Masculino , Dolor/etiología , Dolor/psicología , Umbral del Dolor , Ratas , Ratas Wistar , Nervios Espinales , TactoRESUMEN
Recent observations suggest the involvement of adenosine in the peripheral antinociceptive effect of amitriptyline in nerve-injury-induced neuropathic pain. The aim of the present investigation was to evaluate, firstly, the peripheral and systemic effects of amitriptyline on tactile allodynia in the streptozotocin (STZ)-induced diabetic rat model of neuropathic pain and, secondly, whether caffeine coadministration affects the actions of amitriptyline. Diabetes was induced by a single intraperitoneal (i.p.) injection of STZ (50 mg/kg), and tactile allodynia was detected by application of von Frey filaments to the ventral surface of the hindpaw. Both systemic (0.5-2.0 mg/kg, i.p.) and peripheral (10-100 nmol, subcutaneously (s.c.)) administration of amitriptyline were found to produce increases in paw withdrawal thresholds, at higher doses. Coadministration of caffeine (5 mg/kg, i.p.; 1500 nmol, s.c.), at doses which produced no effect on its own, partially reversed systemic and local anti-allodynic effects of amitriptyline. These results indicate an anti-allodynic effect of both peripheral and systemic amitriptyline, and suggest the involvement of endogenous adenosine in the action of amitriptyline in this rat model of painful diabetic neuropathy. These data also suggest that topical application of tricyclic antidepressants may be useful in treating neuropathic pain in diabetics.