Opioid systems in the lateral hypothalamus regulate feeding behavior through orexin and GABA neurons.

The hypothalamus controls feeding behavior. Since central opioid systems may regulate feeding behavior, we examined the role of µ-, δ- and κ-opioid receptors in the lateral hypothalamus (LH), the hunger center, in feeding behavior of mice. Non-selective (naloxone; 3 mg/kg, s.c.) and selective µ- (ß-funaltrexamine, ß-FNA; 10 mg/kg, s.c.), δ- (naltrindole; 3 mg/kg, s.c.) and κ- (norbinaltorphimine, norBNI; 20 mg/kg, s.c.) opioid receptor antagonists significantly decreased food intake in food-deprived mice. The injection of naloxone (20 µg/side) into the LH significantly decreased food intake whereas the injection of naloxone (20 µg/side) outside of the LH did not affect food intake. The injection of ß-FNA (2 µg/side), naltrindole (1 µg/side) or norBNI (2 µg/side) into the LH significantly decreased food intake. Furthermore, all these antagonists significantly decreased the mRNA level of preproorexin, but not those of other hypothalamic neuropeptides. In addition, the injection of the GABAA receptor agonist muscimol (5 µg/side) into the LH significantly decreased food intake, and this effect was abolished by the GABAA receptor antagonist bicuculline (50 µg/side). Muscimol (1mg/kg, i.p.) decreased the mRNA level of preproorexin in the hypothalamus. Naloxone (3mg/kg, s.c.) significantly increased the GABA level in the LH and both bicuculline and the GABA release inhibitor 3-mercaptopropionic acid (3-MP, 5 µg/side) attenuated the inhibitory effect of naloxone on feeding behavior. 3-MP also attenuated the effects of ß-FNA and norBNI, but not that of naltrindole. These results show that opioid systems in the LH regulate feeding behavior through orexin neurons. Moreover, µ- and κ-, but not δ-, opioid receptor antagonists inhibit feeding behavior by activating GABA neurons in the LH.

Inhibition of opioid systems in the hypothalamus as well as the mesolimbic area suppresses feeding behavior of mice.

Opioid receptors, especially µ-opioid receptors, in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) are reported to regulate food motivation. However, the roles of µ-, δ- and κ-opioid receptors are not fully understood. Moreover, since µ-, δ- and κ-opioid receptors are reported to distribute in the hypothalamus, these receptors in the hypothalamus might regulate feeding behavior. Thus, the present study investigated the role of µ-, δ- and κ-opioid receptors in the VTA, the NAcc and the hypothalamus in the regulation of feeding behavior. Male ICR mice were subjected to a feeding test after food deprivation for 16h. The mRNA levels of proopiomelanocortin (POMC), preproenkephalin (PENK) and prodynorphin (PDYN), the precursors of endogenous opioid peptides, were measured by reverse transcription-polymerase chain reaction (RT-PCR). The systemic injection of non-selective (naloxone) and selective µ (ß-funaltrexamine; ß-FNA), δ (naltrindole) and κ (norbinaltorphimine; norBNI) opioid receptor antagonists markedly reduced food intake. In contrast, the systemic injection of preferential µ (morphine), selective δ (KNT-127) and κ (U-50,488) opioid receptor agonists did not change food intake. The mRNA levels of POMC, PENK and PDYN were decreased in the hypothalamus and the midbrain after food deprivation, whereas the mRNA levels of PENK and PDYN, but not POMC, were decreased in the ventral striatum. The injection of naloxone into the NAcc, VTA and lateral hypothalamus (LH), but not the ventromedial nucleus of the hypothalamus, significantly decreased food intake. The injection of ß-FNA and naltrindole into the LH, but not the VTA or NAcc, decreased food intake. The injection of norBNI into the LH and VTA, but not the NAcc, decreased food intake. These results indicate that µ-, δ- and κ-opioid receptors in the LH play a more important role in the regulation of feeding behavior than those receptors in the VTA and the NAcc.

Activation of spinal cannabinoid CB2 receptors inhibits neuropathic pain in streptozotocin-induced diabetic mice.

The role of spinal cannabinoid systems in neuropathic pain of streptozotocin (STZ)-induced diabetic mice was studied. In normal mice, injection of the cannabinoid receptor agonist WIN-55,212-2 (1 and 3µg, i.t.) dose-dependently prolonged the tail-flick latency, whereas there were no changes with the injection of either cannabinoid CB1 (AM 251, 1 µg, i.t.) or CB2 (AM 630, 4 µg, i.t.) receptor antagonists. AM 251 (1 µg, i.t.), but not AM 630 (4 µg, i.t.), significantly inhibited the prolongation of the tail-flick latency induced by WIN-55,212-2 (3 µg, i.t.). In STZ-induced diabetic mice, the tail-flick latency was significantly shorter than that in normal mice. A low dose of WIN-55,212-2 (1 µg, i.t.) significantly recovered the tail-flick latency in STZ-induced diabetic mice. The effect of WIN-55,212-2 (1 µg, i.t.) in STZ-induced diabetic mice was significantly inhibited by AM 630 (4 µg, i.t.), but not AM 251 (1 µg). The selective cannabinoid CB2 receptor agonist L-759,656 (19 and 38 µg, i.t.) also dose-dependently recovered the tail-flick latency in STZ-induced diabetic mice, and this recovery was inhibited by AM 630 (4 µg, i.t.). The protein levels of cannabinoid CB1 receptors, CB2 receptors and diacylglycerol lipase α (DGL-α), the enzyme that synthesizes endocannabinoid 2-arachidonoylglycerol, in the spinal cord were examined using Western blotting. The protein levels of both cannabinoid CB1 and CB2 receptors were increased in STZ-induced diabetic mice, whereas the protein level of DGL-α was significantly decreased. These results indicate that spinal cannabinoid systems are changed in diabetic mice and suggest that cannabinoid CB2 receptor agonists might have an ability to recover diabetic neuropathic pain.

Olanzapine increases hepatic glucose production through the activation of hypothalamic adenosine 5'-monophosphate-activated protein kinase.

AIMS: To investigate the mechanism of the metabolic disturbance induced by the atypical antipsychotic olanzapine, we examined whether adenosine 5'-monophosphate-activated protein kinase (AMPK) in the hypothalamus and hepatic glucose production are involved in the effect of olanzapine. METHODS: Male 6-week-old ICR mice were used. Blood glucose levels were determined by the glucose oxidase method. The mRNA levels of gluconeogenic or glycolytic enzymes were measured by reverse transcription polymerase chain reaction (RT-PCR). AMPK expression was measured by Western blotting. RESULTS: Systemic injection of olanzapine increased blood glucose levels in both unfasted and fasted mice. However, the increase in fasted mice was less than that in unfasted mice. Central administration of olanzapine also increased the blood glucose levels in unfasted mice, but not in fasted mice. In a pyruvate tolerance test, olanzapine significantly increased blood glucose levels. In addition, olanzapine increased the mRNA levels of glucose-6-phosphatase (G6Pase), a gluconeogenic enzyme, in the liver. Furthermore, olanzapine increased phosphorylated AMPK in the hypothalamus of unfasted mice, and olanzapine-induced hyperglycaemia was inhibited by the AMPK inhibitor compound C. Central administration of the AMPK activator AICAR significantly increased G6Pase mRNA levels in the liver and blood glucose levels. Moreover, both olanzapine- and AICAR-induced hyperglycaemia were attenuated by the ß-adrenergic receptor antagonist propranolol, suggesting that olanzapine and AICAR induce hepatic glucose production through the sympathetic nervous system. CONCLUSIONS: Our results indicate that olanzapine activates AMPK in the hypothalamus, which increases hepatic glucose production via the sympathetic nervous system.

Spiraling dopaminergic circuitry from the ventral striatum to dorsal striatum is an effective feed-forward loop.

Central dopamine systems are key players in the cerebral organization of behavior and in various neurological and psychiatric diseases. We demonstrate the presence of a neurochemical feed-forward loop characterized by region-specific changes in dopamine efflux in serially connected striatal regions, providing evidence in favor of the existence of so-called spiraling striato-nigro-striatal connections. Using in vivo microdialysis of rats, we show that simultaneous stimulation of dopamine D1 and D2 receptors in the accumbal shell decreased dorsal striatal dopamine efflux via a direct or indirect feed-forward loop involving shell, core, ventrolateral and dorsal part of the striatum: simultaneous stimulation of dopamine D1 and D2 receptors in the shell decreased dopamine efflux in the core; flupenthixol-induced inhibition of dopamine D1 and D2 receptors in the core increased dopamine efflux in the ventrolateral part of the striatum, and simultaneous stimulation of dopamine D1 and D2 receptors in the ventrolateral part of the striatum decreased dopamine efflux in the dorsal part of the striatum. Finally, simultaneous stimulation of dopamine D1 and D2 receptors in the shell decreased dopamine efflux in the dorsal part of the striatum. Thus, distinct striatal regions act also in series, providing a better understanding of the neural mechanisms underlying dopamine-dependent behaviors and the progression of dopamine-dependent disorders such as depression, schizophrenia, attention deficit hyperactivity disorder (ADHD), and addiction.

Effect of chronic pain on morphine-induced respiratory depression in mice.

Respiratory depression is the most well-known and dangerous side-effect of opioid analgesics. Clinical investigations have revealed that this opioid-induced respiratory depression is less severe in patients with chronic pain, but the mechanisms that underlie this phenomenon are unknown. Therefore, the present study was designed to examine the influence of chronic pain on morphine-induced respiratory depression. Respiration was detected by double-chamber, flow-through whole-body plethysmography. Respiratory frequency was dose-dependently and significantly decreased after morphine administration. This effect peaked at 30 min after administration and lasted 3 h. In contrast, tidal volume was increased. Minute volume was significantly decreased by morphine at a higher dose, but not a lower dose. In nerve-ligated mice, a morphine-induced decrease in respiratory frequency was observed, whereas the increase of tidal volume was more prominent. A decrease in minute volume was not observed in nerve-ligated mice. This attenuation of the morphine-induced decrease in minute volume in nerve-ligated mice was reversed by treatment with the serotonin (5-HT)4a receptor antagonist GR125487. Moreover, treatment with the 5-HT4 receptor agonist mosapride antagonized the morphine-induced decrease in minute volume, due to the enhancement of tidal volume. Finally, the expression of 5-HT4a receptor in the brainstem was enhanced in nerve-ligated mice compared to that in sham-operated mice. These results suggest that the decrease in morphine-induced respiratory depression under chronic pain is mediated by the enhancement of 5-HT4a receptor systems in the brainstem.

Characterization of cerebral salt wasting after subarachnoid hemorrhage model induced by endovascular puncture.

Cerebral salt wasting (CSW) frequently occurs concomitantly with an aneurysmal subarachnoid hemorrhage (SAH). CSW induces excessive natriuresis and osmotic diuresis, and reduces the total volume of blood. We previously reported that a rat model with SAH induced by endovascular puncture (EP) exhibited CSW. Therefore, we investigated the relationship between the spread of bleeding in the subarachnoid space and the intensity of CSW. We also investigated the development of CSW in different SAH models. SAH was induced by EP or by 0.3 mL of blood injection (BI) into the cisterna magna. To evaluate the occurrence of CSW, urine was cumulatively collected at the onset of SAH to 6 h later and analyzed for sodium (Na) excretion. SAH was classified from grade 1 (no bleeding) to grade 4 (severe bleeding) based on the spread of bleeding in the subarachnoid space. In the EP model (SAH grade > 2) as the SAH grade increased, the volume of urine and Na excretion also significantly increased. Although the BI model rats exhibited SAH of grade 4, the volume of urine and Na excretion did not change. Therefore, our conclusion is that the spread of bleeding in the subarachnoid space may not cause CSW.

Inhibitory effect of hydrocortisone on cerebral salt wasting after subarachnoid hemorrhage in rats.

Cerebral salt wasting (CSW) frequently occurs concomitantly with subarachnoid hemorrhage (SAH). CSW induces excessive natriuresis and osmotic diuresis, reduces total blood volume, aggravates cerebral vasospasm and causes cerebral ischemia after SAH. This study examined the inhibitory effect of hydrocortisone on CSW in rat SAH models. Hydrocortisone had an inhibitory effect on CSW because hydrocortisone functioned in a dose-dependent manner to inhibit the increase in sodium excretion and sodium/potassium ratio after SAH onset. We conclude that hydrocortisone is a useful drug for the treatment of CSW after SAH.

New approach for chronic renal failure model by direct kidney injection of doxorubicin in rats.

Several experimental chronic renal failure (CRF) models are available for testing new drugs. A CRF model induced by the intravenous injection of 2 mg/kg of doxorubicin (DXR) twice during a 20-day interval reportedly results in pathological characteristics similar to glomerular sclerosis seen clinically. However, it normally takes more than 16 weeks to create this CRF model. We used three methods of direct drug injection into the kidney of rats to determine the method that would induce CRF within 4 weeks; Method A: DXR was injected directly into both kidneys; Method B: DXR was injected directly into the left kidney immediately after right nephrectomy; Method C: DXR was injected directly into the left kidney 1 week before right nephrectomy, and DXR was injected again directly into the left kidney. As a result, urinary protein, blood urea nitrogen (BUN), creatinine and creatinine clearance were significantly changed >1 week after the injection of DXR by Method C. Quantification of tissue transforming growth factor-beta1 (TGF-beta1), which is a prime fibrogenic cytokine in renal fibrosis, significantly increased in the kidney. A light microscopic image showed glomerular decrement, tubular dilation and atrophy and vacuolation of parenchyma. In conclusion, the results of this study demonstrate that the DXR model using Method C develops CRF within 4 weeks.

Análisis de la respuesta sexual femenina y grado de satisfacción sexual en parejas de hombres tratados de una disfunción eréctil / Analysis of the female sexual answer and sexual satisfaction degree in couples with men treated for erectile dysfunction

La función sexual (FS) y las disfunciones sexuales femeninas (DSF) son poco conocidas y estudiadas hasta hoy, y más desconocida aún es la respuesta sexual de las mujeres que son parejas de pacientes tratados de una disfunción eréctil (DE). Con el objeto de contribuir a conocer este aspecto en la relación de pareja, investigamos la respuesta y grado de satisfacción sexual en 155 mujeres, parejas estables de pacientes tratados de una DE. Para ello entrevistamos en forma personal y privada a dichas parejas, a quienes informamos sobre el fin del estudio, 137 mujeres aceptan voluntariamente responder el test del Indice de Función Sexual Femenino (FSFI). Promedio de edad de las mujeres 54 años (rango 24-68 años). Promedio de edad de los pacientes 56 años (rango 32-76 años). Encontramos las siguientes DSF: ausencia de deseo 100 mujeres (73 por ciento); falta de orgasmo 96 mujeres (70 por ciento); falla en la lubricación 90 mujeres (65,6 por ciento); dolor en la relación sexual 53 mujeres (38,6 por ciento). Refirieron obtener satisfacción en la relación sexual 43 mujeres (31,3 por ciento). Conclusión: Encontramos en las parejas de pacientes tratados de una DE, una alta prevalencia de DSF y un bajo grado de satisfacción sexual, los cuales al afectar su calidad de vida, impacta negativamente en la relación de pareja. Creemos que el urólogo debería asumir el estudio y tratamiento de estas mujeres como manejo concomitante y complementario al del paciente.

Prevalencia de trastornos de la sexualidad en mujeres que asisten a Consultorio Externo de Gineco-obstetricia de Hospital La Serena / Prevalence study of sexual disorders in women at the gyneco-obstretic external dispensary in La Serena Hospital

La disfunción sexual femenina (DSF) es causa de deterioro significativo de la calidad de vida de las personas. Por este motivo hemos querido estudiar la prevalencia de DSF en mujeres que asisten a consultorio de Gíneco-Obstetricia (GO) del hospital de La Serena, identificar los trastornos sexuales más frecuentes, y compararlos con la literatura existente al respecto. Para este fin se aplicó encuesta F.S.F.I. (Índice de función sexual femenina) modificada a 217 mujeres en consultorio GO. Presentaron DSF 147 mujeres (67,7 por ciento), quienes presentaron alteración de uno o más de los siguientes aspectos: falla deseo sexual, 115 mujeres (52,9 por ciento); ausencia de orgasmo, 81 mujeres (37,3 por ciento); falta de lubricación, 62 mujeres (28,6 por ciento); dispareunia, 39 mujeres (17,9 por ciento); falta de excitación, 54 mujeres (24,8 por ciento); y satisfacción sexual, 171 mujeres (78,8 por ciento). El 80,6 por ciento consideró a la relación sexual importante en la relación de pareja. Se aprecia una alta prevalencia de DSF en la población estudiada por sobre el promedio de las publicaciones analizadas, predominando la alteración del deseo sexual. También nos llamó la atención el alto grado de satisfacción sexual manifestado por las entrevistadas a pesar de la alta prevalencia de DSF obtenido.

Prevalencia e impacto en calidad de vida de infección, incontinencia urinaria, y disfunción sexual en mujeres en control rutinario en consultorio externo / Prevalence and impact on quality of life of urinary infection, urinary incontinence and sexual dysfunction on women who attend the gyneco-obstetric external dispensary for routine control

Se estudió la prevalencia de la Infección Urinaria (ITU), la Incontinencia Urinaria (IU) y de la Disfunción Sexual Femenina (DSF) y se evaluó el impacto de cada una de estas patologías en la calidad de vida de 250 mujeres que asistieron a control rutinario al consultorio externo de gineco-obstetricia del Hospital de La Serena durante enero de 2005. Promedio de edad 33,7 años (rango 15-69 años). Presentaron DSF 169 mujeres (67,6 por ciento), IU 100 mujeres (40 por ciento) e ITU 73 mujeres (29,2 por ciento). Refirieron impacto severo en su calidad de vida 56 de 73 mujeres con ITU (76,7 por ciento), 40 de 100 mujeres con IU (40 por ciento) y 36 de 169 mujeres con DSF (21,3 por ciento). 54 mujeres (21,6 por ciento) comunicaron IU y DSF y 48 mujeres (19,2 por ciento) informaron de ITU y DSF.

Daily nasal inoculation with the insulin gene ameliorates diabetes in mice.

The present study examined the feasibility of liposome-mediated gene transfer via nasal administration, for treating insulin-dependent diabetes mellitus. The rat insulin gene was packed under control of the CMV promoter, complexed with DC-chol/DOPE-based liposomes and administered daily via the nasal route in mice made severely diabetic by streptozocin. Sustained expression of the insulin gene was achieved and insulinopenia, ketonuria and death were prevented. Hyperglycemia and body weight reduction were significantly suppressed without evidence of hypoglycemia throughout the experimental period. RT-PCR and FISH analysis indicated that insulin was produced in the alveolar epithelial cells of the lung. Liposome-mediated in vivo gene transfer via nasal administration may provide an efficacious route for delivery of hormonal and other gene products into the blood stream.

Effects of the antiepileptics phenytoin and zonisamide on dentin formation and bone mineral density of the mandible in growing rats.

This study was undertaken to examine the effects of the antiepileptics phenytoin and zonisamide on changes in the mineral density of the incisor and bone mineral density (BMD) of the mandibular head, and on the rate of dentin formation using histomorphometric measurements. After repeated administration of phenytoin or zonisamide to male growing rats, the mineral density of the lower incisors and mandibular head were determined by analyzing microradiographs and dentin formation rates were determined by histomorphometric measurements. Results showed a significant decrease in the mean values of BMD of the mandibular head and lower incisors in groups treated with phenytoin or zonisamide compared with the vehicle-treated group (p < 0.05). The percent rates of decrease in mineral density of the incisors for phenytoin and zonisamide were 6.8% and 4.0%, respectively. Phenytoin and zonisamide significantly reduced the dentin formation rate for the mesial and distal areas compared with the vehicle-treated group. Thus, epileptic children who are treated over a long period with antiepileptics, especially at primary school age, should ensure good oral hygiene so as not to suffer bone loss, edentulism or gingival overgrowth.

Toxicological study of a new maintenance fluid, Veen 3G, in rats.

A study of the different volume and infusion rates of a new maintenance fluid, Veen 3G, on the general conditions of rats was investigated during the 14 days after infusion. In Experiment I, 100 ml/kg and 200 ml/kg of Veen 3G were infused at a rate of 300 ml/kg/h in male and female rats. Results were compared with those for Gurunon Ringer solution (GRS) in male and female rats. We observed only transient polyuria in animals administered by each dose of Veen 3G and GRS for 0-15 min after infusion. Necropsy was not observed in any of the animals tested 14 days after infusion. In Experiment II, 200 ml/kg of Veen 3G was infused at rates of 200, 400, 800 and 1600 ml/kg/h in male rats. At 800 and 1600 ml/kg/h, irregular respiration and decrease in movement were observed concomitantly with polyuria. Three out of 4 rats died immediately after the infusion of Veen 3G at a rate of 1600 ml/kg/h, and one rat was still alive 14 days after the infusion. In this experiment, 200 ml/kg Veen 3G was safe when we infused at a rate of less than 400 ml/kg/h in male rats. Since this rate is about 27-80 times higher than that used clinically in maintenance treatment, Veen 3G is suggested to be safe, with the exception of polyuria, in clinical situations at the standard infusion rate (5-15 ml/kg/h).

Nuevos tratamientos adyuvantes en la cirugía del seminoma puro etapa I / New adjuvant treatments in surgery of pure seminoma stage I

En mayo de 1989 iniciamos un protocolo de tratamiento adyuvantes de la cirugía del Seminoma Puro Etapa I con 2 ciclos de quimioterapia, basado en cisplatino. Hasta julio de 1999 ingresaron 27 enfermos operados de seminoma sin extensión extragonadal. Con un seguimiento promedio de 6,7 años (rango 2-12 años) 26 enfermos (96,3 por ciento) se encuentran libres de enfermedad, 18 enfermos (66,6 por ciento) han recuperado la espermatogénesis; 8 han procreado hijos sanos entre 2 y 7 años después de la quimioterapia. Pensamos que la quimioterapia es una alternativa válida, simple, segura, eficaz y con mínimos efectos colaterales precoces y tradíos como tratamiento complementario de la cirugía del Seminoma Puro Etapa I.

Phenytoin-induced bone loss and its prevention with alfacalcidol or calcitriol in growing rats.

Studies were carried out to determine the effects and mechanism of action of phenytoin on the bone metabolism in male rats. Administration of phenytoin, 20 mg/kg/ day for 5 weeks, did not affect the growth curve. Biochemical data indicated that the serum osteocalcin, a marker of bone formation, was decreased significantly but there were no significant differences in the levels of serum calcium, pyridinoline, 25-hydroxyvitamin D3 (25OHD) and parathyroid hormone (PTH) in the phenytoin-treated group compared with the vehicle-treated group. The values of bone mineral density (BMD) were decreased in all regions of bones tested (mandibular head, tibial metaphysis, tibial diaphysis, femoral metaphysis, and femoral diaphysis) in the phenytoin-treated group. In histomorphometric analysis, phenytoin decreased trabecular bone volume and trabecular thickness, and increased osteoclast numbers per area of bone surface in the secondary trabecular bone of the tibia. Additionally, there was no significant difference in osteoid thickness. Combined administration of either alfacalcidol or calcitriol with phenytoin for 5 weeks prevented the reduction of BMD induced by phenytoin. From these findings, it is unlikely that toxic effects on the growth curve caused the decreased BMD induced by phenytoin. It is also evident that repeated administration of phenytoin may cause osteopenia which may be due to bone loss by inhibiting bone formation and/or by accelerating bone resorption rather than osteoid accumulation. The bone loss is not rachitic because of the lack of increase in osteoid thickness. Moreover, combined administration of alfacalcidol or calcitriol with phenytoin showed a preventative effect against bone loss. The bone loss induced by phenytoin in this study may be a convenient model for further research into the problem of drug-induced osteopenia.

Risk factors for development of postoperative hypertension.

One hundred and eighty-nine patients who underwent digestive tract surgery were studied to investigate risk factors for the development of postoperative hypertension. We examined factors related to maximum postoperative systolic blood pressure and postoperative hypertensive urgency, a sign of postoperative hypertension. Data collected included blood pressure, age, sex, body mass index (BMI), medical history, total water balance and grade of surgical stress. Maximum postoperative systolic blood pressure and incidence of postoperative hypertensive urgency were the dependent variables. Mean preoperative systolic blood pressure, age and BMI were significantly related to maximum postoperative systolic blood pressure and postoperative hypertensive urgency. In addition, the grade of surgical stress was significantly related to maximum postoperative systolic blood pressure. In analyses of multiple variables, the adjusted odds ratio for postoperative hypertensive urgency was 1.16 for every 1 mmHg increase in mean preoperative systolic blood pressure, 1.05 for every 1 year increase in age and 0.82 for every 1 kg/m2 increase in BMI. These findings may have important clinical implications for the prevention of postoperative hypertension.

Nociception and allodynia/hyperalgesia induced by intrathecal administration of fenvalerate.

The intrathecal injection of fenvalerate, a sodium channel activator, at doses of 0.01 to 3 microg, dose-dependently induced the duration of a characteristic behavioral syndrome mainly consisting of reciprocal hind limb scratching directed towards caudal parts of the body and biting or licking of the hind legs in mice. Fenvalerate-induced behavior was inhibited by morphine (1-10 mg/kg, i.p.). The characteristic behavior was also inhibited by mexiletine, a sodium channel blocker; MK-801, a N-methyl-D-aspartate ion-channel blocker; and GR82334, a neurokinin-1-receptor antagonist. Calphostin C (3 pmol, i.t.), a protein kinase C inhibitor, inhibited fenvalerate-induced behavior. On the other hand, phorbol-12, 13-dibutyrate (50 pmol, i.t.), a protein kinase C activator, markedly enhanced the fenvalerate-induced behavior. The present results also showed that fenvalerate produced thermal allodynia and hyperalgesia in the tail-flick test. Furthermore, fenvalerate-induced thermal allodynia and hyperalgesia were inhibited by the pretreatment with calphostin C. These results suggest that the intrathecal administration of fenvalerate induces a marked nociceptive response and thermal allodynia/hyperalgesia, and they suggest that tetrodotoxin-resistant sodium channels may play an important role in this effect.