Potassium channel openers exhibit cross-tolerance with morphine in two experimental models of pain / Los abridores de canales de potasio exhiben tolerancia cruzada con la morfina en dos modelos experimentales de dolor

OBJECTIVE: The study was performed to assess the effect of potassium channel openers on morphine tolerance and vice-versa. METHODS: Swiss albino mice of either gender weighing between 25-30 g were used for the study. The study assesses the effect of potassium channel openers (cromakalim, diazoxide and minoxidil) on morphine tolerance and vice-versa, using formalin and tail-flick tests. RESULTS: The antinociceptive effect of cromakalim and minoxidil was significantly reduced when administered to morphine-tolerant mice, in both the behavioural tests. However, reduced analgesic effect of diazoxide was observed on morphine-tolerance in the formalin test but not in the tail-flick test. Tolerance was observed when morphine was administered to animals chronically treated with any of the potassium channel openers. The same effect was observed when morphine was injected into a group treated with a combination of morphine and any of the potassium channel openers. CONCLUSIONS: This study, therefore, suggests that both morphine and potassium channel openers are cross-tolerant. However, such interaction occurs at the level of potassium channels rather than at the level of receptors.

OBJETIVO: El estudio fue realizado para evaluar el efecto de los abridores de canales de potasio en la tolerancia a la morfina, y viceversa. MÉTODOS: Para el estudio, se usaron ratones albinos suizos de ambos sexos que pesaban entre 25-30 g. El estudio evalúa el efecto de los abridores de canales de potasio (cromacalina, diazóxido y minoxidil) en la tolerancia a la morfina, y viceversa, usando la prueba de la sacudida de la cola y la prueba de la formalina. RESULTADOS: El efecto antinociceptivo de la cromacalina y el minoxidil fue significativamente reducido cuando se le administró a los ratones tolerantes a la morfina, en ambas pruebas conductuales. Sin embargo, se observó un efecto analgésico reducido de diazóxido sobre la tolerancia a la morfina en la prueba de la formalina, pero no en la prueba de la sacudida de la cola. Se observó tolerancia al administrar morfina a animales crónicamente tratados con cualquiera de los abridores de canales de potasio. El mismo efecto fue observado cuando se inyectó la morfina al grupo tratado con una combinación de morfina y cualquiera de los abridores de canales de potasio. CONCLUSIONES: Por consiguiente, este estudio sugiere que tanto la morfina como los abridores de canales de potasio son tolerantes cruzados. Sin embargo, tal interacción ocurre a nivel de los canales de potasio más bien que a nivel de los receptores.

[Role of ATP-sensitive potassium channels in the clonic seizure threshold induced by pentylenetetrazole in mice with diabetes type I]

Although there is evidence that diabetes affects seizure susceptibility, the underlying mechanism has not been completely understood. On the other hand, several studies have suggested a pivotal role for K[ATP] channels in the seizure modulation. So, the present study was designed to evaluate the seizure threshold induced by pentylenetetrazole [PTZ] in diabetic mice at different times and to examine the possible role of ATP-sensitive potassium [K[ATP]] channels. In this experimental study, NMRI were diabetic with streptozocine. Then clonic seizure thresholds were determined at different times after induction of diabetes compared with corresponding non-diabetic groups. Each experimental group consisted of ten mice. There was a time-dependent alteration in the threshold in diabetic mice, reaching a peak on week 2 after STZ injection and declining significantly afterwards. The seizure threshold in 8-week diabetic mice was even lower than control levels, though the difference was not significant. The non-effective dose of K[ATP] channel blocker glibenclamide [1 mg/kg, i.p.], but not the voltage-dependent K+ channel blocker 4-aminopyridine [1 mg/kg, i.p.], decreased the seizure threshold in 2-week diabetic mice to the control levels which was blocked by pre-treatment with the K[ATP] channel opener cromakalim [10 micro g/kg, i.p.]. Moreover, the non-effective dose of cromakalim [10 micro g/kg, i.p.] increased significantly the seizure threshold in 8-week diabetic mice which was inhibited by pre-treatment with glibenclamide [1 mg/kg, i.p.] but not with 4-aminopyridine [1 mg/kg, i.p.]. This study indicated that the PTZ-induced seizure threshold is altered in diabetic mice in a time-dependent manner which could be due to the probable alteration in the K[ATP] channel functioning during diabetes

Effect of KATP channel openers on myogenic and neurogenic responses in goat urinary bladder.

Isolated goat detrusor muscle exhibited spontaneous contractility with an irregular amplitude and frequency. The spontaneity of detrusor muscle exhibited a mean amplitude as 11.99 +/- 0.83 mm and frequency as 1.37 +/- 0.16/min. KATP-channel openers namely, cromakalim or pinacidil (10(-7) - 10(-4) M) added cumulatively, elicited a concentration-related inhibition of both amplitude and rate of spontaneous contractions. The mean IC50 values for both amplitude and frequency for cromakalim were 3.3 x 10(-6) M and 2.9 x 10(-6) M, respectively; and for pinacidil were 2.0 x 10(-5) M and 1.5 x 10(-5) M, respectively. Glibenclamide, a KATP-channel blocker inhibited the cromakalim-induced concentration-related relaxation of spontaneous contractions with a significant increase in its mean IC50. ACh-induced concentration-related contractile response was inhibited in the presence of either cromakalim (10(-4) M) or pinacidil (10(-4) M). The mean EC50 value of ACh, in the presence of cromakalim (2.5 x 10(-3) M) was significantly increased as compared to the control (1.2 x 10(-6) M). In the presence of glibenclamide (10(-5) M) the inhibitory effect of cromakalim was significantly reduced with consequent decrease in the EC50 value (1.9 x 10(-5) M). Application of EFS (30 V and 5 ms) on goat urinary bladder strips at 1, 2, 5, 10, 20 and 30 Hz elicited frequency-related contractile responses. Both cromakalim and pinacidil caused a rightward shift in the frequency-related contractile response curve with significant increase in the mean EF25 and EF50 values, respectively. In the presence of glibenclamide (10(-4) M), the frequency-related inhibitory response curve was shifted to left with significant (P < 0.001) increase in the mean EF25, EF50 and EF75. The present results suggest that in the goat detrusor muscle, agonist and EFS-induced contractile responses were more potently inhibited by cromakalim than pinacidil with activation of glibenclamide sensitive KATP channels.

Role of KATP channels in reduced antinociceptive effect of morphine in streptozotocin-induced diabetic mice.

The nociceptive effect was measured using withdrawal latency in tail flick test in mice rendered diabetic by administering streptozotocin (200 mg/kg, i.p.). The antinociceptive effect of morphine (4 and 8 mg/kg, s.c.) and cromakalim, a KATP channel opener, (0.3, 1 and 2 micrograms, i.c.v.) was significantly reduced in diabetic mice. Moreover, co-administration of cromakalim(0.3 microgram) did not alter the reduced antinociceptive effect of morphine(4 mg/kg) in diabetic mice. Spleenectomy in diabetic mice restored the decrease in antinociceptive effect of morphine and cromakalim. Multiple dose treatment with insulin to maintain euglycaemia for 3 days in diabetic mice prevented the decrease in antinociceptive effect of morphine and cromakalim. However, hyperglycaemic tyrode's buffer did not alter the pD2 value of morphine in isolated guinea pig ileum suggesting that hyperglycaemia does not interfere with mu receptor mediated responses in vitro. The results suggest that hyperglycaemia induced decrease in antinociceptive effect of morphine and cromakalim may be due to alteration in KATP channels. Some unknown factor from spleen in diabetic mice may be responsible for this alteration in KATP channels in diabetic mice.