Manuel Barrios

An ATP-dependent potassium channel blocker antagonizes morphine analgesia

We showed that glibenclamide, a blocker of ATP-dependent potassium channels in the CNS, antagonizes morphine-induced analgesia in mice

Subgroups among μ-opioid receptor agonists distinguished by ATP-sensitive K+ channel-acting drugs

1 We evaluated the effects of the i.e.v. administration of different K+ channel blockers (gliquidone, 4‐aminopyridine and tetraethylammonium) and an opener of K+ channels (cromakalim) on the antinociception induced by several μ‐opioid receptor agonists in a tail flick test in mice.

The NMDA receptor antagonist dizocilpine (MK-801) stereoselectively inhibits morphine-induced place preference conditioning in mice

The effect of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on conditioned place preference induced by morphine was studied in mice. As expected, morphine (1–8 mg/kg, IP) elicited a significant preference for the drug-paired compartment. Pretreatment of mice with (+)-dizocilpine (0.1 and 0.2 mg/kg, IP), the more active dizocilpine enantiomer, dose-dependently reversed the conditioned place preference produced by morphine (4 mg/kg, IP), whereas (−)-dizocilpine (0.2 mg/kg, IP) did not modify morphine-induced effects. In contrast, both enantiomers of dizocilpine (at a dose of 0.2 mg/kg, IP) elicited a conditioned place preference. These data suggest that (1) NMDA receptors play a role in morphine-induced place preference, and (2) dizocilpine-reinforcing properties in the place preference paradigm do not seem to be dependent on NMDA receptor blockade.

Effects of K+ channel blockers and openers on antinociception induced by agonists of 5-HT1A receptors.

The modulation by K+ channel-acting drugs of the antinociceptive effect of several 5-HT1A receptor agonists was examined with the hot plate test in mice. All the 5-HT1A receptor agonists tested induced dose-dependent antinociception, the order of potency being (+/-)-8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) > buspirone > or = lesopitron > or = tandospirone. The blockers of ATP-sensitive K+ channels (KATP) gliquidone and glipizide (1-4 and 16-64 micrograms/mouse i.c.v., respectively) reduced the antinociceptive effect of 8-OH-DPAT, whereas cromakalim (32-64 micrograms/mouse i.c.v.), an opener of KATP channels, enhanced the effect. In contrast, 4-aminopyridine (25-250 ng/mouse i.c.v.) and tetraethylammonium (10-20 micrograms/mouse i.c.v.), which antagonize several non-ATP-dependent K+ conductances, were inactive. The same results were found with other agonists of 5-HT1A receptors (lesopitron, buspirone and tandospirone): gliquidone inhibited whereas cromakalim increased their antinociceptive effects. None of the K+ channel-acting drugs modified the binding of [3H]8-OH-DPAT to hippocampal membranes, whereas all the 5-HT1A receptor agonists displaced the ligand. These results suggest that ATP-sensitive K+ conductances are involved in the antinociception induced by agonists of 5-HT1A receptors.

Differential effects of calcium channel blockers and stimulants on morphine withdrawal in vitro

The effects of calcium channel blockers and stimulants on naloxone-precipitated morphine withdrawal in morphine-dependent ileum were evaluated in vitro. Both verapamil and diltiazem (0.01-1 microM) inhibited the naloxone-induced morphine withdrawal contractures in a concentration-dependent way. The effect of diltiazem was stereo-specific. On the other hand, the calcium channel stimulant, Bay k 8644 (0.01 microM), significantly increased the naloxone-induced contractures of morphine-dependent ileum. These results suggest a role for calcium channels in morphine withdrawal in vitro.

Differential effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in mice acutely dependent on morphine

The effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in miceacutely dependent on morphine were evaluated. Verapamil (10–80 mg/kg), diltiazem (20–120 mg/kg) and nicardipine (20–160 mg/kg), when administered subcutaneously, produced a dose-dependent reduction in forepaw tremor and weight loss during the abstinence reaction; jumping was also reduced by all three drugs, although the effect was not statistically significant in the case of nicardipine. By contrast, the calcium agonist Bay K 8644 (0.5–2 mg/kg, SC) increased forepaw tremor and weight loss, although this latter effect did not reach statistical significance. The effects of the calcium channel active drugs on the rotarod test were also explored, no correlation appearing with the results observed in abstinence (except for the jumping response), which suggests that the withdrawal results are not influenced by motor incoordination or unspecific CNS depression. These findings suggest that L-type calcium channels probably play an important role in withdrawal after acute morphine dependence. Taken together with other observations in chronic models, these results show that calcium channels are similarly involved in morphine abstinence after acute and chronic dependence, in contrast to the differences in the content and uptake of neuronal calcium induced by morphine under both conditions.

ATP-sensitive K+ channel openers inhibit morphine withdrawal.

We studied the effects of two different ATP-sensitive K+ channel openers on naloxone-precipitated withdrawal in morphine-dependent mice. The i.c.v. administration of cromakalim and diazoxide (both at 5-40 micrograms/mouse) dose-dependently inhibited several signs of morphine withdrawal (number of jumps and episodes of forepaw tremors, and body weight loss). At present it is impossible to specify the exact mechanism(s) involved in this effect. However, considering that morphine opens K+ channels in neurons, it is tempting to suggest that K+ channel openers can mimic the effects of morphine on neuronal K+ currents, and as a consequence can act as substitutes for this drug during morphine withdrawal.

Centrally administered aminoglycoside antibiotics antagonize naloxone-precipitated withdrawal in mice acutely dependent on morphine

The effects of i.c.v. administration of several aminoglycoside antibiotics on naloxone-precipitated morphine withdrawal symptoms were evaluated in mice acutely dependent on morphine. Neomycin (10-40 micrograms/mouse), gentamicin (40-160 micrograms/mouse) and kanamycin (80-320 micrograms/mouse) produced a dose-dependent reduction of the number of precipitated jumps, forepaw tremors and head shakes. The order of potency of the aminoglycoside antibiotics on all withdrawal symptoms was neomycin > gentamicin > kanamycin, which is the same order that these drugs show as N-type calcium channel blockers. The capacity of several drugs that decrease neuronal calcium availability (such as lanthanum and L-type calcium channel blockers) to antagonize opiate withdrawal is well known. In the light of these findings, our results suggest that the mechanism of aminoglycoside-induced inhibition of morphine abstinence may be related to the capacity of these antibiotics to block N-type calcium channels, and to decrease neuronal calcium availability.

Role of L-type calcium channels on yohimbine-precipitated clonidine withdrawal in vivo and in vitro.

SummaryThis study was designed to elucidate the possible participation of L-type calcium channels in the expression of clonidine-withdrawal precipitated by yohimbine in clonidine-dependent animals. Mice implanted for 5 days with osmotic minipumps containing the α2-adrenoceptor agonist clonidine showed symptoms of a withdrawal syndrome (jerks, headshakes, defecations and weight loss) when yohimbine, an α2-adrenoceptor antagonist, was injected. Similarly, isolated rat ilea incubated with clonidine in vitro showed a withdrawal contracture when yohimbine was added to the organ bath. The effects of L-type calcium channel blockers (verapamil and diltiazem) and the stimulant Bay K 8644 on these two different types of withdrawal responses were evaluated. A dose-dependent decrease in yohimbine-precipitated clonidine withdrawal in vivo was observed when verapamil (10–40 mg/kg, s.c. and 120 μg/mouse, i.cv.) or diltiazem (5–20 mg/kg, s.c. and 160 μg/mouse, i.c.v.) were administered to mice dependent on clonidine. No effect was found after Bay K 8644 (0.5–5 mg/kg, s.c. and 1–5 μg/mouse) was injected under these conditions. In vitro, both verapamil (0.1–5 μM) and d-cis-diltiazem (1–50 μM) concentration-dependently reduced the height of the yohimbine-precipitated withdrawal contracture in rat ileum incubated with clonidine. Furthermore, the effect of diltiazem was stereospecific, as d-cis-diltiazem 10 μM markedly inhibited clonidine withdrawal, whereas the same concentration of l-cis-diltiazem had no effect. In contrast, the calcium channel stimulant Bay K 8644 (0.1–1 μM) increased the height of the ileum withdrawal contrature. These results confirm that yohimbine-precipitated clonidine withdrawal can be obtained both in vivo and in vitro, and suggest that the expression of these abstinence responses involves activation of L- type calcium channels. The present results, together with those of previous studies of the effects of calcium channel-acting drugs on ethanol-, opiate- and benzodiazepine-withdrawal, suggest that L-type calcium channels play an important role in the expression of the withdrawal responses to CNS depressant drugs.