The role of T-type calcium channels in morphine analgesia, development of antinociceptive tolerance and dependence to morphine, and morphine abstinence syndrome (original) (raw)
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Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance
European Journal of Pharmacology, 1988
The influence of calcium channel blockers on morphine-induced analgesia and on tolerance to the chronic administration of the opiate was investigated in mice. The effects of a test dose of morphine were significantly increased by the administration of diltiazem, flunarizine, nicardipine and verapamil. In contrast, nifedipine induced an antagonistic effect. The calcium channel antagonists did not change the reaction time to thermal stimulation in mice (hot plate test). The administration of nifedipine, flunarizine and verapamil reduced the intensity of the tolerance induced by a single dose of morphine administered in a slow release preparation. Diltiazem induced a non-significant decrease of the process. The present results are in accordance with the known interaction of acute and chronic morphine administration with the intracelhilar calcium concentration in neurones of the central nervous system.
Hormones and …, 2008
Both opioids and calcium channel blockers could affect hypothalamic-pituitary-adrenal (HPA) axis function. Nifedipine, as a calcium channel blocker, can attenuate the development of morphine dependence; however, the role of the HPA axis in this effect has not been elucidated. We examined the effect of nifedipine on the induction of morphine dependency in intact and adrenalectomized (ADX) male rats, as assessed by the naloxone precipitation test. We also evaluated the effect of this drug on HPA activity induced by naloxone. Our results showed that despite the demonstration of dependence in both groups of rats, nifedipine is more effective in preventing of withdrawal signs in ADX rats than in shamoperated rats. In groups that received morphine and nifedipine concomitantly, naloxone-induced corticosterone secretion was attenuated.
Pain, 2001
We examined the effects of amlodipine, a selective L-type voltage dependent Ca 21 channel (VDCC) blocker, and mibefradil, a selective Ttype VDCC blocker on the antinociceptive effects of morphine, and m, d and k opioid receptor selective agonist-induced antinociception at the spinal level. Intrathecally administered amlodipine and mibefradil potentiated morphine and [d-Ala 2 , N mePhe 4 , Gly-ol 5 ] enkephalin (DAMGO)-induced antinociception by shifting their dose response curves to the left. However, intrathecally administered amlodipine and mibefradil did not affect [d-Pen 2 , D-Pen 5 ]enkephalin (DPDPE) and [trans-(^)-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl] benzene acetamide (U-50, 488H)-induced antinociception. These data indicate that L-type and T-type VDCC blockers synergistically potentiate the analgesic effects of m opioid receptor agonists, but not d and k opioid receptor agonists, at the spinal level. Additionally, these data suggest that there is an important functional interaction between L-type and/ or T-type VDCC and m opioid receptors in the process of analgesia. .tr (A. Dog AErul).
Differential effects of calcium channel blockers and stimulants on morphine withdrawal in vitro
European Journal of Pharmacology, 1988
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/xM) inhibited the naloxoneinduced morphine withdrawal contractures in a concentration-dependent way. The effect of diltiazem was stereospecific. On the other hand, the calcium channel stimulant, Bay k 8644 (0.01 /xM), significantly increased the naloxone-induced contractures of morphine-dependent ileum. These results suggest a role for calcium channels in morphine withdrawal in vitro
Role of calcium in morphine dependence and naloxone-precipitated withdrawal in mice
Journal of Experimental Pharmacology, 2011
To explore the role of calcium in morphine withdrawal syndrome using various agents affecting calcium levels in cytoplasm. Methods: Mice were rendered dependent on morphine by subcutaneous injection of morphine, and withdrawal was induced 4 hours later by injecting the opioid antagonist, naloxone. Mice were observed for 30 minutes for signs of withdrawal, ie, characteristic jumping, hyperactivity, urination, and diarrhea. Various calcium channel blockers were injected intraperitoneally 30 minutes before naloxone to evaluate their influence on the severity of the withdrawal syndrome. We also tested the effect of combination levodopa-carbidopa pretreatment and its interaction with a selective alpha-1 blocker, terazosin, on naloxone-precipitated withdrawal in mice acutely dependent on morphine. Results: A significant dose-dependent attenuation of naloxone-induced morphine withdrawal syndrome was observed with calcium channel blockers, ie, verapamil 20 mg/kg (P , 0.05) and diltiazem 30 mg/kg (P , 0.01). Combination levodopa-carbidopa pretreatment facilitated the morphine withdrawal syndrome, and this was found to be blocked by terazosin, although not to a statistically significant (P. 0.05) extent. Conclusion: The results indicate that calcium plays an important role in the genesis of morphine dependence and withdrawal, and suggest the usefulness of calcium channel blockers in the management of morphine withdrawal syndrome.
Basic and clinical neuroscience, 2014
We investigated the role of ATP-sensitive potassium channels and L-type calcium channels in morphine-induced hyperalgesia after nociceptive sensitization. We used a hotplate apparatus to assess pain behavior in male NMRI mice. Nociceptive sensitization was induced by three days injection of morphine and five days of drug free. On day 9 of the schedule, pain behavior test was performed for evaluating the effects of morphine by itself and along with nimodipine, a blocker of L-type calcium channels and diazoxide, an opener of ATP-sensitive potassium channels. All drugs were injected through an intraperitoneal route. The results showed that morphine (7.5, 10 and 15 mg/kg) induced analgesia in normal mice, which was prevented by naloxone (1 mg/kg). After nociceptive sensitization, analgesic effect of morphine (10 and 15 mg/kg) was significantly decreased in sensitized mice. The results showed that nimodipine (2.5, 5, 10 and 20 mg/kg) had no significant effect on pain behavior test in eit...
Brain Research, 2009
We have earlier reported that nifedipine and nimodipine, both L-type voltage-sensitive calcium channel (L-VSCC) antagonists, attenuate the development of tolerance to chronic administration of morphine in the rat. In the present study, we have investigated the expression of L-and N-type VSCC using immunohisto-chemistry, in the cervical region of the spinal cords from animals treated chronically with morphine alone or in combination with nimodipine. The highest expression of both VSCCs within the spinal cord was detected within the superficial laminae of the dorsal horn, which indicates that these channels play an important role in the spinal processing of pain. After morphine tolerance, the expression of both the channels in the superficial laminae was significantly higher than control animals. However, morphine + nimodipine administration produced a differential effect, that is, the expression of L-VSCC decreased while that of N-VSCC increased. The study shows that the expression of these channels is plastic and subject to change depending upon the drug administered. This in turn can determine overall responsiveness to morphine.
L-type calcium channel blockers, morphine and pain: Newer insights
Indian Journal of Anaesthesia, 2010
Earlier, we had reported that co-administration of opioids and L-type calcium channel blockers (L-CCBs) like diltiazem could prove useful in the treatment of cancer pain. Much of this report was based upon earlier published work involving animal models of pain exposed to brief periods of noxious radiant heat without any tissue injury. However, pain in clinical situations usually result from tissue injury. Thus, the aim of the current investigation was to study the analgesic effect of this combination of drugs in the rat formalin test which is associated with actual tissue injury. Wistar rats (n=60) received either L-CCB (nifedipine/nimodipine/verapamil/diltiazem i.p.) or morphine (s.c.) or both drugs. The formalin test was done 30 min after morphine or placebo injection. The naloxone reversal test was also done. Administration of L-CCBs alone, particularly diltiazem, increased pain in the formalin test. In contrast, co-administration of these L-CCBs with morphine led to decreased pain response, though statistically significant decrease was noted only with nimodipine + morphine. Naloxone reversed this analgesic effect, indicating that it was primarily an opioid-mediated effect. The results show that administration of L-CCBs alone may prove counterproductive in the therapeutic management of pain (anti-analgesic effect). However, co-administration of both drugs (morphine and nimodipine) in quick succession could lead to adequate pain relief.
European Journal of Pharmacology, 1993
The role of the L-type Ca 2+ channel in the acute effects of morphine on the hypothalamo-pituitary-adrenocortical (HPA) system was studied by administration of the Ca 2÷ channel agonist, BAY K 8644, and the antagonists, verapamil and nimodipine, to rats. Morphine (30 mg/kg i.p.) induced an increase in corticosterone secretion 30 min after injection, which was correlated with a simultaneous change in hypothalamic noradrenaline (NA) and dopamine (DA) contents. Pretreatment with verapamil (10 or 20 mg/kg i.p.) or nimodipine (5 mg/kg i.p.) antagonized the HPA activation induced by morphine, blocking both the decrease in hypothalamic NA levels and the elevation in plasma corticosterone induced by the opioid. BAY K 8644 (2 mg/kg i.p.) potentiated the effects of morphine, decreasing the hypothalamic NA content and increasing the release of corticosterone. The Ca 2+ channel antagonist, nimodipine, given alone induced a slight reduction in hypothalamic NA content but did not modify plasma corticosterone levels. Verapamil given alone did not alter HPA activity. Instead, the Ca 2÷ agonist decreased the hypothalamic catecholamine content and increased plasma corticosterone levels. These results indicate that Ca 2+ influx is necessary for the expression of opioid actions on the HPA system, and suggest that the Ca 2+ flux in hypothalamic neurons is functionally linked to activation of opioid receptors.