Comparison of the effect of levodopa and bromocriptine on naloxone-precipitated morphine withdrawal symptoms in mice

In this study, the effect of l-dopa and bromocriptine on morphine withdrawal syndrome was compared. Both l-dopa (125, 250 mg/kg, i.p.) and low doses of bromocriptine (0.04, 0.08 mg/kg, i.p.) potentiated naloxone-induced morphine withdrawal symptoms such as jumping, climbing and rearing in mice. Higher doses of bromocriptine (0.16, 0.32 mg/kg, i.p.) attenuated these naloxone-induced symptoms. SKF 83566, D(1) dopamine antagonist (0.4, 0.8 mg/kg, i.p.) and sulpiride, D(2) dopamine antagonist (5, 10 mg/kg, i.p.) when used alone, also produced inhibitory effects on naloxone-induced morphine withdrawal symptoms. Pretreatment with sulpiride (5, 10 mg/kg, i.p.) and SKF 83566 (0.4, 0.8 mg/kg, i.p.) attenuated the potentiating effects of l-dopa on withdrawal symptoms significantly. Pretreatment with sulpiride also decreased the potentiating effect of bromocriptine and reinforced the inhibitory action of it, but SKF 83566 pretreatment just reinforced the effect of higher doses of bromocriptine. Concurrent pretreatment of animals with sulpiride (10 mg/kg, i.p.) and SKF 83566 (0.8 mg/kg, i.p.) markedly decreased the potentiating effects of l-dopa and bromocriptine and reinforced the inhibitory action of bromocriptine on the naloxone-induced morphine withdrawal syndrome. Prazosin, alpha(1) antagonist (1, 2 mg/kg, i.p.) decreased the naloxone-induced morphine withdrawal syndrome significantly. Pretreatment with yohimbine, alpha(2)-antagonist (5 mg/kg, i.p.) reversed the inhibitory effects of bromocriptine (0.16, 0.32 mg/kg, i.p.) on naloxone-induced morphine withdrawal syndrome significantly. In conclusion, our results show that bromocriptine at lower doses (0.04, 0.08 mg/kg, i.p.) acts similar to l-dopa, but at higher doses (0.16, 0.32 mg/kg, i.p.) shows different effects on naloxone-induced morphine withdrawal syndrome which may be due to the interaction of bromocriptine with alpha-adrenoceptors. Copyright 2000 John Wiley & Sons, Ltd.     

The effect of chronic administration of caffeine on morphine-induced analgesia, tolerance and dependence in mice

Morphine-induced analgesia, and the development of morphine-induced tolerance and dependence was determined in mice which had drunk caffeinated water (1 mg/ml) for 14 days or in mice which had received (-)-N6-(phenylisopropyl)-adenosine (PIA) 1 mg/kg i.p. for 14 days. Analgesia was assessed by the tail flick assay. The development of dependence was assessed by determining the ED50 of naloxone to precipitate withdrawal jumping (3 h after 100 mg/kg morphine pretreatment or 72 h after s.c. implantation of a morphine 75 mg pellet) and by determining the extent of naloxone-precipitated hypothermia in morphine-implanted animals. In mice chronically administered caffeine, the ED50 for morphine-induced analgesia was significantly decreased while the naloxone ED50 for withdrawal jumping increased by 2-fold after both types of morphine pretreatment. In control animals (tap water for 14 days), doses of 1 and 10 mg/kg of naloxone caused significant hypothermia in morphine-implanted animals. Doses of naloxone up to 100 mg/kg did not cause significant hypothermia in morphine-implanted animals which had received chronic caffeine. The development of tolerance was determined by computing the morphine potency ratio for the tail flick assay (tolerant ED50/control ED50). In mice chronically administered caffeine, the potency ratio was decreased significantly in morphine-implanted animals when compared to control. Morphine-induced analgesia, tolerance and dependence was not changed significantly in animals chronically administered PIA. Neither the distribution of morphine to the brain nor the opioid receptor binding parameters for [3H]etorphine and [3H]naltrexone were altered in mice chronically administered caffeine or PIA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulatory role of D-1 and D-2 dopamine receptor subtypes in nociception in mice

The role of D-1 and D-2 dopamine (DA) receptors in nociception in naive as well as reserpinized mice and the modulation of the nociceptive action of morphine or naloxone by the selective D-1 and D-2 DA agonists, was investigated in mice. The D-2 DA agonists, B-HT 920 and bromocriptine produced an anti-nociceptive effect in naive mice and reversed the hyperalgesic effect of reserpine (2 mg/kg, 4 h prior) pre-treatment. The D-1 DA agonist, SKF 38393 (5 mg/kg) failed to alter the nociceptive responsiveness of naive and reserpinized mice. Apomorphine, a mixed D-1/D-2 DA agonist, produced significant analgesia in naive mice and also reversed reserpine-induced hyperalgesia. SKF 38393 (5 mg/kg) enhanced the anti-nociceptive effect of B-HT 920 (0.1 mg/kg) in naive and reserpine-pre-treated mice. The anti-nociceptive response of morphine (5 mg/kg) was enhanced by B-HT 920 while SKF 38393 reduced the same. Apomorphine (0.5 mg/kg) or the combination of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) failed to enhance the anti-nociceptive effect of morphine. Reserpine (2 mg/kg, 4 h prior) pre-treatment significantly reduced the anti-nociceptive effect of morphine. Similarly, the hyperalgesic action of naloxone (20 mg/kg) was reversed by B-HT 920, bromocriptine and apomorphine but not by SKF 38393. The reversal of the hyperalgesic action of naloxone by B-HT 920 was blocked by pre-treatment with haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg). SKF 38393 (5 mg/kg) failed to potentiate the reversal action of B-HT 920 against naloxone. These data suggest a predominant role of D-2 DA receptors in anti-nociception and the possibility of the existence of an interlink between the DAergic and opioid systems.     

Dose-dependent effects of prolyl-leucyl-glycinamide on morphine-induced analgesia, tolerance and dependence

Prolyl-leucyl-glycinamide (PLG) at a low dose (10 ng/mouse) administered intracerebroventricularly (i.c.v.) did not affect morphine analgesia, but produced a greater increase in the ED50 of morphine-pretreated (100 mg/kg of morphine sulfate) mice as compared to control mice. PLG at doses of 10 and 100 micrograms/mouse antagonized morphine analgesia. Development of morphine tolerance was unaffected by 10 micrograms/mouse but antagonized by 100 micrograms/mouse of PLG. Development of morphine dependence was assessed by changes in body weight and temperature during naloxone-induced withdrawal. PLG (10 ng/mouse) potentiated, 10 micrograms/mouse had no effect and 100 micrograms/mouse antagonized development of morphine dependence. PLG at doses of 10 and 100 micrograms/mouse precipitated withdrawal in morphine-dependent mice. When mice were pretreated with 1.0 mg/kg naloxone i.p. 15 min before PLG, all doses of PLG had no effect on morphine analgesia, but potentiated the development of morphine tolerance and dependence. None of the doses of PLG altered whole brain levels of morphine. PLG did not alter the affinity of opioid receptors for etorphine or the maximal number of binding sites but PLG did exhibit a very weak affinity for opioid receptors. These results indicate that PLG potentiated development of morphine tolerance and dependence through a mechanism not involving opioid receptors. However, at very high doses it was a weak opioid receptor antagonist.     

Influence of prazosin and clonidine on morphine analgesia,tolerance and withdrawal in mice

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (₂-adrenoceptor agonist) and prazosin (₁-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another ₁-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of ₂-adrenoceptors in opioid actions, also ₁-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.     

Methysergide and metergoline reduce morphine analgesia with no effect on the development of tolerance in rats

A single subcutaneous injection of 5 mg/kg metergoline or 10 mg/kg methysergide, two serotonin antagonists, or 1 mg/kg naloxone, significantly reduced the effect of a subcutaneous dose of 3 mg/kg morphine in the tail immersion test in rats. The same drugs and doses were administered concurrently with 10 mg/kg morphine twice daily for 3 days and nociceptive responses were measured 96 h later. Tolerance to the effect of 3 mg/kg morphine was comparable in animals which had received vehicle + morphine or serotonin antagonists + morphine, whereas naloxone completely prevented the development of tolerance. The results argue against a role of serotonin in the development of tolerance to the antinociceptive effect of morphine and suggest it may be possible to dissociate morphine analgesia from tolerance development, at least in the conditions used in the present study.     

Methysergide and metergoline reduce morphine analgesia with no effect on the development of tolerance in rats

A single subcutaneous injection of 5 mg/kg metergoline or 10 mg/kg methysergide, two serotonin antagonists, or 1 mg/kg naloxone, significantly reduced the effect of a subcutaneous dose of 3 mg/kg morphine in the tail immersion test in rats. The same drugs and doses were administered concurrently with 10 mg/kg morphine twice daily for 3 days and nociceptive responses were measured 96 h later. Tolerance to the effect of 3 mg/kg morphine was comparable in animals which had received vehicle+morphine or serotonin antagonists+morphine, whereas naloxone completely prevented the development of tolerance. The results argue against a role of serotonin in the development of tolerance to the antinociceptive effect of morphine and suggest it may be possible to dissociate morphine analgesia from tolerance development, at least in the conditions used in the present study.     

Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice.

1. The possible involvement of nitric oxide (NO) in the induction and expression of morphine tolerance and dependence was studied in mice. A two-day repeated injection regimen was used to induce morphine tolerance and dependence. Tolerance was assessed by the tail flick test and physical dependence by naloxone challenge, on the third day. 2. Two days pretreatment with L-arginine (20 mg kg-1, twice daily) or D-NG-nitro arginine methyl ester (D-NAME, 20 mg kg-1, twice daily) alone had no effect on subsequent morphine antinociception. L-NG-monomethyl arginine (L-NMMA, 10 mg kg-1, twice daily) for two days led to a slight increase (not statistically significant) in morphine antinociception; while L-NG-nitro arginine methyl ester (L-NAME, 10 mg kg-1, twice daily) for two days led to attenuation of morphine analgesia. None of the animals treated with these drugs alone showed signs characteristic of the opioid withdrawal syndrome upon naloxone challenge. 3. Induction phase L-arginine slowed the development of opioid tolerance and physical dependence, while L-NAME and L-NMMA led to a higher degree of tolerance but had no effect on the development of physical dependence. 4. L-Arginine and D-NAME had no effect on the expression of morphine tolerance and physical dependence. Expression phase L-NAME and L-NMMA, on the other hand, attenuated morphine tolerance and reduced the incidence of withdrawal signs. 5. NO may, therefore, play a role in both phases of morphine tolerance and dependence: elevation of NO levels during the induction phase delays the development of opioid tolerance/dependence, while inhibition of NO synthase accelerates the development of tolerance. Inhibition of NO attenuates the expression of both tolerance and physical dependence.     

Facilitation of morphine-induced tolerance and physical dependence by prolyl-leucyl-glycinamide

The pretreatment of mice with 30 mg/kg morphine s.c. did not alter the analgesic effect of morphine in mice pretreated with saline but decreased the analgesic effect of morphine in mice pretreated with prolyl-leucyl-glycinamide (PLG). Tolerance was evaluated by the effect of PLG on morphine-induced enhancement of naloxone potency which is a measure of the capacity of naloxone to antagonize morphine-induced analgesia and is postulated to be an indicator of tolerance development. The naloxone potency of PLG-treated mice was 2-fold greater than that of control mice. PLG did not alter the whole brain levels of morphine, nor did it alter the naloxone potency in mice which were not pretreated with 30 mg/kg morphine. In mice treated with 100 mg/kg morphine or implanted with 50 mg morphine pellets for 24 or 72 h, the amount of naloxone required to induce jumping was not altered by PLG. However, PLG treatment did increase the hypothermia and body weight loss seen after naloxone-induced withdrawal. Administration of PLG to morphine-dependent mice 1 h prior to naloxone did not modify the resultant hypothermia or body weight loss. These results indicate that PLG facilitated the development of morphine tolerance and dependence.     

Alterations of bromocriptine-induced penile erection by chronic lithium in rats

In the present study, the effects of chronic lithium pre-treatment (30 days) on penile erection (PE) induced by bromocriptine were investigated in rats. Intraperitoneal administration of the dopamine receptor agonist, bromocriptine (4-32 mg/kg) induced PE in a biphasic manner. The maximum response was obtained with 8 mg/kg of bromocriptine and the effect was decreased with increasing doses of the drug from 8 to 32 mg/kg. When animals were pre-treated with different doses of the D-1 dopamine receptor antagonist, SCH 23390, or the D-2 dopamine receptor antagonist, sulpiride, the PE response was decreased. The response induced by bromocriptine (4-32mg/kg) was reduced in animals pre-treated with chronic lithium. SCH 23390 did not produce a larger inhibitory effect on the bromocriptine response in animals pre-treated with chronic lithium, but the inhibitory effect of sulpiride was increased in this condition. It is concluded that chronic lithium treatment may alter the D-1/D-2 receptor activity and inhibit bromocriptine-induced PE.     

Dopamine receptor mechanism(s) and morphine tolerance in mice

Based on our previous demonstration of the involvement of dopamine-2 (D2) dopamine receptors in morphine antinociception, we examined the role of D2 dopamine receptors in the expression and development of tolerance to morphine antinociception in mice. Tolerance to morphine antinociception was assessed by the tail-flick response after the administration of morphine (50 mg/kg) once daily for 3 days. The D2 dopamine receptor agonist, quinpirole (0.01, 0.02 and 0.03 mg/kg), but not the D2 dopamine receptor antagonist, sulpiride (12.5, 25 and 50 mg/kg), increased morphine antinociception in morphine non pre-exposed mice. The response of quinpirole was decreased by the lower doses of sulpiride. Both quinpirole and sulpiride decreased the expression and development of tolerance to antinociception induced by morphine (1.5, 3 and 6 mg/kg). The effect of quinpirole on the expression and development of tolerance, was reduced by a lower and per se non-effective dose of sulpiride. It was concluded that D2 dopaminergic receptors may play a part in the expression and development of tolerance to the antinociceptive effect of morphine.     

Inhibition of morphine tolerance and dependence by MS-153, a glutamate transporter activator

We investigated the effects of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), which is reported to accelerate glutamate uptake, on the development of morphine tolerance and physical dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10-45 mg/kg, s.c.) for 5 days. First, co-administration of MS-153 (12.5 mg/kg, s.c.) did not affect the morphine's potency for its acute antinociceptive effect (1 and 3 mg/kg, s.c.). Next, co-administrations of MS-153 (1, 3 and 12.5 mg/kg, s.c.) during repeated morphine treatments significantly attenuated the development of tolerance to the antinociceptive effect of morphine (3 mg/kg, s.c.) and suppressed the naloxone (10 mg/kg, i.p.)-precipitated withdrawal signs (jumps and body weight loss). The inhibitory effect of MS-153 on the withdrawal signs was due to the attenuation of the development of dependence rather than that of expression of withdrawal signs. These results suggest that MS-153, a glutamate transporter activator, has an inhibitory effect on the development of morphine tolerance and physical dependence.     

Role of sodium cromoglycate on analgesia,locomotor activity and opiate withdrawal in mice

The role of sodium cromoglycate (CRO) on analgesia, locomotor activity and morphine withdrawal in mice was studied in morphine-dependent and drugnaive mice. CRO (0.5, 1, 5, 10, 30, 50 and 100 mg/kg, SC) induces analgesia (hot plate), an effect blocked by previous administration of the opiate antagonist naloxone (1 mg/kg). Furthermore, CRO (30 mg/kg) potentiates morphine analgesia. In morphine-tolerant mice, moderate doses of CRO (0.5, 1, 5, 10 and 30 mg/kg) do not induce analgesia, which suggested the development of cross tolerance between CRO and morphine, whereas coadministration of CRO and morphine in morphine tolerant animals restored the sensitivity to morphine. Administration of CRO (10 and 30 mg/kg) induces an increase in spontaneous locomotor activity, and previous administration of naloxone (1 mg/kg) blocks this effect, whereas CRO (10 mg/kg) blocks morphine (10 mg/kg) and amphetamine (3 mg/kg)-induced hyperactivity. CRO (10, 50 and 100 mg/kg) induces a significant and dose-dependent reduction in the number of jumps (jumping up) during naloxone (1 mg/kg)-induced withdrawal in morphine-dependent mice. Finally, CRO (100 mg/kg) reduces the wet dog shake phenomenom during naloxone-induced withdrawal in morphine-dependent mice. These results suggest a possible stabilizing effect of CRO on the membranes of neurones that mediate analgesia, locomotor activity and opiate abstinence. Changes and inhibition of DA, NA and 5-HT release may also explain these effects.This work was supported by a grant from the CICYT (Program FAR 90/0543).     

Repeated administration of nicotine attenuates the development of morphine tolerance and dependence in mice

Clinical use of morphine in pain management is a controversial issue. Both nicotine and morphine are widely abused. So, investigating the interaction between nicotinic and opioid receptors is of great interest to both basic mechanistic and clinical view. We investigated the influence of repeated administration of nicotine on the development of morphine tolerance and dependence. Adult male albino mice were rendered dependent on morphine by subcutaneous (s.c.) injections three times daily for 3 days. Repeated intraperitoneal (i.p.) injection of nicotine (0.001-2 mg/kg) or saline (1 ml/kg) was performed 15 min prior to each morphine injection. Maximal possible effect (MPE%) of morphine (50 mg/kg; s.c.) was used on the fourth day as an index for the development of tolerance. Likewise, to assess the occurrence of dependence in drug-treated mice, naloxone (5 mg/kg; i.p.) was injected 2 h after the last dose of morphine. Repeated nicotine administration significantly attenuated the development of tolerance in a dose-dependent manner whereas it significantly decreased withdrawal jumping behavior in a biphasic profile (V-shape) manner. Furthermore, the central nicotinic receptor antagonist mecamylamine (0.01-0.1 mg/kg; i.p.) neither the peripheral nicotinic receptor antagonist hexamethonium (0.01 and 0.1 mg/kg; i.p.) nor the muscarinic receptor antagonist atropine (2.5-10 mg/kg; i.p.), dose-dependently antagonized both the inhibition of withdrawal jumping as well as increase in MPE% which was produced by repeated nicotine administration (0.1 mg/kg; i.p.). On the other hand, 3 days of solely nicotine treatment resulted in significant jumping behavior precipitated by naloxone after single morphine injection on the test day. The data suggests that the inhibitory effect of nicotine on the morphine tolerance and dependence is mediated by central nicotinic receptors and there is a cross-dependence between nicotine and morphine.     

The effects of cholinergic compounds on the development of morphine tolerance,dependence and increased naloxone potency in mice

The effects of chronic treatment with morphine and cholinergic compounds on the development of morphine tolerance, physical dependence and increased naloxone potency were studied. Using the abdominal constriction method, it was shown that morphine tolerance was apparent after s.c. administration of morphine 20.0 mg/kg three times a day for four days. It was found that, in animals which showed a low degree of morphine tolerance, the naloxone potency was similar to that determined in mice which had been pretreated with only a single dose of morphine which causes no measurable tolerance. Thus, the development of increased naloxone potency and tolerance to morphine do not parallel each other. In addition, while atropine inhibited, and anti-cholinesterase drugs enhanced, the development of increased naloxone potency caused by morphine treatment they had no or little effect on the development of morphine tolerance. Futhermore, chronic treatment with cholinergic agonists reduced, while muscarinic antagonist enhanced, the development of physical dependendence on morphine as assessed by withdrawal jumping and body weight loss. It is concluded that the increased potency of naloxone in antagonising the antinociceptive effect of morphine can be dissociated from the development of tolerance to, and physical dependen on, morphine in mice.     

Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selective glutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA.

Inhibition of glutamate carboxypeptidase II (GCP II; NAALADase) produces a variety of effects on glutamatergic neurotransmission. The aim of this study was to investigate effects of GCP II inhibition with the selective inhibitor, 2-PMPA, on: (a) development of tolerance to the antinociceptive effects, (b) withdrawal, and (c) conditioned reward produced by morphine in C57/Bl mice. The degree of tolerance was assessed using the tail-flick test before and after 6 days of twice daily (b.i.d.) administration of 2-PMPA and 10 mg/kg of morphine. Opioid withdrawal was measured 3 days after twice daily morphine (30 or 10 mg/kg) administration, followed by naloxone challenge. Conditioned morphine reward was investigated using conditioned place preference with a single morphine dose (10 mg/kg). High doses of 2-PMPA inhibited the development of morphine tolerance (resembling the effect of 7.5 mg/kg of the NMDA receptor antagonist, memantine) while not affecting the severity of withdrawal. A high dose of 2-PMPA (100 mg/kg) also significantly potentiated morphine withdrawal, but inhibited both acquisition and expression of morphine-induced conditioned place preference. Memantine inhibited the intensity of morphine withdrawal as well as acquisition and expression of morphine-induced conditioned place preference. In addition, 2-PMPA did not affect learning or memory retrieval in a simple two-trial test, nor did it produce withdrawal symptoms in morphine-dependent, placebo-challenged mice. Results suggest involvement of GCP II (NAALADase) in phenomena related to opioid addiction.     

Opioid mechanisms of some behavioral effects of ketamine

The effect of naloxone on the duration of sleep and on analgesia produced by ketamine, and on the development of tolerance and cross-tolerance with morphine to ketamine analgesic effects were investigated in mice. Ketamine produced a dose-dependent analgesia. Naloxone (4 mg/kg) significantly inhibited the analgesic effects of ketamine (40 mg/kg), but (given in a dose of 2 mg/kg) did not affect the duration of ketamine sleep. Chronic administration of ketamine (160 mg/kg twice daily for 7 days) resulted in a gradual shortening of ketamine sleep and in the development of tolerance to the analgesic action of ketamine. There also developed cross-tolerance between analgesic effects of morphine and ketamine. Ketamine (20 mg/kg) significantly inhibited symptoms of morphine abstinence produced in morphine-pelleted mice by naloxone administration or by pellet removal. The results suggest that at least some elements of the mechanism of action of ketamine and morphine may be common and related to the endogenous opioid system.     

The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat

The effects of the selective CCK-A antagonist L-365,031 and the selective CCK-B antagonist L-365,260 on morphine analgesia and opiate tolerance and dependence in rats were examined. L-365,031 and L-365,260 had no effect on baseline pain thresholds in the radiant heat tail flick test but enhanced analgesia induced by a submaximal dose of morphine (4 mg/kg). Similarly, L-365,260 did not effect pain thresholds in the paw pressure test but enhanced morphine analgesia in this model. Rats injected twice daily for 6 days with incremental doses of morphine became tolerant to the analgesic effects of the drug. Twice daily injections of either 8 mg/kg L-365,031 or 0.2 mg/kg L-365,260 prevented the development of tolerance to morphine analgesia. In contrast, L-365,260 had no influence on the development of opiate dependence in these animals, as assessed by naloxone-precipitated withdrawal. The results of the present study, when considered together with previous data, indicate that the rank order of potency of non-peptide CCK antagonists for enhancing morphine analgesia is L-365,260 greater than MK-329 greater than L-365,031. This rank order correlates well with the potency of the antagonists in blocking CCK-B receptors in rodents and suggests that CCK/opiate interactions in this species are mediated by CCK-B receptors.     

A dual action of valproic acid upon morphine analgesia and morphine withdrawal

Effects of valproic acid administration on morphine analgesia and on morphine tolerance and dependence were investigated in mice. Valproate increased the reaction time to thermal stimulation in naive animals. This effect was additive with morphine when valproate was administered shortly before the analgesic. However, an antagonism was observed if a 4-hour period elapsed between valproate and morphine administration. When administered to mice receiving a sustained release preparation of morphine, valproate antagonized the development of tolerance to morphine. Valproate elicited a dual action on the abstinence signs observed after naloxone administration in morphine-treated mice. The effect consisted in a reduction of abstinence behavior if the anticonvulsant was administered a few minutes before naloxone; the same treatment increased the severity of the abstinence behavior when valproate was injected 1 h before the precipitating dose of naloxone. In this latter schedule, concomitant administration of gamma-vinyl-GABA failed to reduce the severity of the convulsions observed during the abstinence syndrome. These results suggest that valproate is metabolized to a compound responsible for decreased analgesia and intensified withdrawal signs.     

Extracellular signal-regulated kinase (ERK) inhibition does not prevent the development or expression of tolerance to and dependence on morphine in the mouse

The clinical use of opioids is limited by the development of tolerance and physical dependence. Opioid tolerance and dependence are believed to result from complex adaptations in the CNS, representing a form of neural plasticity. Extracellular signal-regulated kinases (ERKs) are involved in many forms of neural plasticity, and therefore could also be involved in the development of opioid tolerance and dependence. In this study, we investigated the effect of a systemically bioavailable MEK (ERK kinase) inhibitor, SL327, upon the development and the expression of tolerance to and dependence on morphine in mice. In tolerance and dependence development studies, two strains of mice were treated daily for 8 or 9 days with 5mg/kg morphine s.c. Tolerance development was assessed by tail flick latency. Withdrawal was then precipitated by subcutaneous injection of 2mg/kg naloxone s.c. and signs recorded. Co-administration of 50mg/kg SL327 i.p. prior to morphine administration had no effect on the development of tolerance or withdrawal signs. To study possible effects of ERK inhibition on the expression of tolerance and dependence, mice were implanted with 75mg morphine pellets s.c. Tolerance and dependence were assessed as previously described. An acute i.p. injection of 50mg/kg SL327 after 4 days of morphine exposure had no effect on the expression of either morphine tolerance or physical dependence. To verify that this dose of SL327 inhibited morphine-induced ERK modulation, mice received an acute i.p. injection of 50mg/kg SL327 prior to morphine administration, and sacrificed 30min later. Western blots demonstrated that SL327 did inhibit morphine-induced ERK modulation. Taken together, these data suggest that unlike many other observed forms of neural plasticity, the ERK signaling cascade is not involved in the development or expression of opioid tolerance and dependence.