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PubMed1989

[Changes of the release of atrial natriuretic factor (ANF) and its gene transcription in morphine tolerance rat atrium].

Specific radioimmunoassay and molecular hybridization technique were used in the present work. Compared with the control rats, we found for the first time a significant decrease of ANF in plasma and a marked increase of ANF in atria in morphine tolerant rats. Simultaneously a raised level of ANF messenger RNA in morphine tolerant rat atria was observed. It is suggested that the biosynthesis and storage of ANF in atria be increased and its release from atria decreased in morphine tolerant rats.

Animals↗

PubMed1998

Blockade of the development of morphine tolerance by U-50,488, an AVP antagonist or MK-801 in the rat hippocampal slice.

1. In this study, we investigated the effects of different drugs (a kappa-opioid receptor agonist U-50,488, a vasopressin receptor antagonist dPTyr(Me)AVP or an N-methyl-D-aspartate (NMDA) receptor antagonist MK-801) on the development of morphine tolerance in rat hippocampal slices. 2. Hippocampal slices (450 microm) of Sprague-Dawley rats (250-300 g) were used. Slices were continuously superfused with artificial CSF or drugs at 1 ml min(-1). Nichrome wire electrodes were placed in the Schaffer-collateral pathway and used to deliver biphasic 0.2 ms pulses of 5-30 V (0.033 Hz). A glass microelectrode was placed in the CA1 area to record population spikes. 3. When the slices were superfused with 10 microM morphine, the amplitude of population spikes increased 2-3 fold in 30-40 min. However, this effect of morphine decreased, i.e. tolerance developed after continuous superfusion of morphine for 2-6 h. 4. When either U-50,488 (200 nM) or dPTyr(Me) AVP (500 pM) or MK-801 (500 pM) was co-superfused with morphine (10 microM), it significantly blocked the development of morphine tolerance. Nor-BNI (a kappa-opioid receptor antagonist, 200 nM) significantly reversed the inhibitory effect of U-50,488 but not those of dPTyr(Me)AVP or MK-801 on the development of morphine tolerance. 5. These data indicate that kappa-opioid receptors, AVP receptors and NMDA receptors are all involved in the development of morphine tolerance. The suppression of kappa-opioid receptor activity after chronic morphine may occur before the activation of AVP receptors or NMDA receptors during the development of morphine tolerance.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1994

Interactive effects of MK-801 and morphine on EEG, EEG power spectra and behavior in rats: I. Morphine tolerance development.

This study investigated a potential interaction between MK-801 and morphine tolerance using electroencephalography (EEG), EEG spectral parameters and behavior in the rat. Rats were treated for 7 days with morphine alone or with morphine and MK-801. Control groups received chronic MK-801 alone or saline. On day 8 all rats received morphine alone. Co-treatment significantly accelerated the development of tolerance to morphine-induced total power and latency to sleep onset. Co-treatment, but not morphine alone, produced tolerance to morphine-induced complexity and edge frequency, and produced tolerance equal to that from morphine alone in duration of EEG bursting. MK-801 co-treatment decreased, where chronic morphine alone increased, the excitatory response to morphine. Our results support recent reports that chronic morphine treatment produces supersensitivity to glutamate in the rat cortex and alteration in mesolimbic dopamine levels that are modulated by glutamatergic activity.

Animals↗

PubMed1994

Cholecystokinin gene expression in rat amygdaloid neurons: normal distribution and effect of morphine tolerance.

Previous studies have shown that repeated opioid administration induces a tolerance to opioid, presumably due in part to an opioid-mediated compensatory increase in brain cholecystokinin (CCK) synthesis and/or release. In this study, in situ hybridization histochemistry was used to examine the effect of morphine tolerance on CCK gene expression in the amygdala of rat brains, by using a 35S-labeled synthetic oligonucleotide probe. CCK mRNA-positive neurons in normal rats were seen throughout the amygdaloid complex, with the most heavily labeled neurons in lateral, basal, and cortical nuclei, followed by the medial nucleus. Only a few labeled neurons were found in central and intercalated nuclei. The development of morphine tolerance in the rat was associated with increased hybridization signals for CCK mRNA in each subnucleus of the amygdala. Increases were seen in the numbers of positively labeled neurons and/or the numbers of hybridization grains per positively labeled neuron. Furthermore, differential patterns of increase in CCK mRNA in morphine tolerant rats occurred in different subnuclei of the amygdala, with the highest magnitude of increase in the cortical nucleus, followed in order by the medial, central, basal, intercalated and lateral nuclei. The present study demonstrated that repeated administration of morphine increased CCK gene expression in the amygdaloid complex, and suggested that the development of the tolerance to morphine analgesia is due, in part, to an increase in CCK activity in the amygdaloid complex. These findings substantiate the hypothesis that long-term administration of opioid may induce a compensatory increase in CCK synthesis and/or release, which then results in a progressive antagonism of opioid analgesia.

Amygdala↗

PubMed1976

Morphine tolerance and physical dependence: influence of cholinergic agonists and antagonists.

The effects of centrally acting agents which alter cholinergic activity were assessed in mice rendered tolerant to and dependent on morphine (M mice) and in naive mice (N mice). In both N and M mice, physostigmine potentiated morphine analgesia slightly, and this action was blocked by atropine and scopolamine. When administered 10 min before naloxone in dependent mice atropine enhanced precipitated withdrawal jumping; when given 30 min before naloxone, atropine produced an inhibition of the response. Physostigmine abd oxotremorine greatly inhibited the jumping response, while echothiophate had no effect. The inhibitory effect of physostigmine on naloxone precipitated withdrawal jumpimg was reversed by atropine and scopolamine but atropine did not alter morphine tolerance and dependence development. Brain acetylcholine (ACh) levels in both N and M mice were increased by physostigmine, the increase being greater in M mice. This increase was blocked by prior administration of atropine or scopolamine. When atropine was administered to M mice 10 min before sacrifice, brain AC-h levels decreased. However, when brain ACh levels were determined 30 min after atropine, no change was found. It was concluded that ACh does not play a major direct role in the development of tolerance and dependence, but that ACh is involved in the manifestations of acute morphine effects and in some of the withdrawal signs in the dependent state.

Acetylcholine↗

PubMedDate not supplied

Role of vasopressin in the blockade of the development of morphine tolerance by footshock and psychological stress.

To elucidate the underlying mechanism for the blockade of the development of morphine analgesic tolerance by footshock and psychological stress, we examined the role of arginine vasopressin in this process. Daily pretreatment with intracerebroventricular anti-arginine vasopressin antiserum suppressed the development of tolerance to morphine. The radioimmunoassayable arginine vasopressin content was decreased in the hypothalamus but not in other regions of mouse brain after exposure to an acute footshock or psychological stress. However, this change disappeared after 5 daily repeated treatments. Neither the development of morphine tolerance nor the brain levels of arginine vasopressin were affected by exposure to forced swimming stress. Neither a single nor 5 daily treatments with morphine induced any appreciable changes in arginine vasopressin content. However, morphine in combination with footshock, lowered this content as did, be it insignificantly, the combination of morphine and psychological stress after chronic treatment. Blockade by footshock and psychological stress of the tolerance development was dose-dependently abolished by daily pretreatment with intracerebroventricular arginine vasopressin. These findings suggest that arginine vasopressin plays a critical role in the blockade, by footshock and psychological stress, of the development of analgesic tolerance to morphine.

Analgesia↗

PubMed1999

Morphine tolerance in arthritic rats and serotonergic system.

To understand whether chronic inflammation alters the development of morphine tolerance, the tail-flick test was used to evaluate the analgesic effect of morphine (75 mg tablet, s.c.) in the arthritic rats at the day 9-12 after the inoculation with Freund's adjuvant. Spinal cord monoamines and amino acid neurotransmitters were concomitantly measured. Chronic inflammation attenuated the antinociceptive effect of morphine as tolerance developed faster in the arthritic rats compared to the vehicle-treated controls. In addition, ratio of 5-hydroxyindole-3-acetic acid/5-hydroxytryptamine (5-HIAA/5-HT) increased in the lumbar spinal cord of arthritic rats without any change in the concentrations of norepinephrine, glutamate, aspartate or GABA. Interestingly, increased serotonin turnover in the spinal cord was observed in both control and arthritic rats 24 hours after morphine treatment. Overall, the results suggest a significant role of serotonin up-regulation in the spinal cord during chronic pain and the development of morphine tolerance.

Analgesics, Opioid↗

PubMed1991

Delayed application of MK-801 attenuates development of morphine tolerance in rats.

To investigate the possible involvement of enduring or delayed changes at the N-methyl-D-aspartic acid (NMDA) receptor in the mechanisms of morphine tolerance, rats were treated with the specific NMDA receptor antagonist, MK-801 (0.15 mg/kg) 2 h after morphine injection (20 mg/kg) during a 4-day induction period of tolerance. On the fifth day rats were injected only with morphine (15 mg/kg), and analgesia was assessed using the hot-plate test. Morphine tolerance was significantly reduced by MK-801. These findings suggest that long-lasting or delayed changes at the NMDA receptor underlie the development of morphine tolerance. Moreover, because MK-801 was delivered 2 h after morphine and therefore could not serve as a cue for morphine administration, these findings indicate that the attenuating effect of MK-801 on the development of morphine tolerance is not attributable to state-dependent learning.

Analysis of Variance↗

PubMed2006

Peripheral mechanisms of intestinal dysmotility in the morphine tolerant and dependent rats.

Changes of intestinal motility and transit produced by tolerance to and dependence upon morphine have been partly attributed to peripheral mechanisms. We evaluated the effect of chronic peripheral morphine administration and peripheral mu-receptor blockade on vagal afferent activity (VAA) and c-Kit positive intramuscular cells of Cajal (ICCs). Ten rats were subjected to chronic subcutaneous morphine infusion for 72 h with subsequent VAA recording. Potential frequency was evaluated within recordings before and after mu receptor blockade by (D)-Phe -Cys -Tyr -(D)-Trp -Orn -Thr -Phe -Thr (CTOP) i.p. injections. Afterwards the rats were sacrificed and intramuscular c-Kit antigen expression was assessed by image analysis within removed fragments of duodenum and ascending colon. An equal group of rats served as a control for VAA and c-Kit expression. Analysis of VAA revealed similar frequencies of potentials in morphine tolerant / dependent rats before CTOP and in the controls. CTOP increased potential frequency in the morphine group which effect was visible mostly within the first 20 minutes (p=0.01). The morphine infused animals presented also higher c-Kit expression in both the duodenum (p<0.001) and the ascending colon (p<0.001) in comparison to the control group. Results of our study may indicate the involvement of both the intestinal wall and the long vago-vagal reflexes in tolerance to and dependence upon opioids.

Animals↗

PubMed1987

Intrathecally administered dynorphin-(1-17) modulates morphine-induced antinociception differently in morphine-naive and morphine-tolerant rats.

The intrathecal (i.t.) administration of morphine, but not of dynorphin-(1-17), dose dependently inhibited thermal nociceptive responses to radiant heat. In morphine-naive rats, i.t. dynorphin-(1-17) slightly antagonized morphine analgesia but potentiated it in morphine-tolerant rats. These data provide further evidence that dynorphin-(1-17) modulates the effects of exogenously administered opiates differently, depending upon whether the animals are opiate-naive or opiate-tolerant.

Analgesics↗

PubMed1988

Morphine tolerance decreases the analgesic effects of ketamine in mice.

Previous studies have shown that ketamine interacts with opiate receptors, and it has been suggested that ketamine-induced analgesia is mediated through opiate receptors. If so, ketamine should produce less analgesia in morphine tolerant animals, just as morphine does. To test this hypothesis, the analgesic effects of ketamine were tested in mice implanted with placebo pellets and in mice made tolerant to morphine through implantation of morphine pellets, using the abdominal constriction test. The test consisted of ip injection of 1% acetic acid, which caused stretching of hind limbs and constriction of abdominal muscles, also called writing. The number of writhes was counted for each mouse 10-15 min following acetic acid injection. Morphine pellet implanted mice treated with saline writhed 12.2 +/- 0.8 times (mean +/- SEM), not significantly different from 9.8 +/- 0.9 times seen in placebo pellet implanted mice. Treatment of the animals with ketamine at three doses of 20, 25, and 30 mg/kg, subcutaneously (sc), reduced the number of writhes in the placebo pellet implanted group to 5.8 +/- 0.8, 4.2 +/- 0.7, and 1.3 +/- 0.3, respectively. In the morphine pellet-implanted group, with the same doses of ketamine, the numbers of writhes were 10 +/- 0.9, 9.3 +/- 1.1, and 5.2 +/- 0.9, respectively. Morphine-tolerant animals writhed significantly more at each dose of ketamine, indicating that they were cross tolerant to the analgesic effects of ketamine.

Analgesia↗

PubMed2001

Morphine tolerance in mice is independent of polymorphisms in opioid receptor sequences.

Pharmacogenomics links individual drug response variation to genetic differences, such as single nucleotide polymorphisms (SNPs). In particular, pharmacogenomics will allow clinicians to use genetic diagnostics to predict the response of a patient to a drug. We investigated whether SNPs in opioid receptors correlated with the development of morphine tolerance in mouse strains that showed either high or low tolerance to morphine. Sequencing identified five silent SNPs in the delta opioid receptor that varied from the published sequence in some strains, but which were found in both high and low tolerance strains. The mu and kappa opioid receptor sequences had no SNPs. Taken together, these data definitively demonstrate that morphine tolerance development in mice is independent of opioid receptor sequence.

Animals↗

PubMed1989

Down-regulation of proopiomelanocortin synthesis and beta-endorphin utilization in hypothalamus of morphine-tolerant rats.

We investigated regulation of the dynamic state of enkephalin and endorphin brain stores during morphine tolerance and dependence using cDNA hybridization and radioimmunoassay of the biologically active peptide(s) and their respective peptide precursors. Rats were made tolerant to morphine with the subcutaneous implantation of three morphine pellets (75 mg each) for a period of five days. Hypothalamic proopiomelanocortin (POMC) mRNA, POMC, and corticotropin-like intermediate lobe peptide content were decreased by 50% in morphine-dependent rats. However, beta-endorphin content remained unchanged. Enkephalin and proenkephalin mRNA content in various brain structures failed to change. A single injection of naltrexone (2 mg/kg) 1 hour before decapitation did not reverse the decrease in POMC mRNA and POMC content elicited by morphine. However, a slower, spontaneous withdrawal caused by removal of the pellets did reverse (after two days) the down-regulation of the hypothalamic POMC system. A single injection of morphine (10 mg/kg) failed to affect any parameter used to assess the dynamic state of opioid peptides.

Animals↗

PubMed1996

Unsignaled morphine delivery does not disrupt the development of associative morphine tolerance in the rat.

When morphine administration is paired with a distinctive context, tolerance to morphine's analgesic effects comes readily under the associative control of the drug-paired context. These associative tolerance effects are eliminated when a relatively short (i.e., 6 h) interdose interval (IDI) is used for conditioning. Contemporary models of learned tolerance explain the absence of learning at short IDIs by positing that residual morphine effects from a recent drug exposure disrupt the formation of drug-context associations. The present studies examined the impact of unsignaled morphine injections given 6 h prior to drug-context pairings on the development of associative tolerance. Analgesia was measured by the tail-flick method, and tolerance levels were assessed by dose-response curve methodology. Morphine preexposure had no detectable influence on the acquisition of associative tolerance when rats were tested immediately after conditioning, after a 30-day rest interval, or after a 30-day period of daily saline injections in their home-cage environment. These data suggest disruption of associative tolerance effects at short IDIs is not attributable to residual effects of morphine from the immediately preceding trial.

Animals↗

PubMed1989

Brain and spinal cord 5-HT2 receptors of morphine-tolerant-dependent and -abstinent rats.

The effects of morphine tolerance-dependence and abstinence on 5-HT2 receptors in brain and spinal cord of the rat were determined. Tolerance to and physical dependence on morphine was induced in male Sprague-Dawley rats by implanting six morphine pellets (each containing 75 mg of morphine free base) during a seven day period. Two groups of rats were used for binding studies. In one group the pellets were left intact and in the other they were removed. The rats were killed and spinal cords and brains were excised and dissected into six regions (amygdala, hippocampus, hypothalamus, striatum, midbrain and pons + medulla). 5-HT2 receptors were characterized by using [3H]spiperone as the ligand and unlabelled ketanserin to determine the non-specific binding. In morphine and placebo abstinent rats the binding of [3H]spiperone to 5-HT2 receptors in brain regions and spinal cord did not differ. The Bmax values of [3H]spiperone to bind to membranes prepared from non-abstinent morphine-dependent rats were increased in amygdala (78.0%), midbrain (65.0%) and pons + medulla (92.0%). The Kd values were unaffected. It is concluded that in morphine-tolerant-dependent rats 5-HT2 receptors are up-regulated in amygdala, midbrain and pons + medulla, but in morphine-abstinent rats they are unaffected.

Animals↗

PubMed1983

Morphine tolerance and withdrawal in capsaicin--pretreated rats.

Thermoregulatory reactions to warm exposure and naloxone treatment, as well as behavioral reactions to morphine withdrawal, were recorded in morphine tolerant rats after capsaicin pretreatment. Enhanced behavioural reactions to morphine withdrawal were found in capsaicin pretreated rats, although no differences in degree of withdrawal hypothermia were seen. Morphine tolerant rats displayed increased thermal tolerance; this was partially prevented by capsaicin pretreatment. The results provide further evidence concerning the interference of neural mechanisms sensitive to capsaicin and opiates.

Animals↗

PubMed1980

A demonstration of naloxone-precipitated opiate withdrawal on single neurones in the morphine-tolerant/dependent rat brain.

1 A comparison has been made between the effects of microelectrophoretically applied naloxone on single neurones in the frontal cerebral cortex and the striatum of naive and of morphine-tolerant/dependent rats, anaesthetized with a mixture of alpha-chloralose and urethane. 2 Specificity of the results obtained was evaluated by contrasting the effects of alternate applications of the (+)- and (-)-isomers of naloxone to the same neurones. 3 In naive rats naloxone had predominantly no effect, only a few cells revealing non-specific depressant responses to the drug. 4 In morphine-tolerant/dependent rats a higher proportion of neurones responded to naloxone; either with stereospecific excitatory responses, in which the activity evoked by L-glutamate or acetylcholine was increased, or with a non-specific inhibition, similar to that observed in naive animals. 5 It is suggested that these excitatory responses to microelectrophoretically applied (-)-naloxone represent opiate withdrawal responses at the single neurone level and that they reflect a latent hyperexcitability of the postsynaptic membrane in the morphine-tolerant/dependent state.

Acetylcholine↗

PubMed1983

Conditioned morphine tolerance in the rat: absence of a compensatory response and cross-tolerance with stress.

In four separate experiments with rats as subjects, strong evidence was obtained that tolerance development to morphine analgesia occurs most rapidly when morphine delivery is paired with salient contextual cues. However, contextual cues previously paired with morphine did not elicit conditioned drug-compensatory responses when presented to nondrugged animals. These results were obtained by different analgesia assessments, with different drug-administration--analgesia-test latencies, and in environments differing with respect to stress level. Stress level did influence nociceptive response, as it was found that the combination of bright illumination, white noise, and a strong odor resulted in antinociception in the absence of drug. Moreover, rats that had a history of receiving morphine in this stressful context were tolerant to this stress-induced antinociception, but only when morphine was present in their systems. In the final two studies, this antinociception, which was cross-tolerant with morphine, was characterized with respect to naloxone reversibility and brain levels of met- and leu-enkephalin as determined by radioimmunoassay.

Animals↗