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PubMed1988

Distinctive effect of ginseng saponins on development of morphine tolerance in guinea-pig ileum and mouse vas deferens.

Studies on the effect of ginseng saponins on the development of tolerance to morphine have been carried out using isolated preparations of guinea-pig ileum (GPI) and mouse vas deferens (MVD). Incubation of GPI preparation with morphine resulted in the development of tolerance to the inhibitory effect of morphine on the electrically evoked contractions. Ginseng total saponins and one of the constituents, protopanaxatriol saponin, suppressed the development of morphine tolerance in a concentration dependent manner in GPI preparation, though another constituent, protopanaxadiol saponin, did not affect the tolerance development substantially. In the MVD preparation, the development of tolerance to the morphine effect was observed as well, but none of the ginseng saponins affected it. It has been well established that electrically evoked contractions of GPI and MVD are mediated by acetylcholine and norepinephrine, respectively, and presumably their release is regulated presynaptically by opioid receptors. The fact that ginseng saponins suppressed the development of morphine tolerance only in the GPI preparation suggest that the inhibitory effect is mediated through and effect on the cholinergic system, without the involvement of direct action on opioid receptors.

Animals↗

PubMed1982

Effect of morphine on the stimuli-induced calcium uptake into synaptosomes isolated from morphine-tolerant rats.

Effects of morphine on calcium uptake into synaptosomes isolated from acutely or chronically morphine-tolerant rat brain was studied. Addition of morphine inhibited the depolarization-stimulated uptake of calcium without affecting uptake under nondepolarizing conditions. This inhibition was prevented by simultaneous addition of naloxone with morphine before calcium uptake was initiated. Acute tolerance to morphine increased depolarization-stimulated synaptosomal calcium uptake. On the other hand, chronic exposure of rats to morphine to elicit tolerance to and physical dependence on morphine did not influence synaptosomal calcium uptake. However, these preparations apparently lost the ability of in vitro morphine-inhibition of calcium uptake into the synaptosomes. Our results suggested that adaptive changes of synaptosomal calcium uptake produced by exposure to morphine may be involved in tolerance and physical dependence development, but influence of morphine on calcium uptake by the synaptosomes isolated from the rats acutely tolerance to morphine was differed from that of chronic tolerant rats.

Absorption↗

PubMed1983

Drug withdrawal prior to hatch in the morphine tolerant chick embryo.

Morphine tolerance and dependence were produced in chick embryos by injecting 20 mg/kg into the air space of the egg daily from incubation day 12. Starting on day 16, two groups of eggs were withdrawn from morphine by either substituting water or by treating with naloxone. Chick embryo activities were monitored on incubation day 18. Activities of the embryos withdrawn from morphine did not differ from control, but naloxone injection produced a substantial increase in activity. Neither regimen of morphine withdrawal affected the hatchability of the eggs. When these chicks were 1 day old, the effect of 1 mg morphine/kg on the rate of distress vocalization was measured. The withdrawn chicks were 1 day old, the effect of 1 mg morphine/kg on the rate of distress vocalization was measured. The withdrawn chicks vocalized at a rate that was intermediate between that of controls and that of nonwithdrawn chicks indicating that tolerance was still present one week after the last morphine injection.

Animals↗

PubMed1993

[The effect of catecholamine and serotonin antibodies on pain sensitivity and the development of morphine tolerance in experimental drug addiction].

The effect of antibodies to catecholamine and serotonin on the thermal pain sensitivity and tolerance to morphine was studied in rats immunized by protein-conjugated neurotransmitters before chronic drug intoxication. The antibodies to catecholamine have been found to affect bifunctionally on the nociception bifunctionally: either accelerating or delaying the pain reaction to thermal irritation. The antibodies to serotonin were ineffective as modulators both of the pain sensitivity and tolerance to morphine development. In contrast, the antibodies to catecholamine suppressed the expression of tolerance to chronic morphine. Serotonin antibodies virtually produced no effects on pain sensitivity and the development of morphine tolerance.

Animals↗

PubMed1980

Absence of cross-tolerance to heroin in morphine-tolerant mice.

Mice implanted with morphine pellets demonstrated a 30-fold increase in tolerance to subcutaneously administered morphine but showed no cross-tolerance to subcutaneously administered heroin. When given morphine intracerebroventricularly, the mice showed no tolerance to morphine or cross-tolerance to heroin. These observations depended on the presence of the morphine pellet. If the pellets were removed prior to determinations of potency, the expected responses--tolerance to morphine and cross-tolerance to heroin--were obtained. The blood-brain barrier may be a prime site for the expression of morphine tolerance in mice.

Animals↗

PubMed2005

Inhibition of morphine tolerance by spinal melanocortin receptor blockade.

Chronic use of morphine is accompanied by the development of morphine tolerance, which is one of the major problems associated with opiate treatment. Possible modulation of opioid effects by melanocortin receptor ligands has been recently demonstrated. Therefore, we investigated the influence of repeated intrathecal injection of a melanocortin receptor antagonist (SHU9119, JKC-363) on the development of morphine tolerance as measured by tail-flick test. It was also examined whether a single i.t. SHU9119 and JKC-363 administration could counteract the loss of analgesic potency of morphine in morphine tolerant rats. We examined also the influence of chronic morphine administration on mu-opioid receptor (MOR) and melanocortin 4 receptor (MC4-R) mRNAs in the rat spinal cord and dorsal root ganglia (DRG) during morphine tolerance. Morphine treatment (10mg/kg, i.p. twice daily) over 8 days induced tolerance as reflected by a significant reduction of withdrawal latency from 181 to 25% above baseline in the tail-flick test. Repeated co-administration of morphine and SHU9119 or JKC-363, significantly prevented the development of morphine tolerance. A single administration of an MC4-R antagonist restored morphine analgesic potency in morphine tolerant rats. Using RT-PCR we demonstrated no changes in the spinal cord but there was a decrease in MOR and increase in MC4-R gene expression in the DRG of rats tolerant to morphine. These results suggest that MC4-R may be involved in the mechanisms of opioid tolerance and antagonists of this receptor may be a possible new target in the search for strategies preventing the development of opioid tolerance.

Analysis of Variance↗

PubMed2004

Role of endothelin in neonatal morphine tolerance.

Management of neonatal opioid tolerance and withdrawal symptoms remains a major challenge in neonatal intensive care units. We provide evidence that central endothelin (ET) mechanisms are involved in the development of morphine tolerance in neonatal rats. Pregnant rats were rendered tolerant to morphine and rat pups were delivered by cesarean section. The effect of morphine tolerance on characteristics of ET receptors in neonatal rats was determined. The affinity (Kd) and density (Bmax) of [I]ET-1 binding in the brain was found to be similar in placebo and morphine-tolerant neonatal rats. Morphine and ET-1-induced G-protein stimulation was determined in placebo and morphine-tolerant neonatal rats by [S]GTPgammaS binding assay. Morphine produced significantly lower (P < 0.05) maximal stimulation in morphine-tolerant neonatal rats (33.10%) when compared with placebo-treated neonatal rats (90.90%). Maximal stimulation produced by ET-1 in morphine-tolerant neonatal rats (41.26%) was also significantly lower (P < 0.05) as compared with placebo-treated neonatal rats (92.23%). This is the first report indicating the involvement of ET in neonatal morphine tolerance as evidenced by attenuation of ET-1-induced stimulation of GTP binding in neonatal rats tolerant to morphine.

Analgesics, Opioid↗

PubMed1978

Effects of furosemide and spironolactone on the behavior of morphine-tolerant rats.

In morphine-tolerant rats, a reappearance of morphine catalepsy and a disappearance of the turning behavior characteristic of brain-lesioned tolerant animals were observed under the influence of furosemide and spironolactone. The administration of spironolactone together with daily morphine treatment resulted first in an intensification of the morphine symptoms as measured by catalepsy and a retarded appearance of tolerance, typically characterized by a shift from catalepsy to turning movements in animals with single-sided brain lesions. Nontoxic doses of spironolactone raised the sensitivity of morphine-tolerant rats so that previously tolarated morphine doses become lethal.

Animals↗

PubMed1984

Influence of morphine tolerance and withdrawal on intestinal salt and water transport in the rat in vivo and in vitro.

Intestinal water and electrolyte transport was investigated in vivo and in vitro in rats made tolerant to morphine and subsequently withdrawn with naloxone. Rats were rendered tolerant by injection of a slow-release emulsion containing morphine (75 mg/rat over 48 h), and when challenged with naloxone, they exhibited a characteristic withdrawal syndrome that included acute diarrhea. Morphine tolerance did not influence water absorption from ileal or colonic loops in vivo but naloxone-induced withdrawal provoked a rapid and sustained reduction in absorption. Naloxone did not affect absorption in control animals. In further experiments, sodium and chloride fluxes were measured in isolated stripped ileal mucosa derived from animals made tolerant to morphine and withdrawn with naloxone. Net sodium and chloride absorption was markedly reduced in mucosa derived from withdrawn animals compared with that derived from tolerant animals (Na+: 1.12 +/- 0.76 vs. 5.52 +/- 0.46, and Cl-: 0.60 +/- 0.52 vs. 4.70 +/- 0.80 microEq/cm2 X h, in withdrawn and tolerant animals, respectively; n = 8; p less than 0.001 and p less than 0.005). When an attempt was made to induce withdrawal by adding naloxone in vitro to isolated mucosa derived from tolerant animals, no effect on transport was detected whether the mucosa was stripped of muscle layers or not. Thus naloxone had to be given in vivo to produce withdrawal effects in mucosa studied subsequently in vitro. Naloxone also had an effect in control rats when a 50% reduction in net chloride absorption was observed in isolated ileal mucosa derived from these animals. Net sodium absorption was unaffected. These data support a role for endogenous opiates in the control of intestinal transport and provide a mechanism for the diarrhea associated with opiate withdrawal.

Animals↗

PubMed2004

Up-regulation of mu-opioid receptors in the spinal cord of morphine-tolerant rats.

Though morphine remains the most powerful drug for treating pain, its effectiveness is limited by the development of tolerance and dependence. The mechanism underlying development of tolerance to morphine is still poorly understood. One of the factors could be an alteration in the number of micro-receptors within specific parts of the nervous system. However, reports on changes in the micro-opioid receptor density in the spinal cord after chronic morphine administration are conflicting. Most of the studies have used subcutaneously implanted morphine pellets to produce tolerance. However, it does not simulate clinical conditions, where it is more common to administer morphine at intervals, either by injections or orally. In the present study, rats were made tolerant to morphine by injecting increasing doses of morphine (10-50 mg/kg, subcutaneously) for five days. In vitro tissue autoradiography for localization of micro-receptor in the spinal cord was done using [3H]-DAMGO. As compared to the spinal cord of control rats, the spinal cord of tolerant rats showed an 18.8% increase or up-regulation in the density of micro-receptors in the superficial layers of the dorsal horn. This up-regulation of micro-receptors after morphine tolerance suggests that a fraction of the receptors have been rendered desensitized, which in turn could lead to tolerance

Analgesics, Opioid↗

PubMed1989

Differential cross-tolerance to opioid agonists in morphine-tolerant pigeons responding under a schedule of food presentation.

Effects of the opioid agonists morphine, l-methadone, ethylketazocine, U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide methanesulfonate hydrate], cyclazocine and bremazocine, and the nonopioid chlorpromazine were determined in pigeons responding under a fixed-ratio 30 schedule of food presentation before, during and after chronic morphine administration. Before chronic morphine administration, all drugs produced dose-dependent decreases in response rates. After daily administration of up to 56 mg/kg of morphine for 7 weeks, dose-effect curves for the mu agonists morphine and l-methadone, as well as the mu/kappa agonist ethylketazocine shifted to the right approximately 1 1/4, 3/4 and 1/2 log units, respectively. In contrast, dose-effect curves for the mixed agonist/antagonists cyclazocine and bremazocine each shifted to the left approximately 3/4 log unit, whereas dose-effect curves for the kappa agonist U50,488 and the nonopioid chlorpromazine did not shift during chronic morphine administration. Dose-effect curves for all drugs except bremazocine returned to their prechronic positions within the period 3 to 8 weeks after termination of chronic morphine administration. The present study demonstrates that repeated administration of morphine produces tolerance to its rate-decreasing effects as well as cross-tolerance selective to other opioids possessing mu agonist properties. The cross-tolerance to ethylketazocine observed in morphine-tolerant pigeons corroborates studies of the discriminative stimulus effects of ethylketazocine in pigeons, suggesting that in this species ethylketazocine possesses predominantly mu agonist properties.

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

PubMed1998

Inhibition of protein phosphatases alters the expression of morphine tolerance in mice.

Recently our laboratory found that tolerance to morphine-induced antinociception could be completely reversed with intracerebroventricular (i.c.v.) administration of a protein kinase A inhibitor, whereas intrathecal (i.t.) administration of the inhibitor produced hyperalgesia in morphine-tolerant mice. In the experiments described here, we sought to characterize further the role of phosphorylation events in supraspinal versus spinal opioid-mediated pain pathways and how such events might be involved in the development of antinociceptive tolerance. Two phosphatase inhibitors were administered centrally to determine whether they affected morphine-induced antinociception in naive or chronically morphine-treated mice. By the i.c.v. route, okadaic acid enhanced morphine-induced antinociception in tolerant mice and produced toxicity by the i.t. route. The calcineurin inhibitor ascomycin had no effect on antinociception following acute or chronic morphine treatment. These results suggest that increased activity of protein phosphatase types 1 and/or 2A in the brain may contribute to the development of morphine tolerance.

Analgesics, Opioid↗

PubMed2005

Spinal glucocorticoid receptors contribute to the development of morphine tolerance in rats.

BACKGROUND: Opioid analgesic tolerance is a pharmacologic phenomenon involving the mechanisms of cellular adaptation. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid tolerance. In a rat model of morphine tolerance, the authors examined the hypothesis that spinal GRs would play a significant role in the development of tolerance to the antinociceptive effect of morphine. METHODS: In experiment 1, each group of rats received the GR antagonist RU38486 (0.5 or 1 microg), the mineralocorticoid receptor antagonist spironolactone (3 microg), or a vehicle, given intrathecally with morphine (10 microg) twice daily for 6 days. In experiment 2, four groups of rats were used, and each group received intrathecally 10 microg morphine plus 5 micromol GR antisense oligodeoxynucleotide, sense oligodeoxynucleotide, mixed-base oligodeoxynucleotide, or vehicle. Western blotting was used to examine the expression of GRs within the spinal cord dorsal horn. In experiment 3, the GR agonist dexamethasone (4 microg) was given intrathecally twice daily in combination with 10 microg morphine. For all experiments, the development of morphine antinociceptive tolerance was assessed using the tail-flick test. RESULTS: The development of tolerance to the antinociceptive effect of morphine was substantially attenuated when the GR antagonist RU38486 (1 > 0.5 microg > vehicle) but not spironolactone was coadministered with morphine for 6 days. A single treatment with RU38486 did not affect morphine antinociception, nor did it reverse morphine tolerance on day 7. A similar reduction of morphine tolerance was observed in those rats treated with a GR antisense oligodeoxynucleotide but not a sense or mixed-base oligodeoxynucleotide. The administration of the GR antisense oligodeoxynucleotide also prevented GR up-regulation within the spinal cord dorsal horn. Moreover, the GR agonist dexamethasone facilitated the development of morphine tolerance. CONCLUSIONS: The results indicate an important role of spinal GRs in the cellular mechanisms of morphine tolerance in rats and may have significant implications in clinical opioid therapy.

Analgesics, Opioid↗

PubMed1994

Modulation of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist LY274614: assessment of opioid receptor changes.

Recent reports have demonstrated that the coadministration of morphine with an N-methyl-D-aspartate (NMDA) receptor antagonist can attenuate and/or reverse the development of morphine tolerance. In the present study we used an experimental tolerance paradigm using morphine pellets (75 mg) to produce an 1-fold shift in the morphine dose-response curve in rats. Coadministration of the competitive NMDA receptor antagonist LY274614 [(+-)-6-phosphonomethyl-decahydroisoquinolin-3-carboxylic acid] via continuous s.c. infusion (24 mg/kg/24 hr) significantly attenuated the development of morphine tolerance. In addition, animals made tolerant to morphine and then infused with LY274614 (24 mg/kg/24 hr) regained their analgesic sensitivity to morphine more rapidly than morphine-tolerant animals given a saline infusion. To determine whether LY274614 treatment modifies the subsequent development of tolerance, LY274614 was administered to nontolerant animals for 1 week. One week after LY274614 treatment was discontinued the animals were challenged with morphine and then implanted with morphine pellets. Neither the expression of morphine analgesia nor the development of morphine tolerance differed when LY274614- and saline-treated animals were compared. The infusion of LY274614 for 7 days did not increase the affinity or density of mu, delta, kappa-1 or kappa-3 opioid receptors in rat brain homogenates as measured by ligand binding assays. Additionally, the IC50 values for LY274614 in mu-1, mu-2, delta, kappa-1 or kappa-3 ligand binding assays were greater than 10 microM. Taken together these results demonstrate that the competitive NMDA receptor antagonist LY274614 can both attenuate and reverse the development of morphine tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1990

Modification of rat thermal responses to morphine by alpha-FMH suggests a role for neural histamine in morphine tolerance.

In rats, morphine may either raise or lower body temperature depending on the dose. A morphine dose of 50 mg/kg, i.p., consistently produced a nearly maximal hypothermic response in non tolerant rats, whereas this dosage induced an elevation of body temperature in tolerant rats. In rats pretreated with alpha-fluoromethylhistidine (alpha-FMH), an irreversible inhibitor of histidine decarboxylase which induces a reduction in brain histamine synthesis, this morphine dose of 50 mg/kg, i.p. produced an elevation of rectal temperature resembling that observed in morphine-tolerant rats. To confirm the suggestion that hyperthermic effects of the higher dose of morphine in morphine-tolerant rats or in alpha-FMH-pretreated rats could be related to a possible involvement of mediators of fever, e.g. prostaglandins, animals were pretreated with acetylsalicylic acid (aspirin, Bayer) 30 mg/kg, i.p., 60 min before morphine. Results showed that acetylsalicylic acid prevented the hyperthermic response of morphine, resulting in a fall in body temperature. Since morphine releases histamine and alpha-FMH inhibits histamine synthesis, our data demonstrating that an inhibitor of prostaglandin-synthetase showed efficacy only in animals responding with fever to the higher dose of the opiate, suggests a physiological antagonism between histamine and prostaglandins on mechanisms underlying hyper/hypothermic responses to morphine.

Animals↗

PubMed1994

Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C.

In a rat model of morphine tolerance, we examined the hypotheses that thermal hyperalgesia to radiant heat develops in association with the development of morphine tolerance and that both the development and expression of thermal hyperalgesia in morphine-tolerant rats are mediated by central NMDA and non-NMDA receptors and subsequent protein kinase C (PKC) activation. Tolerance to the analgesic effect of morphine was developed in rats utilizing an intrathecal repeated treatment regimen. The development of morphine tolerance and thermal hyperalgesia was examined by employing the tail-flick test and paw-withdrawal test, respectively. Intrathecal MK 801 (an NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; a non-NMDA receptor antagonist), or GM1 ganglioside (an intracellular PKC inhibitor) treatment was given to examine the effects of these agents on the development and expression of thermal hyperalgesia in morphine-tolerant rats. Tolerance to the analgesic effect of morphine was reliably developed in rats following once daily intrathecal (onto the lumbosacral spinal cord) injection of 10 micrograms of morphine sulfate for 8 consecutive days as demonstrated by the decreased analgesia following morphine administration on day 8 as compared to that on day 1. In association with the development of morphine tolerance, thermal hyperalgesia to radiant heat developed in these same rats. Paw-withdrawal latencies were reliably decreased in morphine-tolerant rats as compared to nontolerant (saline) controls when tested on day 8 before the last morphine treatment and on day 10 (i.e., 48 hr after the last morphine treatment). The coincident development of morphine tolerance and thermal hyperalgesia was potently prevented by intrathecal coadministration of morphine with MK 801 (10 nmol) or GM1 (160 nmol), and partially by CNQX (80 nmol). MK 801 (5, 10 nmol, not 2.5 nmol) and CNQX (80, 160 nmol, not 40 nmol), but not GM1 (160 nmol), also reliably reversed thermal hyperalgesia in rats rendered tolerant to morphine when tested 30 min after each drug treatment on day 10 (48 hr after the last morphine treatment). The data indicate that thermal hyperalgesia develops in association with the development of morphine tolerance and that the coactivation of central NMDA and non-NMDA receptors is crucial for both the development and expression of thermal hyperalgesia in morphine-tolerant rats. Furthermore, intracellular PKC activation plays a critical role in the development of thermal hyperalgesia in morphine-tolerant rats.(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1990

Evidence for involvement of cyclic GMP phosphodiesterase in morphine tolerance.

Preliminary evidence had suggested that changes in cyclic GMP (cGMP) hydrolysis via cyclic nucleotide phosphodiesterase(s) occurred during development of tolerance to morphine. To examine this finding further and its possible role in development of tolerance to morphine, rats (150-175 g) were injected with 1 ml of a sustained-release morphine preparation (40 mg/ml). Control rats received 1 ml of the oily vehicle. Antinociception, decreased locomotor activity, respiratory depression and mydriasis were measured at various times from 0.5 through 96 hr of exposure to the drug. Particulate and soluble cGMP hydrolysis were measured for the same time periods from periaqueductal gray (PAG), striatum, medulla and oculomotor nucleus, the brain areas believed to mediate the respective behaviors. Each of the behaviors except mydriasis showed development of complete tolerance (no difference from control behaviors) during the 96 hr of continuous exposure. During development of tolerance, particulate cGMP hydrolysis decreased in PAG and increased in striatum and medulla. Particulate cGMP hydrolysis was not altered in oculomotor nucleus, the brain area mediating mydriasis to which tolerance development was partial or incomplete. Significant changes in soluble cGMP hydrolysis occurred only in PAG before decline in the behavioral effect and did not appear to be involved in tolerance phenomena. Modulation of cyclic nucleotide levels by changes in particulate cGMP hydrolysis may produce or allow for development of complete tolerance to various morphine-induced behaviors.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1996

Ketamine attenuates and reverses morphine tolerance in rodents.

BACKGROUND: The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance. METHOD: Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed. RESULTS: Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine. CONCLUSIONS: Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.

Analgesia↗