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PubMed1975

[Dependence on and preference for morphine. (III) Improvement of spontaneous drug intake after combined treatment with morphine and cocaine].

One group of rats (n equals 6) was allowed free access to food combined with morphine and cocaine for 3 weeks, another group combined with either morphine or cocaine alone for 3 weeks. Intensity of decrease in body weight by withdrawal and ratios of spontaneous morphine and cocaine intake were compared, and the cross-spontaneous drug intake between morphine and cocaine using cocaine and morphine dependent rats was investigated, respectively. The results indicate that (a) decreased rate in body weight by withdrawal after 3 weeks administration with morphine-cocaine mixtures increased slightly, and spontaneous intake ratio for the higher drug-admixed food during administration period was also slightly increased as compared with a morphine added diet alone. (b) However, spontaneous intake ratio of both morphine [morphine (1 mg/g of food) vs. a normal diet (N.D.)] and cocaine [cocaine (2 mg/g of food) vs. N.D] increased 30 and 50 approximately 60% respectively, and these changes were maintained for about two months. (c) Spontaneous cocaine intake ratio after 3 weeks administration of morphine was almost the same level as that in cocaine dependent rats and decreased dependently when the administration period was extended. Spontaneous morphine intake ratio after 3 weeks administration of cocaine was 20% lower in total daily intake ratio as compared to morphine dependent rats, but spontaneous morphine intake ratio as compared to morphine dependent rats was gradually increased as in morphine dependent rats. (d) Furthermore, morphine-quinine combined treatment and cocaine or codeine treatment had no effect on spontaneous intake of quinine. These data suggest that combinations of morphine and cocaine have promoting properties of morphine and cocaine intake, respectively. Cross-spontaneous drug intake between morphine and cocaine was successful only in cocaine dependent rats using this method.

Animals↗
PubMed2003

Endothelin receptor antagonists restore morphine analgesia in morphine tolerant rats.

Several neurotransmitter mechanisms have been proposed to play a role in the development of morphine tolerance. The present study provides evidence for the first time that endothelin (ET) antagonists can restore morphine analgesia in morphine tolerant rats. Tolerance to morphine was induced by subcutaneous implantation of six morphine pellets during a 7-day period. The degree of tolerance to morphine was measured by determining analgesic response (tail-flick latency) and hyperthermic response to morphine sulfate (8 mg/kg, subcutaneously (s.c.)) in placebo and morphine pellet implanted rats. The maximal tail-flick latency in morphine pellet-vehicle treated rats (7.54 s) was significantly lower (P<0.05) when compared to placebo pellet-vehicle treated rats (10s), indicating that tolerance developed to the analgesic effect of morphine. In separate sets of experiments, ET antagonists, BQ123 (10 microg, intracerebroventricularly (i.c.v.)) and BMS182874 (50 microg, i.c.v.) were administered in placebo and morphine tolerant rats. BQ123 was injected twice daily for 7 days and once on day 8. BMS182874 was administered only on day 8. Morphine (8 mg/kg, s.c.) was administered 30min after BQ123 or BMS182874 administration. It was found that both BQ123 and BMS182874 potentiated morphine analgesia in placebo and morphine tolerant rats. BQ123 potentiated tail-flick latency by 30.0% in placebo tolerant rats and 94.5% in morphine tolerant rats compared to respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo tolerant rats and 66.7% in morphine tolerant rats. Morphine-induced hyperthermic effect was also potentiated by BQ123 and BMS182874. The duration of analgesic action was also prolonged by BQ123 and BMS182874. The effect of BMS182874 was less as compared to BQ123. BQ123 and BMS182874 are selective ET(A) receptor antagonists. Therefore, it is concluded that ET(A) receptor antagonists restore morphine analgesia in morphine tolerant rats.

Animals↗
PubMed2005

Antianalgesia: stereoselective action of dextro-morphine over levo-morphine on glia in the mouse spinal cord.

We have previously shown that the naturally occurring levo-morphine at a subanalgesic picomolar dose pretreated i.t. induces antianalgesia against levo-morphine-produced antinociception. We now report that the synthetic stereo-enantiomer dextro-morphine, even at an extremely low femtomolar dose, induces antianalgesia against levo-morphine-produced antinociception using the tail-flick (TF) test in male CD-1 mice. Intrathecal pretreatment with dextro-morphine (33 fmol) time-dependently attenuated the i.t. levo-morphine-produced TF inhibition for 4 h and returned to the preinjection control level at 24 h. Intrathecal pretreatment with dextro-morphine (0.3-33 fmol), which injected alone did not affect the baseline TF latency, dose-dependently attenuated the TF inhibition produced by i.t.-administered levo-morphine (3.0 nmol). The ED(50) value for dextro-morphine to induce antianalgesia was estimated to be 1.07 fmol, which is 71,000-fold more potent than the ED(50) value of levo-morphine, indicating the high stereoselective action of dextro-morphine over levo-morphine for the induction of antianalgesia. Like levo-morphine, the dextro-morphine-induced antianalgesia against levo-morphine-produced TF inhibition was dose-dependently blocked by the nonopioid dextro-naloxone and its stereo-enantiomer levo-naloxone, a nonselective mu-opioid receptor antagonist. The antianalgesia induced by levo-morphine and dextro-morphine is reversed by the pretreatment with the glial inhibitor propentofylline (3.3-65 nmol), indicating that the antianalgesia is mediated by glial stimulation. The findings strongly indicate that the antianalgesia induced by levo-morphine and dextro-morphine is mediated by the stimulation of a novel nonopioid receptor on glial cells.

Analgesia↗
PubMed1986

Demonstration of cell sidedness in hepatic transfer of morphine and morphine glucuronide in the rat.

The purpose of this study was to demonstrate hepatic cell sidedness for the transfer of [14C]morphine and [14C]morphine glucuronide. A tracer dose of [14C]morphine was administered by segmented retrograde intrabiliary injection into the bile duct cannula of the urethane-anesthetized rat or the in situ isolated perfused liver preparation. The bile from the first, and the single pass perfusate from the second preparation, respectively, were analyzed for the radioactive components. Various doses of morphine were given intraportally in these preparations 5 min before the [14C]morphine to influence the recovery of the radioactive components. As the dose of morphine increased, the recovery in bile of [14C]morphine glucuronide decreased while [14C]morphine remained unchanged. In the perfusate, the morphine loading increased the recovery of [14C]morphine, but the [14C]morphine glucuronide content was unchanged. These sets of results indicated that morphine loading inhibited the formation of morphine glucuronide by isotope dilution, which should have led to an increase in [14C]morphine in the cell. Because of the presence of cell sidedness, the increased intracellular [14C]morphine was directed toward the perfusate and not toward the bile. The decrease in [14C]morphine glucuronide synthesis was manifested by a decrease in its excretion into bile, but not into perfusate. Further demonstration of cell sidedness was obtained by manipulation of these systems by chlordecone and trans-stilbene oxide pretreatment of the rats. The directionality of flow of [14C]morphine and [14C]morphine glucuronide out of the liver emanates from liver cell sidedness.

Animals↗
PubMed1984

Morphine-morphine glucuronide pools in the rat liver: effects of Triton X-100.

The purpose was to determine the effect on the morphine-morphine glucuronide systems of Triton X-100 instilled into the area of the hepatic canalicular membrane by segmented retrograde intrabiliary injection (40 microliters of 0.4% Triton + 31 microliters of saline) in the isolated in situ perfused livers of male Sprague-Dawley rats. In all experiments, [14C]morphine was given by segmented retrograde intrabiliary injection (40 microliters of [14C]morphine + 110 microliters of saline). The control single pass perfusate contained 15.8% [14C]morphine glucuronide (MG) and 6.2% [14C]morphine. With Triton, the major changes observed were an unusual plateau-like pattern of egress of the [14C]MG into the perfusate and a profound decrease in the [14C]MG excretion into bile. In controls, 45 mg of unlabeled morphine sulfate intraportally 5 min before the [14C]morphine reduced the perfusate [14C]MG and increased [14C]morphine as expected by isotope dilution. Also, [14C]MG recovery in bile was accordingly decreased (intact pentobarbital-anesthetized rat); however, the [14C]morphine in bile did not change even though intracellular availability of [14C]morphine must have been increased. In pulse chase experiments, [14C] morphine was followed in 2 min with 45 mg of morphine sulfate intraportally. The perfusate [14C]MG declined and [14C]morphine increased. However, on the canalicular side (intact pentobarbital-anesthetized rat) no isotope dilution was evident: [14C]MG and [14C]morphine content in bile was similar to controls given no morphine sulfate. Triton treatment decreased the amount of [14C] morphine which could be chased into the perfusate. Several different pools of morphine and MG exist in the liver; the canalicular and sinusoidal sites respond very differently to manipulation of these pools.

Animals↗
PubMed1989

Stereospecific effects of a kappa-opiate antagonist on the actions of morphine in morphine-tolerant rats.

The effects of kappa-opiate receptor antagonist, MR 2266 and its dextro isomer, MR 2267 on morphine-induced analgesia and changes in colonic temperature were determined in morphine-naive and morphine-tolerant male Sprague-Dawley rats. Intraperitoneal administration of morphine (8 mg/kg) produced analgesia and hyperthermia in morphine-naive rats. MR 2266 (0.3-3.0 mg/kg) antagonized morphine-induced analgesia and hyperthermia in morphine-naive rates but MR 2267 was inactive. Subcutaneous implantation of six morphine pellets during a 7 day period induced tolerance to the analgesic and hyperthermic effects of morphine in the rat. MR 2266 also antagonized morphine analgesia and hyperthermia in morphine-tolerant rats, however, MR 2267 had no effect. A high dose (3 mg/kg) of MR 2266 produced an intense hypothermic response in morphine-tolerant rats. Previously we have shown that kappa-opiate receptor agonists antagonize morphine analgesia in morphine-naive rats but potentiate it in morphine-tolerant rats. The results of the present studies indicate that the antagonist of kappa-opiate receptors, on the other hand, antagonize morphine effects in both morphine-naive and morphine-tolerant rats in a stereospecific manner.

Analgesia↗
PubMed2006

PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice.

Male Swiss Webster mice exhibited antinociception, hypothermia and Straub tail 3h following a 75mg morphine pellet implantation. These signs disappeared by 72h, and the morphine-pelleted mice were indistinguishable from placebo-pelleted ones, although brain morphine concentrations ranged from 200 to 400ng/gm. We previously demonstrated that chemical inhibitors of protein kinase C (PKC) and A (PKA) are able to reverse morphine tolerance in acutely morphine-challenged mice. However, it was not known whether the reversal of tolerance was due to the interaction of kinase inhibitors with the morphine released from the pellet, the acutely injected morphine to challenge tolerant mice, or both. The present study aimed at determining the interaction between the PKC and PKA inhibitors and the morphine released "solely" from the pellet to reinstate the morphine-induced behavioral and physiological effects, 72h after implantation of morphine pellets. Placebo or 75mg morphine pellets were surgically implanted, and testing was conducted 72h later. Our results showed that the intracerebroventricular (i.c.v.) administration of the PKC inhibitors, bisindolylmaleimide I and Gö-6976 as well as the PKA inhibitors, 4-cyano-3-methylisoquinoline and KT-5720, restored the morphine-induced behaviors of antinociception, Straub tail and hypothermia in morphine-pelleted mice to the same extent observed 3h following the pellet implantation. The tail withdrawal and the hot plate reaction time expressed as percent maximum possible effect (%MPE) was increased to 80-100 and 41-90%, respectively, in PKC and PKA inhibitor-treated morphine tolerant mice compared to 2-10% in non-treated mice. Similarly, a significant hypothermia (1.3-4.0 degrees C decrease in body temperature) was detected in PKC and PKA inhibitor-treated morphine tolerant mice compared to an euthermic state in non-treated morphine tolerant mice. Finally, the Straub tail score was increased to 1.1-1.6 in PKC and PKA inhibitor-treated tolerant mice, whereas it was totally absent in non-treated animals. It is noticeably that the kinase inhibitors used in the study had no effect in placebo-pelleted mice. Our results provide the first evidence on the ability of PKC and PKA inhibitors to reinstate the behavioral and physiological effects of morphine in non-challenged morphine-tolerant animals.

Analgesics, Opioid↗
PubMed1991

Morphine actions on supraoptic oxytocin neurones in anaesthetized rats: tolerance after i.c.v. morphine infusion.

1. The effects of acute i.v. administration of morphine on putative oxytocin neurones of the supraoptic nucleus were studied in urethane-anaesthetized female rats which had been exposed to i.c.v. infusion of morphine (up to 50 micrograms h-1) or vehicle for 5 days. 2. In vehicle-infused rats, i.v. morphine inhibited the spontaneous activity of six out of seven putative oxytocin neurones. Increasing doses of morphine were given, from 1 microgram kg-1 to 5 mg kg-1. The median cumulative threshold dose to produce significant inhibition was 20 micrograms kg-1 (seven cells in six rats); six out of seven cells were inhibited at 161 micrograms kg-1. The highest doses tested inhibited by approximately 90% (excluding one unaffected cell). Inhibition was fully reversed by i.v. naloxone without overshoot, indicating a lack of acute dependence. 3. Injection of morphine i.c.v. inhibited firing at doses that were ineffective by i.v. injection and the effects of i.c.v. morphine were reversed by i.v. naloxone. 4. Acute morphine (500 micrograms kg-1 i.v.) reduced the plasma concentration of oxytocin, measured after 15 min by specific radioimmunoassay, by 34% (n = 14). 5. In lactating rats i.c.v. injection of morphine (1-2 micrograms) inhibited the activity of supraoptic neurones identified as oxytocinergic by their responses to suckling. 6. In seventeen rats infused with i.c.v. morphine the initial firing rate of twenty-eight spontaneously active, non-phasic neurones was significantly less, by 24%, than thirty-four similar cells in control rats, indicating incomplete tolerance to i.c.v. morphine. Morphine (up to 161 micrograms kg-1 given i.v.) inhibited none of nine active non-phasic neurones (P less than 0.01 compared to control rats), but at higher doses inhibited four of nine cells; the overall median threshold cumulative dose (1660 micrograms kg-1) was significantly greater than in vehicle-infused controls, indicating tolerance to i.v. morphine. In contrast with control rats, some cells (5/9) were modestly excited by low doses of morphine. Naloxone (5 mg kg-1 i.v.) produced withdrawal excitation: the firing rate of putative oxytocin neurones increased to approximately 260% of the pre-i.v. morphine value, indicating dependence in mechanisms regulating the firing rate of these neurones. 7. In morphine-infused rats, the basal firing rate of nineteen phasically active, putative vasopressin supraoptic neurones was not different in nineteen phasic cells in controls (6.4 +/- 0.7 vs. 4.2 +/- 0.6 Hz). 8. Thus morphine potently inhibits the firing of magnocellular oxytocin neurones in the female rat, inhibiting oxytocin secretion. Morphine tolerance and dependence develop during i.c.v. infusion of morphine for 5 days. Similar tolerance to and dependence upon endogenous opioids during pregnancy may be important in the preparation of oxytocin neurones for parturition.

Animals↗
PubMed1976

Prenatal administration of morphine to the rat: tolerance to the analgesic effect of morphine in the offspring.

The analgesic activity of morphine was assessed by the hot-plate technique in the offspring of female CFE rats that had received morphine twice daily on days 5 to 12 of pregnancy. A dose of 5.0 mg/kg of morphine was administered for the first 3 injections; 10 mg/kg was used for each of the remaining 13. Morphine dose-response curves were determined in the offspring at 5 weeks of age. The analgesic effect of morphine in the offspring of morphine-treated females (morphine offspring) was attenuated by as much as 50% compared to the offspring of saline-treated females (saline offspring). This same relationship between the morphine and saline offspring was also observed in offspring rendered tolerant to the analgesic effect of morphine. A diminished analgesia in the morphine offspring compared to the saline offspring was also observed after the injection of graded doeses of levorphanol in both nontolerant and morphine-tolerant offspring. The analgesic effect of a single dose of morphine was also attenuated in 3-, 5- and 11-week-old morphine offspring. No differences were found in either brain or plasma concentration of morphine between the morphine and saline offspring. The long-term effect of prenatal morphine administration could not be explained on the basis of maternal influences since cross-fostering procedures failed to abolish it. It is concluded that the administration of moderate doses of morphine to gestating rats can induce a long-lasting tolerance to the analgesic effect of morphine in the offspring.

Aging↗
PubMed1984

Microiontophoretically applied morphine and naloxone on single cell activity in the parafasciculus nucleus of naive and morphine-dependent rats.

Responses of parafasciculus (PF) thalamic neurons to microiontophoretically applied morphine and naloxone were examined in morphine-naive and morphine-dependent rats. The PF neurons exhibited high responsiveness (65%) to microiontophoretically applied morphine. Five different patterns of response to morphine in naive animals were obtained from the PF neurons. In morphine-dependent rats, the total responsiveness to microiontophoretic application of morphine was reduced dramatically (to 30%) and the response patterns to morphine were significantly (P less than .01) altered; this indicates that the PF neurons exhibit tolerance to morphine. Naloxone applied together with morphine only blocked the morphine-induced decreases in firing rates, but not the increases to which naloxone exhibited opiate agonist effects. Microiontophoretic application of naloxone alone, before morphine ejections in morphine-naive rats, induced changes in 51% of the PF neuronal population studied. Most of them (73%) responded with decreased firing rates. In morphine-dependent rats, more units responded to naloxone ejection (64%) as compared with the morphine-naive group. Excitation was the dominant response (73%) to naloxone treatment. The application of naloxone alone in naive and morphine-dependent rats demonstrated that the PF units responded in a characteristic dose-response manner to incremental naloxone administration. The present observations support our previous experiments using systemic applications of morphine and naloxone in freely behaving animals.

Animals↗
PubMed2003

Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants.

BACKGROUND: To investigate clinical variables such as gestational age, sex, weight, the therapeutic regimens used and mechanical ventilation that might affect morphine requirements and plasma concentrations of morphine and its metabolites. METHODS: In a double-blind study, neonates and infants stratified for age [group I 0-4 weeks (neonates), group II > or =4-26 weeks, group III > or =26-52 weeks, group IV > or =1-3 yr] admitted to the paediatric intensive care unit after abdominal or thoracic surgery received morphine 100 micro g kg(-1) after surgery, and were randomly assigned to either continuous morphine 10 micro g kg(-1) h(-1) or intermittent morphine boluses 30 micro g kg(-1) every 3 h. Pain was measured using the COMFORT behavioural scale and a visual analogue scale. Additional morphine was administered on guidance of the pain scores. Morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) plasma concentrations were measured before, directly after, and at 6, 12 and 24 h after surgery. RESULTS: Multiple regression analysis of different variables revealed that age was the most important factor affecting morphine requirements and plasma morphine concentrations. Significantly fewer neonates required additional morphine doses compared with all other age groups (P<0.001). Method of morphine administration (intermittent vs continuous) had no significant influence on morphine requirements. Neonates had significantly higher plasma concentrations of morphine, M3G and M6G (all P<0.001), and significantly lower M6G/morphine ratio (P<0.03) than the older children. The M6G/M3G ratio was similar in all age groups. CONCLUSIONS: Neonates have a narrower therapeutic window for postoperative morphine analgesia than older age groups, with no difference in the safety or effectiveness of intermittent doses compared with continuous infusions in any of these age groups. In infants >1 month of age, analgesia is achieved after morphine infusions ranging from 10.9 to 12.3 micro g kg(-1) h(-1) at plasma concentrations of <15 ng ml(-1).

Age Factors↗
PubMed1995

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study.

1. The effect of morphine (10 mg kg-1, s.c.) on the analgesic response measured by the tail-flick method was determined in male Sprague-Dawley rats. The analgesic response to morphine was correlated with the levels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF). 2. The analgesic response to morphine lasted for 4 h. The concentration of morphine during a 4 h collection period was significantly higher than the metabolites concentration. The relative concentration of morphine and its metabolites during the 4 h period was 70 and 30% respectively. 3. The analgesic response during the first 2.25 h period accounted for more than 82% of the total analgesia as determined by the area under the time-response curve (AUC). The concentration of morphine and its metabolites during the same period were 78 and 22%, respectively, but they did not differ during the 2.25-4.0 h period (52 and 48%). 4. The half-life for morphine and its metabolites were similar, the maximal achievable concentration Cmax and AUC0-4 h were lower for metabolites but the time to reach maximum concentration was higher for morphine metabolites than for morphine. The ratio of the concentration of metabolites to the concentration of morphine in the cortical ECF increased with time whereas the analgesic response to morphine decreased with time. 5. At several time points following morphine injection even though the levels of morphine were the same, the concentration of metabolites (mainly M3G) differed and thus the ratio [metabolite/morphine]. A plot of [metabolite]/[morphine] vs. analgesia gave a high correlation coefficient. Since M3G has been shown to be antianalgesic and is the only metabolite of morphine in the rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.

Analgesia↗
PubMed2005

The influence of central administration of dopaminergic and cholinergic agents on morphine-induced amnesia in morphine-sensitized mice.

In the present study, effects of intracerebroventricular (i.c.v.) injections of dopaminergic and cholinergic agents on morphine-induced amnesia in morphine-sensitized mice were investigated by using a one-trial passive avoidance task. Amnesia induced by pre-training morphine was significantly reversed in morphine-sensitized mice, which had previously received once daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days. Three daily injections of SKF 38393 (1, 2 and 4 g/mouse, i.c.v.) or SCH 23390 (0.25, 0.5, 0.75 and 1 g/mouse, i.c.v.) before morphine, and during morphine-sensitization, decreased and increased the amnesia induced by pre-training morphine respectively. Three daily injections of quinpirole (0.3, 1 and 3 g/mouse, i.c.v.) or sulpiride (0.03, 0.1, 0.3 and 1 g/mouse, i.c.v.) before morphine, also decreased and increased the amnesia induced by pre-training morphine respectively. Morphine-sensitized mice received similar injections of cholinergic agents. Three daily injections of physostigmine (1, 3 and 5 g/mouse, i.c.v.) or atropine (1, 4 and 7 g/mouse, i.c.v.) before morphine, and during morphine-sensitization, decreased and increased the amnesia induced by pre-training morphine respectively. Three daily injections of nicotine (0.75, 1 and 2 g/mouse, i.c.v.) or mecamylamine (1, 3 and 6 g/mouse, i.c.v.) before morphine, also decreased and increased the amnesia induced by pre-training morphine respectively. The results suggest that morphine sensitization affects the impairment of memory formation and thus it is postulated that central dopaminergic and cholinergic systems may play an important role in this effect.

Amnesia↗
PubMed1997

DynorphinA-(2-17) restores spinal/supraspinal morphine synergy in morphine-tolerant mice.

Morphine administered simultaneously to intracerebroventricular (i.c.v.) and intrathecal (i.t.) sites exhibits synergism, with the antinociceptive potency much greater than would be predicted from a simple addition of the potencies of the same dose administered to either site alone. This synergism was quantified in mice using both a fixed dose method, in which the morphine dose at one site was fixed while the AD50 (antinociceptive dose at 50% effectiveness) of morphine at the other site was determined; and a variable dose method, in which different doses of morphine were administered simultaneously to both sites at a fixed ratio, and the AD50 determined and compared to the AD50 at a single site alone. When animals were made tolerant to morphine by implantation of a 75-mg morphine pellet for 3 days, this synergism was eliminated, so that morphine administered simultaneously to i.c.v. and i.t. sites had an additive effect. However, administration of the peptide DynorphinA-(2-17) i.v. simultaneously to the test doses of morphine in morphine-tolerant animals resulted in a partial restoration of synergism. These results suggest that morphine-induced antinociception is highly dependent on an intact integrated central nervous system system and that the initial tolerance development is the result of a disruption of synergism between the central nervous system sites. Morphine tolerance results not from a reduced sensitivity to morphine at discrete central nervous system sites, but rather from a reduced synergistic interaction of morphine at spinal and supraspinal sites. In support of this conclusion, there was no tolerance observed in morphine-pelleted animals to morphine administered to i.c.v. or i.t. sites alone. DynorphinA-(2-17), a nonopioid peptide has previously been shown to enhance the antinociceptive potency of morphine in morphine-tolerant animals, appears to act by restoring this synergism.

Animals↗
PubMed2002

Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers.

OBJECTIVE: This investigation focused on the development of a predictive model of morphine, including morphine-6-glucuronide (M6G) for healthy young volunteers after morphine administration. METHODS: Population compartmental pharmacokinetic modeling with NONMEM was applied to the plasma concentration-time data of morphine and M6G obtained from 8 healthy volunteers (4 men and 4 women; age range, 23 to 30 years) after intravenous bolus injection of 5.64 mg morphine base (7.5 mg morphine sulfate) and of 1 mg deuterium-labeled M6G. RESULTS: Two models were identified that described the plasma concentration versus time courses of morphine and M6G after administration of morphine. The model consisted of a standard 3-compartment model for morphine and a standard 2-compartment model for M6G, with input into and output from the central compartments. The formation of M6G from morphine was modeled as a fraction of morphine clearance of about 14%, which accounted for the formation of M6G, and a delay of the appearance of M6G in plasma modeled as a first-order process, with a mean metabolic transit time of 17.2 minutes. An alternative model assigned the formation of M6G among the first peripheral compartment of morphine and the central compartment of M6G. Therefore the alternative 3-compartment model of morphine had the input into the central compartment and renal excretory elimination from the central compartment, but the metabolic clearance of morphine started from the first peripheral compartment. M6G was again modeled with a standard 2-compartment model. Both models predicted morphine and M6G plasma concentrations available from an independent study with acceptable accuracy and without bias. CONCLUSIONS: Two models are provided that can predict plasma concentrations of morphine and M6G with acceptable accuracy in healthy young volunteers.

Adult↗
PubMed1990

The effect of halothane on morphine disposition: relative contributions of the liver and kidney to morphine glucuronidation in the dog.

The present study determined the effect of halothane on the disposition of morphine by defining the effect of halothane anesthesia on the systemic, renal, and hepatic clearance of the parent compound, morphine, and on the generation of the primary metabolite, morphine-3-glucuronide (M3G) in the dog. Unlabeled morphine, 3H-morphine, and 14C-morphine were simultaneously administered into the portal vein, femoral vein, and renal artery, respectively, first during pentobarbital anesthesia and second during halothane (1.5 MAC) anesthesia; blood samples were taken for estimation of unlabeled plasma morphine and M3G concentrations by high performance liquid chromatography (HPLC). 3H- and 14C-morphine concentrations and corresponding M3G concentrations were determined by dual-channel liquid scintillation counting of the eluant corresponding to the appropriate peak on the HPLC. The portal clearance of morphine was not altered by halothane. However, intravenous (iv) morphine clearance (CLs) decreased (P less than 0.05) by 40% from 963 +/- 131 to 579 +/- 91 ml/min during halothane anesthesia, accompanied by an increase (P less than 0.05) in half-life from 78 +/- 8 to 106 +/- 8 min. The reduction in CLs of morphine occurred putatively on the basis of a halothane-induced decrease in hepatic blood flow, whereas morphine metabolism, reflected by morphine portal (intrinsic) clearance, was not significantly decreased by halothane. There was no significant effect of halothane on the partial metabolic clearance of morphine to M3G, and the ratio of area under the plasma concentration-time curve (AUC)-M3G to AUC unchanged morphine was not significantly altered by halothane, indicating that morphine glucuronidation is unaffected by halothane anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed2002

Pain, sedation and morphine metabolism in cancer patients during long-term treatment with sustained-release morphine.

BACKGROUND: Morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) are the two most important metabolites of morphine. Both are pharmacologically active, however, with different effects. M-6-G has been demonstrated capable of inducing anti-nociception and sedation, and M-3-G may induce behavioural excitation and possibly antagonise anti-nociception. Their impact on pharmacodynamics in patients in long-term treatment with oral morphine remains to be settled. METHODS: Forty-two cancer patients treated with oral sustained-release (SR) morphine were assessed for pain, sedation and other side effects related to morphine treatment. Blood samples were analysed for morphine, M-3-G and M-6-G by high-performance liquid chromatography (HPLC). RESULTS: Significant correlations were found between the daily dose of SR morphine and plasma morphine (M) (r = 0.535, P < 0.001), plasma M-6-G (r = 0.868, P < 0.001) and plasma M-3-G (r = 0.865, P < 0.001). There was no relationship between plasma morphine, M-6-G, M-6-G/M and pain and sedation scores. Seventy-nine percent of the patients suffered from dryness of the mouth, which was the most frequent side effect observed. Patients in this group had higher plasma morphine and M-6-G concentrations than patients who did not suffer from this side effect. CONCLUSION: The plasma concentrations of morphine and its metabolites, M-3-G and M-6-G, are significantly correlated to the daily dose of SR morphine. Although M-6-G has analgesic properties, no associations were found between pain and plasma morphine and morphine metabolites. This may be due to the multitudinous factors affecting the dose-effect relationship. Patients with dryness of the mouth had higher concentrations of morphine and M-6-G than patients without this side effect.

Adult↗