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PubMed1975

Delayed clearance of morphine from the circulation of rabbits immunized with morphine-6-hemisuccinate bovine serum albumin.

Morphine clearance from the circulation of normal rabbits and rabbits with circulating anti-morphine antibody was studied. Individual animals were injected with 14C trace-labeled morphine in saline (6 mg morphine/kg body weight). The rabbits were bled at various times after morphine injection and the amount of morphine present in the serum at each time interval was determined. Morphine could be detected in the serum of normal animals for 1 week following injection and up to 12 weeks following injection in at least one animal with antibodies to morphine. The rate of morphine clearance in animals immunized to morphine-6-hemisuccinate-bovine serum albumin was not significantly different from normal during the first 4 hr after morphine injection. However, by 24 hr after injection, the rate of morphine clearance in morphine-6-hemisuccinate-bovine serum albumin-immunized animals was significantly slower than in normal animals. The amount of morphine present in the sera of the rabbits 24 hr after injection was related to the antigen-binding capacity and independent of antibody avidity. However, the rate of morphine clearance at times greater than 24 hr after injection was related to the average antibody avidity and not related to the antigen-binding capacity.

Animals↗
PubMed1981

Effects of intraventricular morphine and enkephalins on schedule-controlled behavior in nondependent, morphine-dependent and postdependent rats.

The effects of intraventricular morphine and the metabolically stable enkephalin analogs, D-ala2-leu- and D-ala2-met-enkephalinamide, were compared on food-reinforced operant responding in nondependent, morphine-dependent and postdependent rats. Dependence was induced and maintained by scheduled access to 0.05% morphine solution for 10 min every 6 hr for at least 8 weeks before testing. In nondependent animals, the lowest dose of the three drugs increased responding, whereas higher doses, i.e., 0.3 to 3.9 micrograms of morphine and 0.1 to 30 micrograms of the two enkephalins, produced graded decreases in responding. On a molar basis, morphine was 2 to 3 times more potent than the enkephalins in decreasing response rate. Naloxone (0.1 and 1.0 mg/kg) competitively antagonized the rate-decreasing effect of all three compounds. However, chronic morphine treatment produced varying changes in the effects of morphine and the enkephalins. Morphine-dependent rats were tolerant to the rate-decreasing action of morphine, whereas the rate-decreasing effect of D-ala2-met-enkephalinamide was unchanged and that of D-ala2-leu-enkephalinamide was enhanced. Protracted changes in the rate-decreasing effect of morphine, but not the enkephalins, were evident in postdependent animals that were tested 5 weeks after withdrawal from morphine. Thus, the effects of morphine and the enkephalins on operant responding are differentially altered as a result of chronic morphine treatment. These results could reflect an allosteric interaction between the neuronal binding sites for morphine and the enkephalins.

Animals↗
PubMed1997

Distribution of free and conjugated morphine in body fluids and tissues in a fatal heroin overdose: is conjugated morphine stable in postmortem specimens?

The tissue distribution of free and conjugated morphine in a male individual who died after self-injection of heroin and methamphetamine was investigated, and the postmortem stability of morphine in the blood, liver and urine, and that of 6-monoacetylmorphine in the urine was determined. Confirmation and quantitation of morphine, 6-monoacetylmorphine and methamphetamine were performed by gas chromatography/mass spectrometry and gas chromatography, respectively. Blood levels of free and total morphine were very site-dependent with ranges of 462-1350 and 534-1570 ng/mL, respectively. Large amounts of total morphine, 5220, 4200, and 2270 ng/g, had accumulated in the stomach contents, liver, and lung, respectively. The concentration of free morphine in the cerebrospinal fluid was correlated very closely with that in the cerebrum. The proportion of free morphine in various fluids and tissues ranged from 23.0% to 98.8% of total morphine: less than 30% in the stomach contents and urine; 30-60% in the liver, cerebrospinal fluid, lung, and pericardial sac fluid; 61-90% in the spleen, right femoral muscle, myocardium, blood in the left and right ventricles of the heart, and right femoral vein blood; more than 91% in the right kidney and cerebrum. Detectable amounts of 6-monoacetylmorphine, 417 ng/mL and 78 ng/g, existed in the urine and stomach contents, respectively, indicating that this individual might have died within several hours after heroin injection. Methamphetamine concentrations in the blood were also site-dependent within the range 551-1730 ng/mL. In an in vitro experiment, free and conjugated morphine were stable in the blood and urine at 4, 18-22, and 37 degrees C for a 10-day study period. In the liver, however, conjugated morphine had been converted almost completely to free morphine at 18-22 and 37 degrees C by the end of the experiment, although it was stable at 4 degrees C. Urine 6-monoacetylmorphine, although degraded slightly at 37 degrees C, was stable at 4 and 18-22 degrees C during the experiment. Thus it appears that non-specific hydrolysis of conjugated morphine to free morphine would not occur in corpses at least for a few days after death. Femoral muscle may be a specimen of choice for roughly predicting the ratio of free to total morphine in blood even when blood specimens are not available, because the femoral muscle is relatively spared of both postmortem diffusion of drugs and bacterial invasion.

Adult↗
PubMed2001

Co-release of noradrenaline and dopamine in the prefrontal cortex after acute morphine and during morphine withdrawal.

RATIONALE: Acute morphine and abstinence from chronic morphine have been shown to increase and to decrease extracellular dopamine (DA) in the nucleus accumbens, respectively. In contrast, extracellular DA in the prefrontal cortex (PFC) is not modified by acute morphine and is markedly increased during abstinence syndrome. OBJECTIVES: We investigated whether the peculiar behaviour of PFC DA might depend on the fact that extracellular DA originates not only from DA but, mainly, noradrenaline (NA) terminals. Accordingly, we studied if the effect of acute morphine and morphine-abstinence was modified by the inhibition of DA or NA neurons. METHODS: Extracellular DA and noradrenaline (NA) concentrations were determined by microdialysis in the PFC (densely innervated by DA) and in the parietal cortex (lacking DA afferents) both after acute morphine and in morphine-dependent rats during naloxone-precipitated abstinence syndrome. Dialysate catecholamine levels were evaluated by high performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: Acute morphine (5 mg/kg IP) reduced extracellular NA (by 30%) and failed to modify extracellular DA level in the PFC, but reduced both amines by 40% in the parietal cortex. The co-administration of morphine and the D(2) agonist quinpirole (0.5 mg/kg IP) decreased both extracellular DA and NA by 40% in the PFC. In morphine dependent rats the administration of naloxone (1.0 mg/kg, SC) precipitated a typical abstinence syndrome associated with a concomitant dramatic increase in extracellular DA and NA by about 200 and 100%, respectively, in the PFC. The alpha(2)-adrenoceptor agonist clonidine (0.15 mg/kg IP) suppressed naloxone precipitated abstinence symptoms and brought both NA and DA output in the PFC to <50% baseline values. In contrast, quinpirole was totally ineffective. CONCLUSIONS: The results suggest that: a) morphine-stimulated DA release from DA terminals is compensated by reduced DA release from NA terminals; b) morphine abstinence-induced inhibition of DA release from DA terminals is overshadowed by a marked increase in DA released from NA terminals. Thus, the paradoxical response of PFC DA to morphine and morphine abstinence may be explained by the fact that extracellular DA in the PFC mainly represents the amine co-released from NA terminals.

Adrenergic alpha-2 Receptor Antagonists↗
PubMedDate not supplied

Postoperative analgesia and recovery course after major colorectal surgery in elderly patients: a randomized comparison between intrathecal morphine and intravenous PCA morphine.

BACKGROUND AND OBJECTIVES: Intrathecal morphine is a widely used method for postoperative pain relief after major abdominal surgery. The aim of this randomized, double-blinded study was to compare intrathecal morphine and intravenous PCA morphine for postoperative analgesia and recovery course after major colorectal surgery in elderly patients. METHODS: After written informed consent, patients >70 years of age were prospectively and randomly assigned to receive either preoperative intrathecal morphine (0.3 mg) and postoperative patient-controlled (PCA) intravenous morphine (IT morphine) or PCA alone (group control). Results are presented as mean +/- SD (95% confidence interval). RESULTS: Twenty-six patients successfully completed the study in each group. In the IT morphine group, rate of awakening was delayed. Pain intensity and daily intravenous morphine consumption were significantly reduced 1 and 2 days after surgery in the IT morphine group (P < .01). Mental function (assessed by Mini Mental State and Digit Symbol Substitution Test) was similar in both groups. Episodes of postoperative delirium/confusion occurred similarly in both groups. Time to ileus resolution and time to ambulation without assistance did not differ between the 2 groups. The duration of hospitalization was 8.4 +/- 1.7 (7-11) days and 7.9 +/- 2.0 (6-9.9) days for control and IT morphine, respectively (nonstatistical difference). Patients in the IT morphine group had longer time to awakening from anesthesia and experienced more sedation. CONCLUSIONS: Intrathecal morphine, as compared with intravenous PCA morphine alone, improves immediate postoperative pain and reduces parenteral morphine consumption but does not improve postoperative recovery in elderly patients after major colorectal surgery.

Aged↗
PubMed2003

Pre-exposure to the cannabinoid receptor agonist CP 55940 enhances morphine behavioral sensitization and alters morphine self-administration in Lewis rats.

Three experiments examined the influence of pre-exposure to the cannabinoid receptor agonist CP 55940 ((-)-cis-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(3-hydroxypropyl)cyclohexanol) on the sensitization of morphine-induced locomotor hyperactivity and self-administration in Lewis rats. In Experiment 1, rats received daily injections of vehicle or CP 55940 (0.1 mg/kg for 7 days then 0.2 mg/kg for a further 7 days). Four weeks later, the locomotor response to morphine (10 mg/kg s.c.) was tested once per day over a 3-h period for 14 consecutive days. Rats given morphine showed hypoactivity during the first hour following morphine but hyperactivity during the second and third hours. A progressive increase in hyperactivity to morphine was seen over the 14 days of administration, which was significantly greater in rats pre-treated with CP 55940. In Experiment 2, rats were given morphine (10 mg/kg) once a day for 14 days in combination with either vehicle, CP 55940 (0.1 mg/kg) or the cannabinoid CB(1) receptor antagonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (3 mg/kg). Both CP 55940 and SR 141716 initially inhibited the hyperactive response to morphine, but these effects gradually wore off and by the end of 14 days, hyperactivity was similar in all morphine-treated groups. When tested 3 weeks later for their response to morphine (10 mg/kg) given alone, rats previously given the morphine/CP 55940 combination, but not the SR 141716/morphine combination, showed a greater locomotor stimulation than those previously exposed to morphine only. In Experiment 3, rats were pre-exposed to CP 55940 or vehicle for 14 days and were subsequently trained to self-administer morphine intravenously (1 mg/kg per lever press) for 14 days. Rats pre-exposed to CP 55940 self-administered a significantly greater number of morphine infusions than vehicle pre-exposed rats. However, both active and inactive ('dummy') lever presses were increased by cannabinoid pre-treatment. Overall, these results suggest that cannabinoid pre-exposure can lead to an exaggeration of morphine-induced hyperactivity and may alter the reinforcing effects of morphine in Lewis rats. The implications for 'gateway' theories of cannabinoid effects in humans are discussed.

Analgesics↗
PubMed1978

Preference for morphine and drug-seeking behavior in morphine dependent rats.

We have already reported that morphine pretreated rats prefered morphine-admixed food during choice trials with the two cup method. In the present work, we utilized both the five and two cup methods and observed the preference for morphine in rats forcedly pretreated with the drug and the increasing rate of preference for the drug in rats where the feeding time was limited. In morphine pretreated rats, preference rate for morphine was 61.2 +/- 3.0% with the five cup method and 61.8 +/- 3.3% with the two cup method during the choice trials. In rats that were limitedly treated with morphine, each preference rate for morphine during choice trials rapidly increased in the five cup method, i.e. 5.5 leads to 14.4 leads to 31.7 leads to 43.6 leads to 61.2%, and the preference rate for morphine stabilized at approximately 60 percent. Findings with the two cup method were similar. After the preference for morphine was stabilized at the 60 percent level, morphine was given subcutaneously and it was found that the preference rate was dependent on the dose injected. When the drug-admixed concentration was changed from 1 mg/g food to 0.5 and 2 mg/g food, the preference rate changed in parallel with the concentration. When the number of food cups containing morphine-admixed food was changed from 1/5 to 2/5, 3/5 and 4/5 food cup, the preference rate was not effected. These studies clearly demonstrate drug-seeking behavior in rats. In the process of preference for morphine, morphine treatment enhances spontaneous intake of morphine-admixed food.

Animals↗
PubMed1975

Saturable binding of morphine to rat brain-stem slices and the effect of chronic morphine treatment.

The binding of morphine to brainstem slices was studied with nanomolar concentrations of (3H)-morphine. Rat brainstem slices were incubated at 35 degrees C and immediately homogenized. Bound morphine was estimated using Millipore filters to separate unbound morphine. Binding of labelled morphine was markedly inhibited by either non-labelled morphine or naloxone, indicating that a substantial portion of the binding is saturable. The saturable morphine binding to slices was significantly greater than that to brainstem tissue homogenized prior to incubation with morphine, whereas non-saturable binding was the same in both preparations. Saturable binding of morphine to brainstem slices was lower in rats rendered tolerant to morphine (using pellet implantation) than in non-tolerant controls. It appears that chronic morphine treatment decreases the affinity of the opiate receptor for morphine. It is concluded that the slice is the preferable preparation for the in vitro estimation of opiate receptor binding and that chronic morphine treatment alters the binding of morphine to brainstem.

Animals↗
PubMed1989

Identification of morphine- and cyclic AMP-regulated phosphoproteins (MARPPs) in the locus coeruleus and other regions of rat brain: regulation by acute and chronic morphine.

Regulation of cAMP-dependent protein phosphorylation by acute and chronic morphine was studied in the rat locus coeruleus (LC), a brain region that appears to play an important role in mediating morphine action in animals, including humans. Rats were treated chronically with morphine under conditions known to induce states of tolerance and dependence. Protein phosphorylation was then studied in extracts of LC and other brain regions with back-phosphorylation assays under different conditions and with 1- and 2-dimensional electrophoretic procedures. Evidence was obtained to suggest that chronic morphine increased the phosphorylation state of proteins of 165, 55, and 14-20 kDa and increased the total amount of proteins of 145, 71, 62, 58, and 51 kDa in the LC. Concomitant treatment of rats with naltrexone, an opiate receptor antagonist, blocked the ability of morphine to influence each of these proteins, indicating that morphine regulation of protein phosphorylation occurred through the specific activation of opiate receptors. Regulation of 165, 71, 62, 58, 55, and 51 kDa by chronic morphine was specific to the LC among the brain regions studied, whereas regulation of 145 and 14-20 kDa was also observed in the frontal cortex, neostriatum, and dorsal raphe. Most of the phosphoproteins whose phosphorylation state or total amount was increased by chronic morphine treatment in the LC in vivo were also shown to have their phosphorylation state decreased by acute morphine treatment in isolated LC nuclei ex vivo. In addition, the phosphorylation state of most of these morphine-regulated phosphoproteins was stimulated by forskolin or cAMP analogs in isolated LC and by cAMP in broken cell preparations of this brain region, supporting the view that these proteins are physiological substrates for cAMP-dependent protein kinase in the LC. Phosphoproteins regulated by morphine and cAMP were designated "MARPPs," morphine- and cAMP-regulated phosphoproteins, whereas those regulated by morphine but not by cAMP were designated "MRPPs." Taken together, the results of this study indicate that chronic morphine produces specific alterations in cAMP-dependent protein phosphorylation in the LC and raise the possibility that regulation of these specific phosphoproteins contributes to the development of tolerance and/or dependence in these neurons.

Animals↗
PubMed1987

Morphine, saline and naltrexone discrimination in morphine-treated pigeons.

Pigeons responding under a fixed-ratio 20 schedule of food presentation were treated with 10.0 mg/kg/day of morphine and trained to discriminate among i.m. injections of 17.8 mg/kg of morphine, saline and 0.032 mg/kg of naltrexone. Morphine and naltrexone occasioned responding on the injection-appropriate keys at doses greater than or equal to 32.0 and 0.032 mg/kg, respectively. Termination of morphine injections also produced naltrexone-appropriate responding, suggesting that the withdrawal-precipitating actions of naltrexone account for its discriminative stimulus effects in morphine-treated pigeons. The potency of morphine as a discriminative stimulus was similar in 30-hr morphine-abstinent pigeons and in pigeons that had received morphine 6 hr before testing. The opioid antagonists naloxone, nalmefene and diprenorphine substituted as discriminative stimuli for naltrexone at doses greater than or equal to 0.032 mg/kg. Nalorphine, a mixed agonist-antagonist, also substituted for naltrexone, but only at doses larger than 10.0 mg/kg. The mixed agonist-antagonist pentazocine failed to substitute for either training drug; the opioid agonist levorphanol substituted completely for morphine. Naltrexone was 1000 times more potent as a discriminative stimulus and 17.5 times more potent in suppressing responding in morphine-treated compared with untreated pigeons. In contrast, the acute dose of naltrexone required to prevent the discriminative stimulus effects of morphine was not changed by daily morphine injections. Acute injections of morphine attenuated the discriminative stimulus effects of naltrexone. Mutual antagonism between morphine and naltrexone suggests that these drugs exert discriminative stimulus effects by opposing actions at the same receptors.

Animals↗
PubMed1996

Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain.

The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain patients receiving chronic oral morphine therapy with either morphine sulfate solution or controlled-release morphine tablets. There were no differences in morphine, metabolite kinetics, or analgesic efficacy between equivalent doses of conventional or controlled-release formulations. The increase in morphine plasma concentration after a dose (1 hr for normal release, 2 hr for controlled release) was correlated significantly with the dose of morphine (r = 0.914, P < 0.001). There was a significant reduction in pain intensity (P < 0.05) and increase in pain relief (P < 0.001) after the dose of morphine administration, when compared with the predose score. One-half of the patients had mild and tolerable adverse effects. Patients were classified by mean pain relief between doses as having optimal, moderate, or poor pain control. No simple relationship was found between morphine plasma concentration and pain control. Morphine plus M6G concentrations in the "optimal control" group (751.2 +/- 194 nmol/L), however, were more than twice those found in the "moderate control" group (276.9 +/- 41.9 nmol/L) (P < 0.05), and no patient in the moderate control group had a morphine plus M6G concentration greater than 405 nmol/L. These results support the importance of M6G in morphine analgesia. For these hospitalized patients, there appeared to be a therapeutic range of morphine plus M6G plasma concentrations for optimal pain control with a lower limit of 400 nmol/L predose.

Adult↗
PubMed1999

Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis.

BACKGROUND: Conjugation with glucuronic acid represents the major route of biotransformation of morphine. The glucuronides morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are eliminated via the kidneys. Therefore, chronic renal failure should affect the disposition of M3G and M6G. Numerous patients undergoing long-term continuous ambulatory peritoneal dialysis (CAPD) require pain treatment with morphine. There are only limited data available about the disposition of morphine and its active metabolites M6G and M3G in patients on CAPD. We therefore investigated the pharmacokinetics of morphine and its metabolites in CAPD patients. METHODS: This was a single intravenous dose pharmacokinetic study in 10 CAPD patients (1 female, 9 male, age 31-69 years). Morphine-hydrochloride (Mo) (10 mg) was administered intravenously. Serum, urine, and dialysate samples were collected during 24 h. GC-MS-MS and HPLC-MS methods were used to quantify respectively morphine and morphine glucuronides. RESULTS: While systemic clearance of morphine (1246+/-240 ml/min) was in the range observed in patients with normal kidney function, both M3G and M6G showed substantial accumulation. The area under the concentration-time curve (AUC) ratio of M3G:Mo (33.4+/-7.1) and of M6G:Mo (12.2+/-3.2) was 5.5 and 13.5 times higher than in patients with normal kidney function. Renal clearances of morphine, M3G, and M6G (morphine 3.0+/-2.5 ml/min; M3G 3.9+/-2.2 ml/min; M6G 3.6+/-2.2 ml/min) and dialysate clearances (morphine 4.1+/-1.3 ml/min; M3G 3.2+/-0.7 ml/min; M6G 3.0+/-0.8 ml/min) were extremely low. Therefore the accumulation of M6G and M3G is readily explained by kidney failure which is not compensated by CAPD. CONCLUSION: Accumulation of M3G and M6G is due to the substantially lowered clearance by residual renal function and peritoneal dialysis. In view of the accumulation of potential active metabolites, subsequent investigations have to assess the frequency of side-effects in patients on CAPD.

Adult↗
PubMed2005

Morphine withdrawal increases intrinsic excitability of oxytocin neurons in morphine-dependent rats.

To determine whether intrinsic mechanisms drive supraoptic nucleus oxytocin neuron excitation during morphine withdrawal, we calculated the probability of action potential (spike) firing with time after each spike for oxytocin neurons in morphine-naive and morphine-dependent rats in vivo and measured changes in intrinsic membrane properties in vitro. The opioid receptor antagonist, naloxone, increased oxytocin neuron post-spike excitability in morphine-dependent rats; this increase was greater for short interspike intervals (<0.1 s). Naloxone had similar, but smaller (P=0.04), effects in oxytocin neurons in morphine-naive rats. The increased post-spike excitability for short interspike intervals was specific to naloxone, because osmotic stimulation increased excitability without potentiating excitability at short interspike intervals. By contrast to oxytocin neurons, neither morphine dependence nor morphine withdrawal increased post-spike excitability in neighbouring vasopressin neurons. To determine whether increased post-spike excitability in oxytocin neurons during morphine withdrawal reflected altered intrinsic membrane properties, we measured the in vitro effects of naloxone on transient outward rectification (TOR) and after-hyperpolarization (AHP), properties mediated by K+ channels and that affect supraoptic nucleus neuron post-spike excitability. Naloxone reduced the TOR and AHP (by 20% and 60%, respectively) in supraoptic nucleus neurons from morphine-dependent, but not morphine-naive, rats. In vivo, spike frequency adaptation (caused by activity-dependent AHP activation) was reduced by naloxone (from 27% to 3%) in vasopressin neurons in morphine-dependent, but not morphine-naive, rats. Thus, multiple K+ channel inhibition increases post-spike excitability for short interspike intervals, contributing to the increased firing of oxytocin neurons during morphine withdrawal.

Action Potentials↗
PubMed2001

Sex-related differences in antinociception and tolerance development following chronic intravenous infusion of morphine in the rat: modulatory role of testosterone via morphine clearance.

This study investigated possible sex-related differences in levels of antinociception and the rate of development of tolerance to the antinociceptive effects following prolonged (48 h) intravenous (i.v.) morphine administration in the rat. Groups of adult intact male, castrated male, female, and testosterone-pretreated female Sprague-Dawley rats received prolonged (48 h) infusions of i.v. morphine (5 or 10 mg/day) plus intra-arterial (i.a.) saline or i.v. morphine (5 mg/day) plus i.a. chloramphenicol (300 mg/day). Antinociception was quantified using the hotplate test. Serum concentrations of morphine and morphine-3-glucuronide (M3G) were assayed using high performance liquid chromatography with electrochemical detection, whereas the serum testosterone concentrations were quantified using an enzyme-linked immunosorbent assay method. Consistent with our previous findings in intact male rats, prolonged coinfusion of chloramphenicol with morphine produced a marked increase in the extent and duration of morphine antinociception in all experimental groups. Additionally, female and castrated male rats developed tolerance more slowly than either intact male or testosterone-pretreated female rats, when coinfused with parenteral morphine plus chloramphenicol. However, mean levels of antinociception were not significantly correlated with either the mean serum morphine or M3G concentrations, but were significantly inversely correlated with the mean values of the M3G/morphine serum molar concentration ratio. Testosterone pretreatment of female rats for 1 week before chronic morphine infusion abolished antinociception and markedly reduced both the serum morphine and M3G concentrations. These latter findings imply that testosterone modulates antinociception evoked by prolonged morphine infusion in rats via a mechanism that appears to involve modulation of morphine metabolism.

Analgesics, Opioid↗
PubMed1978

Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions.

Rats were housed on a cabinet designed to control their access to water or morphine solutions. They were trained to drink all of their fluid as morphine solutions or tap water during 5-minute access periods scheduled at 2 A.M., 8 A.M., 2 P.M. and 8 P.M. On this schedule, the morphine drinking rats consumed an average of 29, 27, 21 and 23% of their total daily fluid during the four respective access periods. The rats that had access to the 0.05% morphine solution drank an average of 53 mg/kg/day of morphine. Separate groups of rats were tested for morphine tolerance and dependence at 4-day intervals. Tolerance to the analgesic effect of challenge doses of morphine (3, 6 and 9 mg/kg) was first detected after 10 days of morphine drinking and reached a plateau after 18 days. Withdrawal scores for rats injected with 0.3 or 3 mg/kg of naloxone reached a plateau between 14 and 18 days of morphine drinking, whereas the scores of rats given 0.03 mg/kg were still increasing after 26 days of drinking. Plasma levels of morphine ranged between 167 and 300 ng/ml in blood samples collected 1 hour after each access period on the 18th day of morphine drinking. Six hours after the 8 A.M. access period, the levels of morphine in the plasma had decreased to 50% of the levels detected at 1 hour after the access period. Ninety percent of the rats accepted the morphine solutions and drank regularly for the 26 days the solutions were offered. They remained healthy throughout this period and, except for the fact that they gained 11% less body weight over the 26 days, they were visibly indistinguishable from the water drinking control rats.

Animals↗
PubMed1982

Analgesic effects of intraventricular morphine and enkephalins in nondependent and morphine-dependent rats.

The analgesic effects of i.c.v. morphine and the enzyme-resistant enkephalin analogs, D-Ala2-Leu- and D-Ala2-Met-enkephalinamide, measured in the tail-flick test, were compared in nondependent and morphine-dependent rats. Dependence was induced and maintained by scheduled access to 0.05% morphine solution for at least 8 weeks before testing. In the nondependent rats, 1.0 to 10 micrograms of each drug injected into the lateral ventricle produced a dose-related increase in analgesia; on a molar basis, morphine was 1.3 (1.0-1.7) times more potent than the enkephalins. Naloxone (0.3 and 1.0 mg/kg) antagonized the analgesic effect of the three compounds: the effect of morphine was competitively antagonized, whereas the interaction between naloxone and the enkephalins did not appear to be competitive. Chronic morphine treatment produced different changes in the analgesic effects of morphine and the enkephalins. In contrast to the tolerance that was observed after s.c. injection of morphine in morphine-dependent rats, the analgesic effect of i.c.v. morphine was enhanced in these animals. The analgesic effect of D-Ala2-Leu-enkephalinamide was also enhanced in morphine-dependent animals, whereas tolerance developed to the effect of D-Ala2-Met-enkephalinamide. Thus, the analgesic effect of morphine and enkephalins are differentially altered in the presence of naloxone and in morphine-dependent animals. These results could reflect an allosteric interaction between neuronal binding sites for enkephalins and opiate alkaloids.

Analgesics↗
PubMed1995

Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and morphine-6-beta-D-glucuronide in the rat.

The analgesic effects of subcutaneously administered morphine and morphine-6-beta-D-glucuronide (M6G) were determined in male Sprague-Dawley rats. Morphine produced a dose-dependent (2.5 to 10.0 mg/kg) analgesic response as measured by the tail-flick test. M6G in the same doses as morphine produced a greater degree of analgesia with longer duration of action. The concentrations of M6G and morphine were determined in plasma as the protein unbound form after the use of an equilibrium dialysis technique and in BECF after administration of the drugs (10.0 mg/kg s.c.). The concentrations of morphine and M6G in BECF were determined by using microdialysis. The concentration of M6G in plasma and BECF at each time interval after its administration was much higher than morphine. The maximal concentrations in plasma and AUC0-infinity values for M6G were, thus, significantly higher for M6G than for morphine in plasma and BECF. In BECF, the Tmax value for M6G was lower than for morphine, but the t1/2 beta values did not differ. In plasma, Tmax and T1/2 values for M6G and morphine did not differ, but volume of distribution and total clearance values for M6G were lower than for morphine. It is concluded that per milligram, M6G has a much higher analgesic potency than morphine in the rat and these differences may be related, in part, to the higher levels of M6G in comparison to morphine in plasma and BECF.

Analgesia↗
PubMed1990

Tolerance to morphine stimulus control: role of morphine maintenance dose.

Experiments assessed the development of tolerance to morphine stimulus control during treatment with selected maintenance doses of morphine. Separate groups of rats were trained to discriminate saline and either 3.2 mg/kg or 5.6 mg/kg morphine under fixed-ratio schedules of food delivery. Dose-response functions for generalization of morphine stimulus control were determined before, during, and after repeated treatment with selected doses of morphine. Similar experiments were performed with repeated pentobarbital treatment in order to assess the pharmacological selectivity of tolerance. Repeated treatment with saline, 3.2 mg/kg morphine, or twice daily injections of 17.8 mg/kg pentobarbital produced no tolerance to morphine stimulus control. In contrast, treatment with daily injections of 10 mg/kg or twice daily injections of 10 or 17.8 mg/kg morphine produced a dose-dependent increase in the dose of morphine required for stimulus control. The magnitude of tolerance to morphine stimulus control varied directly with the maintenance dose of morphine and was slightly greater for a lower than a higher morphine training dose. Termination of repeated treatment was followed by a return to initial sensitivity, without additional training. Tolerance to morphine stimulus control was not necessarily accompanied by tolerance to its rate-suppressing effects.

Animals↗