Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers

Steady-state pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) after intravenous administration of either morphine or M-6-G were determined in healthy volunteers. With a dosing regimen calculated on the basis of data obtained in a first series of experiments in four subjects (morphine: intravenous loading dose of 0.24 mg/kg for 5 minutes and an intravenous infusion of 0.069 mg.kg-1.hr-1 for 4 hours; M-6-G: loading dose of 0.011 mg/kg for 5 minutes and an infusion of 0.006 mg.kg-1.hr-1 for 4 hours), it was possible to yield plasma concentrations of morphine and M-6-G in another four subjects close to predefined targeted levels (35 and 45.5 ng/ml morphine and M-6-G, respectively). This dosing regimen may be used in further pharmacodynamic studies to compare the analgesic effects of morphine and M-6-G. In addition, metabolite kinetics of M-6-G were calculated as a function of time with use of a linear systems approach to the estimation of rate and fraction of morphine glucuronidation to M-6-G.     

Clinical patterns of neuronal migrational disorders and parental consanguinity

The primary metabolite of morphine, morphine-6-beta-glucuronide (M-6-G), is reported to contribute to the effects of morphine. The authors investigated the effects of M-6-G on the central nervous system (CNS) after short-term intravenous (i.v.) administration by employing both electroencephalograph (EEG) power spectra analyses and clinical signs as indicators of opioid effects. Three dosages of M-6-G, one dosage of morphine (bolus 10 mg/70 kg and 3.5 mg/70 kg/hour for 4 hours), a combination of morphine and M-6-G, and placebo were administered to 20 healthy volunteers as i.v. bolus plus i.v. infusion for 4 hours. M-6-G was dosed to produce steady state plasma concentrations that were either identical, 2 times, or 3 times higher than the M-6-G plasma concentrations observed after administration of morphine. The EEG background activity and clinical effects were recorded 3.5 hours after the infusion started. M-6-G failed to produce effects on any of the investigated EEG or clinical parameters at the doses tested. In contrast, morphine produced a significant increase in the alpha 1 and delta power of the EEG. In addition, morphine increased the subjects' ratings of tiredness, sickness, vertigo, and drowsiness, and decreased their level of performance in a tracking task. It was concluded that after short-term i.v. administration, M-6-G does not affect the CNS at the doses tested. Therefore, its contribution to clinical effects of morphine after short-term administration is questionable. The missing CNS effects were probably caused by the slow brain permeability of M-6-G, which in short-term treatment might not attain effective CNS concentrations.     

Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery

We analyzed morphine clearance values in infants receiving the drug by continuous i.v. infusion for analgesia after surgery, because we found lower steady-state morphine concentrations than we expected from our previous studies. Infants received morphine after a loading dose of 0.05 mg/kg and continuous infusion calculated to reach a steady-state concentration of 20 ng/mL. Blood was sampled twice on Postoperative Day 1 at times separated by at least 2 h, and morphine and morphine-6-glucuronide (M-6-G) concentrations were determined by high-performance liquid chromatography. Clearance of morphine was calculated as infusion rate divided by the steady-state morphine concentration. Morphine given to 26 infants by continuous i.v. infusion after major noncardiac surgery has rapidly increasing clearance values, from a median value of 9.2 mL x min(-1) x kg(-1) in infants 1-7 days old, 25.3 in infants 31-90 days old, and 31.0 in infants 91-180 days old to 48.9 in infants 180-380 days old. Adult clearance values are reached by 1 mo of age, more quickly than in infants of the same age previously studied who received morphine after cardiac surgeries. M-6-G was measured in all infants. The ratio of M-6-G to morphine concentrations was 1.9-2.1 in these infants, which is lower than ratios reported in older infants or adults by others, but higher than those reported in newborns. Infants with normal cardiovascular systems undergoing surgery clear morphine more efficiently than infants of the same age undergoing cardiac surgery. Implications: Morphine removal from the body is slow in newborns but increases to reach adult values in the first months of life. Calculating the clearance of morphine from blood samples drawn during continuous i.v. infusions after surgery shows that this maturation occurs more quickly in infants undergoing noncardiac surgery (by 1-3 mo of age) than in those receiving morphine after cardiac surgery (by 6-12 mo of age).     

The "Wallstent": a new stent for the treatment of urethral strictures

Morphine or morphine-6-glucuronide either alone or in combination with morphine-3-glucuronide was administered intrathecally to rats. Antinociceptive effects were evaluated with the tail flick and the hot plate tests. Motor function was tested using the rotarod test. Estimated ED50 from the dose-response curves for morphine and morphine-6-glucuronide showed about a 30 times more potent antinociceptive effect of morphine-6-glucuronide compared with morphine. Morphine-3-glucuronide had no antinociceptive effect. Simultaneous administration of morphine-3-glucuronide 5.0 micrograms did not show any significant effect on antinociception induced by morphine 1.0 microgram or morphine-6-glucuronide 0.05 microgram.     

High-performance liquid chromatography-mass spectrometry-mass spectrometry analysis of morphine and morphine metabolites and its application to a pharmacokinetic study in male Sprague-Dawley rats

A high-performance liquid chromatography tandem mass spectrometry-mass spectrometry (LC-MS-MS) assay was developed for the analyses of morphine, morphine glucuronides and normorphine in plasma samples from rats. The analytes were extracted by using C2 solid-phase extraction cartridges. The extraction recoveries were 100% for morphine, 84% for morphine-3-glucuronide, 64% for morphine-6-glucuronide and 88% for normorphine. Both intra- and inter-assay variabilities were below 11%. Using a plasma sample size of 100 microliters, the limits of detection were 13 nmol l-1 (3.8 ng ml-1) for morphine, 12 nmol l-1 (5.5 ng ml-1) for morphine-3-glucuronide, 26 nmol l-1 (12 ng ml-1) for morphine-6-glucuronide and 18 nmol l-1 (5.0 ng ml-1) for normorphine, at a signal-to-noise ratio of 3. The present assay was applied to a pharmacokinetic study in rats after intraperitoneal administration of morphine.     

A pharmacokinetic study of sublingual aerosolized morphine in healthy volunteers

A pharmacokinetic study was undertaken to compare the pharmacokinetics of morphine after an intravenous dose with the pharmacokinetics after a sublingual dose administered from an aerosol. Plasma levels of morphine, morphine-3-glucuronide and morphine-6-glucuronide were measured in five normal volunteers after morphine administration by the intravenous route and from a novel sublingual pressurized aerosol formulation. The mean (+/- s.d.) bioavailability of the sublingual aerosol morphine was 19.7 +/- 6.7%. The morphine-3-glucuronide/morphine and the morphine-6-glucuronide/morphine ratios were 5.1 +/- 1.6 and 1.2 +/- 0.4, respectively, for the intravenous route and 28.3 +/- 11.3 and 5.2 +/- 1.4, respectively, for the sublingual route. The combined total areas under the plots of systemic concentration against time (AUC) for the metabolites after the two routes was not significantly different. When compared with published data for oral administration the results demonstrate that the sublingual aerosol morphine might provide an alternative to conventional methods of morphine delivery, and has similar pharmacokinetics to a sublingual morphine tablet. It has no particular pharmacokinetic advantages over oral morphine, except a potential for a faster onset of analgesia. Bioavailability, maximum plasma concentration, Cpmax, and the time at which the maximum plasma concentration is reached, Tmax, are equivalent to those for orally administered morphine.     

Variability of morphine disposition during long-term subcutaneous infusion in terminally ill cancer patients

OBJECTIVE: To study the plasma concentrations of morphine and its glucuronides to assess the intra- and interindividual variability of the disposition of morphine administered by subcutaneous infusion in cancer patients. METHODS: Blood samples were taken repeatedly in eight patients with severe cancer pain who were being treated with morphine (60-3000 mg per day) via chronic (8-160 days) subcutaneous infusion. Venous blood samples were collected at least weekly and, when possible, on 3 consecutive days after dose adaptation or any other major change in the patients' treatment. Concentrations of morphine and its glucuronides in plasma were measured after solid-phase extraction using a validated high-performance liquid chromatography assay. The stability of the morphine solutions was determined by repeated measurement of the concentrations of morphine and its degradation products in the solutions. RESULTS: The morphine concentration in the infusion solutions remained unchanged during storage and infusion. The plasma concentrations of morphine and its glucuronides were within the ranges reported in the literature. There was, as expected, a large interindividual variability: from patient to patient, the mean of the normalised plasma concentrations ranged from 0.3 ng.ml(-1).mg(-1) to 0.8 ng.ml(-1).mg(-1) for morphine, from 1.0 ng.ml(-1).mg(-1) to 3.1 ng.ml(-1).mg(-1) for morphine-6-glucuronide and from 6.8 ng.ml(-1).mg(-1) to 24.3 ng.ml(-1).mg(-1) for morphine-3-glucuronide. Intraindividual variability was also important. The residual standard deviation of the mean normalised plasma concentrations calculated for each patient ranged from 26% to 56% for morphine, from 20% to 51% for morphine-6-glucuronide and from 20% to 49% for morphine-3-glucuronide. The normalised plasma concentrations of morphine and its glucuronides did not increase with dose or time, and no explanation for the pronounced pharmacokinetic intraindividual variability was found. CONCLUSION: During subcutaneous infusion of morphine, there is a large intra- and interindividual variability of the morphine disposition which could be of clinical relevance.     

Analgesic effect of morphine and its metabolites administered by an intracerebroventricular route

Intraventricular morphine administration is indicated, in some selected cases, to alleviate intractable cancer pain. Our pharmacokinetics data in cerebro-spinal fluid allowed us to formulate the theory of "Front de Recrutement". Then we were able to determine in cisternal and ventricular cerebrospinal fluid the morphine 6-glucuronide concentrations. Morphine 6-glucuronide is the main analgesic metabolite of morphine and its presence in cerebro-spinal fluid could be due to a metabolism of morphine in the central nervous system. Our animal studies showed that the analgesic activity of morphine 6-glucuronide was 27 to 67 times higher than that of morphine. By demonstrating the 6-monoacetyl morphine potency (analgesic metabolite of heroin that is 20 times more potent than morphine), we showed the involvement of the 6 position in the analgesic effect of these opioids. When we compared the morphine-6 concentrations in human cerebro-spinal fluid with the analgesic potency of this metabolite, the morphine-6 glucuronide was responsible of 33% to 67% of the supra-spinal analgesic effect. As heroin, morphine must be considered as a precursor whose metabolites have pharmacologic effects.     

Disposition of morphine in the rat isolated perfused kidney: concentration ranging studies

The rat isolated perfused kidney was used to investigate the linearity of the renal disposition of morphine and its potential oxidative and glucuronidative metabolism by the kidney. In a set of single-dose experiments, morphine was administered to recirculating perfusion medium to achieve initial concentrations of 0.2, 2 and 20 microM (n = 4 at each concentration). In a set of multiple-dose experiments, morphine was administered to perfusate as sequential bolus doses to achieve concentrations of 0.2, 2, 20 and 200 microM (n = 6). HPLC was used to determine the concentration of morphine in perfusate and urine. Normorphine, morphine-3-glucuronide and morphine-6-glucuronide could not be detected in perfusate or urine, a result that suggests an absence of oxidative and glucuronidative metabolism of morphine by the rat kidney. The volume of distribution of morphine within the kidney was high (31 +/- 3 ml/g at 0.2 microM), which indicates extensive accumulation, and remained constant with increasing perfusate concentration. The ratio of unbound renal excretory clearance to glomerular filtration rate was always greater than unity for all kidneys, which indicates that the renal excretion of morphine involves net tubular secretion. This ratio was constant (P > .05) over the 100-fold concentration range of the single-dose study. In the multiple-dose study, the ratio was marginally but significantly (P < .05) higher at concentrations of 2, 20 and 200 microM than at 0.2 microM, a difference that cannot be explained by saturation of tubular secretion. The results suggest that the tubular secretion of morphine is not saturated over a wide range of concentrations (0.2-200 microM).     

Determination of common drugs of abuse in body fluids using one isolation procedure and liquid chromatography--atmospheric-pressure chemical-ionization mass spectromery

A method for determining opiate agonists (morphine, morphine-3-glucuronide, morphine-6-glucuronide, 6-monoacetylmorphine, codeine, codeine-6-glucuronide, dihydrocodeine, dihydromorphine, buprenorphine, methadone, tramadol, and ibogaine), cocaine and its metabolites (benzoylecgonine and ecgonine methyl ester) and lysergic acid diethylamide in serum, blood, urine and other biological matrices is presented. Aliquots (0.5-1.5 mL) of biological fluids were spiked with appropriate deuterated internal standards and extracted using a common solid-phase extraction method (C18 cartridges). The extracts were subjected to liquid chromatographic-atmospheric-pressure chemical-ionization mass spectrometric examination using selected ion monitoring procedures. These procedures were developed after analysis of full-scan mass spectra of examined compounds. The extraction method appeared very universal; the recoveries were high for almost all drugs and the extracts were very clean. The procedure was applied for routine forensic casework.     

Identification and cloning of human mitochondrial translational release factor 1 and the ribosome recycling factor

The analysis of morphine in biological fluids is of vital interest in monitoring opiate abuse and in drug abuse research. Although methods for analysis of morphine and its metabolites are well established, studies are still being carried out to improve sample preparation procedures as well as detection levels of morphine in biological samples. In this study, morphine-specific immunosorbents were developed to concentrate morphine prior to HPLC analysis. Urine (0.1 ml) was diluted 10-fold with phosphate-buffered saline, pH 7.4 (PBS), loaded onto a solid-phase immunoextraction column and washed with 15 ml PBS followed by elution with 2 ml of elution buffer (40% ethanol in PBS, pH 4). The eluted fraction was analysed for morphine by HPLC-electrochemical detection using a cyanopropyl (CN) analytical column with 25% acetonitrile in phosphate buffer-sodium lauryl sulphate, pH 2.4 as the mobile phase. Duration of the extraction procedure was approximately 40 min. Calibration graphs were linear from 100 ng ml-1 to 500 ng ml-1 in urine. The inter-assay R.S.D. was < 10% and the recovery of morphine from urine was > 98%. Immunocolumns demonstrated remarkably high specificity towards morphine showing minimal binding with other opiate metabolites such as codeine, normorphine, norcodeine, morphine-3-glucuronide, morphine-6-glucuronide.     

Concentrations of morphine and morphine metabolites in CSF and plasma during continuous subcutaneous morphine administration in cancer pain patients

Plasma and cerebrospinal fluid (CSF) steady-state concentrations (Css) of morphine (M) and the main metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), were determined by high performance liquid chromatography (HPLC) in 21 cancer patients treated with chronic subcutaneous morphine infusion. There was a moderate, but statistically significant correlation between the daily dose of morphine and the concentrations of morphine, M3G and M6G in CSF. A poorer correlation to concentrations were seen in plasma. The mean +/- SEM CSF/plasma morphine concentration ratio was 0.36 +/- 0.07. In plasma and CSF, the mean steady state concentration of M3G but not M6G substantially exceeded that of morphine where the mean CSF M/M3G/M6G ratio was 1:15:0.5 (molar basis), and the mean plasma ratio was M/M3G/M6G 1:31:3 (molar basis). The mean M3G and M6G concentrations in CSF were approximately 8 and 10% of those found in plasma, but there was a wide interindividual variation. Plasma concentrations of both morphine glucuronides were positively correlated to serum creatinine. Neither pain intensity, evaluated by visual analogue scale (VAS), nor side effects showed any relationship to the CSF M3G concentrations, M3G/M or the M3G/M6G ratios. We conclude that during steady state subcutaneous administration of morphine, there is a large interindividual variation in plasma morphine with poor relationship to the daily administered dose. In CSF this correlation was more evident. Plasma and CSF concentrations of M3G and CSF concentrations of M6G correlated with administered morphine dose. There was an accumulation of both morphine glucuronides in patients with elevated serum creatinine. Measurements of morphine, M3G and M6G in CSF did not show any overt relationship to analgesia or side effects.     

Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects

OBJECTIVE: Codeine O-demethylation to morphine is catalysed by the genetic polymorphic sparteine oxygenase (CYP2D6). The objective of the present study was to assess the analgesic effect of codeine on different types of experimental pain in relation to sparteine phenotype. METHODS: Fourteen extensive (EMs) and 14 poor metabolizers (PMs) of sparteine completed a randomized, double-blind, three-way, cross-over study with a single oral dose of codeine (75 or 100 mg) against morphine (20 or 30 mg) and placebo. Pain tests performed before and 1, 2, 3, and 4 h after medication included the cold pressor test and pain thresholds for heat and pressure stimulation. Adverse effects were rated by a structured interview. RESULTS: After morphine, morphine and morphine-6-glucuronide were present in equal amounts in plasma of PMs and EMs. After codeine, neither morphine nor morphine-6-glucuronide could be detected in 13 of the 14 PMs, whereas at least one of the compounds could be detected in all EMs. Peak pain and discomfort rated on a VAS scale during the cold pressor test were significantly reduced by morphine in both EMs and PMs, with a median peak change of 8.5 and 7.0 mm, respectively, for peak pain, and 11.5 and 15.5 mm, respectively, for discomfort. Codeine only reduced these pain measures significantly in EMs, with a median peak change of 5.5 mm for peak pain and 10.5 mm for discomfort. Pain detection and tolerance thresholds to heat and pressure were not consistently altered by either morphine or codeine. In PMs, adverse effects were significantly more pronounced on morphine than on codeine and only showed a slight difference between codeine and placebo. In EMs, there was no difference between codeine and morphine and more pronounced adverse effects on both drugs as compared to placebo. CONCLUSION: This study confirms that codeine O-demethylation depends on CYP2D6; it shows that the 6-glucuronidation of morphine is independent of CYP2D6; it supports the theory that the analgesic effect of codeine depends on its O-demethylation; and it indicates that this is probably also the case for the adverse effects. The results lend no support to the suggestion of a non-opioid analgesic effect of codeine.     

Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar, India, justify its continued use as a first-line drug? An observational study of 80 cases

The results of recent investigations of the analgesic and the nonanalgesic effects of opioid glucuronides are relevant to the research on drug abuse in forensic toxicology. As has been shown for heroin, knowledge of the state of distribution and elimination of active and inactive metabolites and glucuronides offers new possibilities in forensic interpretation of analytic results. Because of similar metabolic degradation, calculation of the time-dependent ratio of the concentration of morphine and its glucuronide metabolites in blood or serum allows a rough estimation of increased dosage and of time elapsed since the last application. Drug effects can be examined with respect to individual case histories, including overdose and survival time if the patient died. However, different methods of administration and the strong influence of different volumes or compartments of distribution of parent compounds and metabolites on concentrations in human body tissues require careful use of glucuronide concentration data. In Germany, dihydrocodeine (DHC) is prescribed as a heroin substitute, and relative overdoses are needed to be effective. DHC metabolism was studied in three patients who died from overdoses. All metabolites (dihydrocodeine-6-glucuronide [DHC6], nor-DHC [NDHC], dihydromorphine [DHM], nor-DHM [NDHM], and DHM-3- and 6-glucuronide [DHM3G, DHM6G]) were determined using HPLC and fluorescence detection. Concentrations of DHM (0.16 mg/L to 0.22 mg/L serum) were found. The DHM glucuronide ratios were similar to those of morphine. Receptor binding studies showed that the binding affinity of DHM to porcine mu-receptor was higher than that of morphine, and DHM6G's binding affinity was as high as that of morphine-6-glucuronide (M6G). Metabolites may play an important role in the effectiveness of DHC in substitution and toxicity. Because of enzyme polymorphism, the formation of DHC poses a risk for proper dosage in patients who are either poor or extensive metabolizers. The distribution of opioid glucuronides in cerebral spinal fluid in relation to transcellular transport in central nervous tissue is discussed with respect to the receptor binding of opiates and drug effect.     

A study of reversibly inactivated lipases for use in a morphine-triggered naltrexone delivery system

A key component of an implant that can be triggered by external morphine to release naltrexone is an inactivated enzyme that can be activated by morphine and which can then rapidly remove a protective coating surrounding a bioerodible polymer containing dispersed naltrexone. In this article we describe a lipase that has been conjugated with O3-carboxymethylmorphine, morphine-beta-3-glucuronide and O3-carboxypropylmorphine. The enzyme conjugate was then inactivated by complexation with affinity-purified goat polyclonal antimorphine antibodies. Antibody lipase interactions were measured by pH Stat and ELISA techniques. Affinity constants of the antibodies determined by radioimmunoassay using tritium-labeled morphine were 4.10 x 10(6), 3.18 x 10(6) and 3.38 x 10(7), respectively. While a concentration of 10(-5)M morphine was required to restore lipase activity, it is likely that a combination of correct morphine tether and correct affinity-purified antibody can increase sensitivity to the desired 10(-8)10(-9)M morphine level. Thus, a functioning device can almost certainly be constructed. However, it is unlikely that reactivation times of 1-2 h necessary for clinical usefulness in treatment of narcotic addiction can be achieved.     

Delayed antinociceptive effect following morphine-6-glucuronide administration in the rat--pharmacokinetic/pharmacodynamic modelling

This study was conducted with the aim of characterising the pharmacokinetics and pharmacodynamics of morphine-6-glucuronide (M6G), a morphine metabolite possessing agonist properties. M6G was administered to three groups of rats as either a bolus dose, a 2 h computer-controlled stepwise infusion or as two consecutive 30-min infusions given 3 h apart. Clearance and initial volume of distribution were estimated to be 27 ml/min/kg for clearance and 339 ml/kg for initial volume. Morphine could not be detected until 4 h after dosing. The antinociceptive response profile, measured using the electrical stimulation vocalisation method, showed a pronounced delay in relation to the plasma concentration profile. The peak concentrations of 12,000 ng/ml, 6270 ng/ml and 12,800 ng/ml in the bolus, the stepwise infusion and the two consecutive infusion groups gave corresponding maximal antinociceptive effects of 49%, 181% and 168%. A pharmacokinetic-pharmacodynamic model was applied to the data and the effect delay was estimated to be 1.4 h, which is considerably longer compared to morphine (0.5 h). Acute tolerance to the antinociceptive response was observed but could not be quantified due to the slowly ascending effect. Based on these results, the importance of study design for potency determination of drugs exhibiting different effect equilibration times was elucidated. Significant increases in the pCO2 levels were observed following the stepwise infusion and the two consecutive infusions. When compared to morphine, there was a tendency of a less pronounced effect on respiration by M6G.     

Role of basic fibroblast growth factor in the regulation of rat basilar artery tone in vivo

An antisense oligodeoxynucleotide directed against the 5'-untranslated region of MOR-1 blocks the analgesic actions of the mu 1 analgesics morphine and [D-Ala2,D-Leu5]enkephalin (DADL) when they are microinjected into the periaqueductal gray. In contrast, morphine-6 beta-glucuronide (M6G) analgesia is unaffected by this treatment. Antisense oligodeoxynucleotides directed against distinct Gi alpha subunits also distinguish between morphine and M6G analgesia. A probe targeting Gi alpha 2 blocks morphine analgesia, as previously reported, but is inactive against M6G analgesia. Conversely, an antisense oligodeoxynucleotide against Gi alpha 1 inhibits M6G analgesia without affecting morphine analgesia. The antisense oligodeoxynucleotide directed against G(o)alpha is ineffective against both compounds. These results confirm the prior association of Gi alpha 2 with morphine analgesia and strongly suggests that M6G acts through a different opioid receptor, as revealed by its insensitivity towards the MOR-1 antisense probe and differential sensitivity towards G-protein alpha subunit antisense oligodeoxynucleotides.     

A single brain stem substrate mediates the motivational effects of both opiates and food in nondeprived rats but not in deprived rats.

Drug-naive and morphine-dependent rats both preferred places paired with morphine over unfamiliar neutral places. Morphine-dependent, but not naive, rats avoided places paired with the lack of morphine (i.e., withdrawal). Food-sated and food-deprived rats both preferred places paired with food over unfamiliar neutral places. Food-deprived, but not sated, rats avoided places paired with the lack of food (i.e., hunger). Lesions of the tegmental pedunculopontine nucleus (TPP) blocked the morphine- and food-conditioned place preferences in drug-naive and food-sated rats, respectively. TPP lesions failed to block morphine- and food-conditioned place preferences as well as morphine withdrawal-conditioned and hunger-conditioned place aversions in morphine-dependent and food-deprived rats, respectively. These results suggest that separate neural mechanisms subserve deprivation- and non-deprivation-induced motivation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Morphine-3-glucuronide (M3G) potentiates noxious stimulus-evoked Fos protein-like immunoreactivity in the rat spinal cord

The effect of morphine-3-glucuronide (M3G) on noxious stimulus-evoked Fos protein-like immunoreactivity in the rat spinal cord were assessed by ABC method. It was found that a dose-dependent increase of Fos-like immunoreactive neurons could be induced by M3G intrathecal injection followed by formaline injection into hindpaw. With high dosage M3G (1.1 x 10(-7) mole), dense Fos-like labelling was found in the superficial and the deep dorsal horn bilaterally, While with low dosage M3G (5.4 x 10(-8) and 1.1 x 10(-8) mole), most of the positively labelled neurons were only found in laminae I and II of the ipsilateral dorsal horn to the injured paw. The above results revealed that M3G exerts a potentiating effect on the noxious stimulus-evoked Fos protein-like immunoreactivity in the rat spinal cord.