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PubMed1975

Saturable binding of dihydromorphine and naloxone to rat brain tissue in vitro.

The binding in vitro of an opiate agonist, 3H-dihydromorphine, was studied using a particulate fraction obtained from rat brain homogenates and compared with that of an opiate antagonist, 3H-naloxone. The binding of 3H-dihydromorphine may be separated into two components: one a saturable component and the other nonsaturable. The saturable binding may be calculated from the differences in binding observed in the absence and presence of high concentrations of levorphanol. The use of dextrorphan results in an artifactual separation of this component, although relative stereospecificity was observed for levorphanol and dextrorphan. There were marked regional differences in the distribution of saturable 3H-dihydromorphine binding in the brain. These were primarily due to the difference in the concentration of the saturable binding sites within various brain regions. It appeared that the saturable binding sites from various brain regions had similar affinities for dihydromorphine except for the binding site from cerebral cortex which had a higher affinity. In contrast, saturable binding sites for naloxone in various brain regions had different affinities for naloxone. It appears that naloxone has at least two types of saturable binding sites, one of which is not available to dihydromorphine. This is based on observations 1) that the total concentration of saturable binding sites for naloxone was greater than that for dihydromorphine in each brain region studied irrespective of the assay medium used and 2) that unlabeled dihydromorphine inhibited the 3H-naloxone binding in striatum but failed to alter it significantly in cerebellum, whereas unlabeled naloxone reduced 3H-naloxone binding significantly in both brain regions. The difference in concentrations of saturable binding sites for naloxone and dihydromorphine was relatively small in striatum but larger in cerebellum, indicating that the saturable binding sites in cerebellum are predominantly naloxone-specific, whereas those in striatum are capable of binding both naloxone and dihydromorphine. In cerebrospinal fluid or in simulated intracellular fluid, the apparent affinity for dihydromorphine was lower and that for naloxone was higher than in Tris-HCl buffer. It is concluded that naloxone binds to dihydromorphine binding site and to another site, which has a different affinity for naloxone and is not available to dihydromorphine. Studies in which opiate receptor binding was assayed in Tris-HCl buffer may need to be re-evaluated. Further, in studies where opiate binding in vitro is assessed following pharmacologic intervention, such binding should be estimated in a relevant physiological medium rather than in Tris-HCl buffer.

Animals↗

PubMed2004

Pharmacological characterization of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin analgesia and their differentiation from morphine.

The present study examined the pharmacology of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin (3,6-diacetyldihydromorphine). Like morphine, dihydromorphine and its acetylated derivatives all were highly selective mu-opioids in receptor binding assays. All the compounds were potent mu-selective analgesics, as shown by their sensitivity towards the mu-selective opioid receptor antagonists naloxonazine and beta-funaltrexamine. However, the actions of dihydromorphine and its analogs were readily distinguished from those of morphine, differences that were surprising in view of the very limited structural differences among them that consisted of only the reduction of the 7,8-double bond. Like heroin and morphine-6beta-glucuronide, the analgesic actions of dihydromorphine and its two acetylated derivatives were antagonized by 3-O-methylnaltrexone at a dose that was inactive against morphine analgesia. Antisense mapping also distinguished between morphine and the dihydromorphine compounds. Antisense oligodeoxynucleotides targeting exon 2 of the cloned MOR-1 gene decreased dihydromorphine analgesia and that of its acetylated derivatives, but not morphine analgesia. Conversely, the exon 1 antisense that effectively lowered morphine analgesia was inactive against dihydromorphine and its analogs. Finally, dihydromorphine and its analogs retained their analgesic activity in a mouse model of morphine tolerance, consistent with incomplete cross-tolerance. Together, these findings imply that the mu-opioid receptor mechanisms mediating the analgesic actions of dihydromorphine and its acetylated analogs are distinct from morphine and more similar to those of heroin and morphine-6beta-glucuronide.

Analgesics, Opioid↗

PubMed1998

The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolizers.

AIMS: Dihydrocodeine is metabolized to dihydromorphine via the isoenzyme cytochrome P450 2D6, whose activity is determined by genetic polymorphism. The importance of the dihydromorphine metabolites for analgesia in poor metabolizers is unclear. The aim of this study was to assess the importance of the dihydromorphine metabolites of dihydrocodeine in analgesia by investigating the effects of dihydrocodeine on somatic and visceral pain thresholds in extensive and quinidine-induced poor metabolizers. METHODS: Eleven healthy subjects participated in a double-blind, randomized, placebo-controlled, four-way cross-over study comparing the effects of single doses of placebo and slow-release dihydrocodeine 60 mg with and without premedication with quinidine sulphate 50 mg on electrical, heat and rectal distension pain tolerance thresholds. Plasma concentrations and urinary excretion of dihydrocodeine and dihydromorphine were measured. RESULTS: In quinidine-induced poor metabolizers the plasma concentrations of dihydromorphine were reduced between 3 and 4 fold from 1.5 h to 13.5 h after dosing (P < 0.005) and urinary excretion of dihydromorphine in the first 12 h was decreased from 0.91% to 0.28% of the dihydrocodeine dose (P < 0.001). Dihydrocodeine significantly raised the heat pain tolerance thresholds (at 3.3 h and 5 h postdosing, P < 0.05) and the rectal distension defaecatory urge (at 3.3 h and 10 h postdosing, P < 0.02) and pain tolerance thresholds (at 3.3 h and 5 h postdosing, P < 0.05) compared with placebo. Premedication with quinidine did not change the effects of dihydrocodeine on pain thresholds, but decreased the effect of dihydrocodeine on defaecatory urge thresholds (at 1.5 h, 3.3 h and 10 h postdosing, P < 0.05). CONCLUSIONS: In quinidine-induced poor metabolizers significant reduction in dihydromorphine metabolite production did not result in diminished analgesic effects of a single dose of dihydrocodeine. The metabolism of dihydrocodeine to dihydromorphine may therefore not be of clinical importance for analgesia. This conclusion must however, be confirmed with repeated dosing in patients with pain.

Adult↗

PubMed1997

Analgesia by dihydrocodeine is not due to formation of dihydromorphine: evidence from nociceptive activity in rat thalamus.

Dihydrocodeine is increasingly used in slow-release preparations for the treatment of chronic pain on step 2 of the "analgesic ladder" of the World Health Organization. Dihydrocodeine is suggested to act after O-demethylation to dihydromorphine. To test this possibility, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from neurons in the ventrobasal complex of the thalamus. Dihydrocodeine administered by intravenous injection reduced the evoked nociceptive activity in a dose-dependent manner. Like morphine, dihydrocodeine was capable of completely suppressing the evoked activity. Maximum depression was caused by 2 mg/kg, and the ED50 is 0.47 mg/kg. Naloxone (0.2 mg/kg) reversed the effect of dihydrocodeine (2 mg/kg). To inhibit O-demethylation of dihydrocodeine to dihydromorphine, metyrapone or cimetidine (50 mg/kg) was injected intraperitoneally 20 min before dihydrocodeine (1 and 2 mg/kg). This failed to markedly reduce the effect of dihydrocodeine. Dihydromorphine injected intravenously also reduced the evoked activity in a dose-dependent way. Maximum depression occurred at a dose of 4 mg/kg, and the ED50 is 0.97 mg/kg. Dihydrocodeine and dihydromorphine were equieffective when administered by intrathecal injection at a dose of 100 microg. It is concluded that dihydrocodeine causes analgesia independent of biotransformation to dihydromorphine.

Analgesics, Opioid↗

PubMed1979

Comparison of binding of [3H]-methionine-enkephalin, [3H]-naltrexone and [3H]-dihydromorphine in the mouse vas deferens and the myenteric plexus and brain of the ginea pig.

[3H]-Methionine-enkephalin, [3H]-naltrexone and [3H]-dihydromorphine are specifically bound in homogenates of not only the brain and myenteric plexus of the guinea pig but also the vas deferens of the mouse. Brain has a ratio of methionine-enkephalin to dihydromorphine binding in favour of methionine-enkephalin binding and the myenteric plexus a ratio in favour of dihydromorphine binding, with the mouse vas deferens being intermediate.

Animals↗

PubMed1982

Stereospecific accumulation of dihydromorphine and naltrexone by corpus striatal slices of morphine-dependent mice.

Stereospecific accumulation of [3H]dihydromorphine and [3H]naltrexone by striatal slices from morphine-dependent mice was examined in Krebs-Ringer bicarbonate medium. Striatal slices showed a saturable and stereospecific accumulation of both [3H]ligands. The accumulation constant of naltrexone, determined by Wilkinson's analysis, was significantly decreased in both morphine-dependent mice and dependent mice abruptly withdrawn for 6 hr. The maximal accumulation of naltrexone was not changed in withdrawn mice, but decreased in dependent mice. This could be due to the high concentration of residual morphine in the slices. There were no significant differences in the accumulation constant or maximal accumulation of dihydromorphine among the striatal slices from control, dependent and withdrawn mice. These data indicate that in morphine-dependent mice, there is an increased affinity of the opioid receptors for the narcotic antagonist, naltrexone but not for the agonist, dihydromorphine.

Animals↗

PubMed1986

Dihydromorphine-peptide hybrids have mu receptor antagonistic and delta receptor agonistic activity on the mouse vas deferens and bind with high affinity to opioid receptors in rat brain.

The actions of three morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated, electrically stimulated mouse vas deferens preparation and upon displacement of specifically bound 3H-etorphine in rat brain membranes. NIH-9834 (N-[6, 14-endoetheno-7, 8-dihydromorphine-7-alpha-carbonyl]-L-phenylalanyl-L-leucinol) and its ethyl ester, NIH-9833, were potent agonists upon the vas deferens. ICI-174864, 100 nM, markedly antagonized the actions of both NIH-9833 and NIH-9834 which indicates that these are delta receptor agonists. NIH-9835 (N-[6, 14-endoetheno-7, 8-dihydromorphine-7-alpha-carbonyl]-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl) differs from NIH-9833 and NIH-9834 by the presence of a single amino acid residue. Although this drug had no agonistic activity on the vas deferens, it was a potent antagonist of mu agonists. All three hybrids were potent displacers of 3H-etorphine in rat cerebral membranes. The observation that addition of a single glycyl residue changes dihydromorphine-peptide analogs from potent delta receptor agonists to equally potent mu receptor antagonists suggests that the two receptor sites might be structurally quite similar.

Animals↗

PubMed1983

Studies on the release by somatic stimulation from rat and cat spinal cord of active materials which displace dihydromorphine in an opiate-binding assay.

Using the spinal superfusion procedure, in anesthetized rats and cats, the presence of active factors which displace dihydromorphine in brain opiate binding studies, has been observed. Separation of this activity on a Sephadex G-10 column reveals the presence of two fractions which occur before (Fraction I) and after (Fraction II) the salt peak which account for over 70% of the observed dihydromorphine-displacing activity. The ratio of activity in Fraction II/Fraction I is 33 and 21, in the resting spinal perfusates of the rat and cat, respectively. High intensity, bilateral stimulation of the sciatic nerve in cats, results in a 30- and 5.4-fold increase in the levels of Fraction I and Fraction II, respectively, over pre-stimulation levels. In rat, bilateral stimulation of the hind paws, resulted in a frequency-dependent increase in the levels of Fraction I (1.9- and 3.2-fold at 5 and 50 Hz, respectively). Dynorphin 1-13 fragment elutes at least partly in Fraction I. With regard to Fraction II, the peak co-chromatographs with hexapeptide derivatives of enkephalin. Met- and Leu-enkephalin (Fraction III), elute off the column at a point where opiate receptor displacing activity is relatively small. Electrophoretic separation of Fraction I radioreceptor activity of alkaline and acid pH on agarose columns revealed two principle peaks which co-migrated with alpha-neoendorphin and dynorphin 1-13. Fraction II activity appeared primarily in a single peak which was isographic with enkephalin hexapeptides. Using radioimmunoassays, detectable levels of dynorphin and Met-enkephalin were observed and sciatic nerve stimulation resulted in significant increases. Neither column-coupled radioreceptor assays nor radioimmunoassays revealed the presence of beta-endorphin. The present experiments demonstrate the releasability by high intensity somatic stimulation of a variety of opioid peptides present in spinal terminals. Significantly, however, the majority of this activity appears to be found in fractions different from those of the pentapeptide enkephalins.

Animals↗

PubMed1989

Effects of cervical spinal hemisection on dihydromorphine binding in brainstem and spinal cord in cat.

Cats were sacrificed 1-3 weeks after cervical (C1-C2) hemisection and receptor binding experiments were carried out with 4.0 and 0.6 nM concentrations of [3H]dihydromorphine [( 3H]DHM); these concentrations were shown by Scatchard analysis to represent the approximate Kd values of high and low affinity dihydromorphine binding sites in brain homogenates. Unilateral cervical hemisection produced significant (P less than 0.05), bilateral, reductions in the levels of [3H]DHM binding in the periaqueductal gray (PAG; 35-40%) and mesencephalic reticular formation (MRF; 47-51%), medial pons (40-56%) and medial medulla (30-37%). In paramedial pons and medulla, numerical reductions in [3H]DHM binding were observed (18 and 28%) which did not achieve statistical significance. In spinal cord, significant reductions were observed in the dorsal (45%) and ventral (29%) ipsilateral but not contralateral quadrants. We believe that these results in the brainstem and spinal cord reflect in part the loss of opiate binding on spinobulbar terminals and bulbospinal terminals, respectively, following orthograde degeneration. These observations support the hypothesis that the analgetic effects of opiates in the brainstem may in part be mediated by the direct inhibition of transmission through spinobulbar terminals.

Animals↗

PubMed1995

Simultaneous determination of dihydrocodeine and dihydromorphine in serum by gas chromatography-tandem mass spectrometry.

A sensitive and specific method was developed for the determination of dihydrocodeine and its metabolite dihydromorphine in human serum using codeine and morphine as internal standards. Measurement is performed with GC-tandem MS after one simple extraction step and derivatization to the pentafluoropropionic esters. Sensitivity of the method is excellent and allows for the reproducible quantification of dihydrocodeine and dihydromorphine with limits of quantification of 2 ng/ml and 40 pg/ml serum, respectively. The method is therefore well suited for investigation of the pharmacokinetics and the metabolism of dihydrocodeine.

Codeine↗

PubMed1997

Determination of the dihydrocodeine metabolites, dihydromorphine and nordihydrocodeine, in hepatic microsomal incubations by high-performance liquid chromatography.

A high-performance liquid chromatographic assay for the oxidative metabolites of dihydrocodeine, nordihydrocodeine and dihydromorphine, formed in human liver microsomal incubations, is described. A simple solvent extraction followed by reversed-phase high-performance liquid chromatography with UV detection allows quantification of both metabolites in a single assay. Standard curve concentration ranges for dihydromorphine and nordihydrocodeine were 0.05-5 and 0.2-20 microM, respectively. Assay performance was assessed by intra- and inter-day accuracy and precision of quality control (QC) samples. The difference between the calculated and the actual concentration and the relative standard deviation were less than 15% at low QC concentrations and less than 10% at medium and high QC concentrations for both analytes. The method provides good precision, accuracy and sensitivity for use in kinetic studies of the oxidative metabolism of dihydrocodeine in human liver microsomes.

Analgesics, Opioid↗

PubMed1981

Alterations in dihydromorphine binding in cerebral hemispheres of aged male rats.

Equilibrium binding of [3H]dihydromorphine was assayed in brain regions of young and aged male F344 rats. Young rats had significantly higher receptor densities than old rats in the frontal poles, anterior cortex, and striatum. In the frontal poles, the decline in receptor concentration with age was accompanied by a significant increase in the apparent affinity of dihydromorphine for receptors, which may be compensatory for the decrease in Bmax. This pattern of receptor alterations is different than that previously observed in aged female rats. Therefore, processes which underlie synaptic alterations with age may be different in males and females.

Aging↗

PubMed1991

Testosterone and postnatal ontogenesis of hypothalamic mu ([3H]dihydromorphine) opioid receptors in the rat.

Brain opioids modulate the activity of the hypothalamo-pituitary complex by binding to specific receptors which have been subdivided at least into 3 subclasses (mu, kappa, delta, etc). mu-Receptors and their ligands seem to be particularly involved in the control of gonadotropin and prolactin release. It is known that the neuroendocrine system, as well as the brain opioid systems and their receptors, are not fully mature at birth; it is also known that the postnatal maturation of many brain machineries is under the control of androgens secreted by the developing testes. Consequently, it has been investigated whether the presence or the absence of testosterone at time of birth may induce changes of the binding characteristics of hypothalamic mu-opioid receptors. The experiments have been performed by evaluating the maximal binding capacity (Bmax, an index of the number of receptors), and the affinity constant (Ka) of the specific mu-ligand dihydromorphine in hypothalamic plasma membrane preparations derived from normal male rats, normal female rats, male rats orchidectomized 2 days after birth and female rats treated 2 days after birth with 1.25 mg of testosterone propionate. Animals belonging to the 4 groups were killed at days 16, 26 and 60 of age. The results obtained show that, at 16 days of age, in the 4 groups of rats the number of hypothalamic mu receptors is identical. At 26 days a significant increase in the number of mu-receptors occurs in normal female animals, while their levels remain similar to those found at 16 days in the other 3 groups of animals. At 60 days of age, the number of mu-receptors in normal females remains elevated, while the number of mu-receptors increases to reach normal female levels in the hypothalamus of neonatally castrated males. At 60 days, there were no changes in normal males or in androgenized females. The variations here reported took place without any change of the Ka of dihydromorphine for the mu-receptors. These data show a sexual dimorphism of hypothalamic mu-receptors and suggest that their ontogenetic development may be linked to the presence or the absence of androgens at time of birth.

Animals↗

PubMed1975

Iodination of morphine and dihydromorphine, as related to radioimmunoassay.

Direct iodination of morphine or dihydromorphine with iodine-125 results in products that bind to antibody raised by immunization of animals with a 3-O-carboxymethylmorphine/bovine serum albumin immunogen. Iodination of morphine or dihydromorphine with iodine-127 under identical conditions failed to yield these immunologically active products, suggesting that the results obtained with iodine-125 are in part due to a radiolytic reaction not observed with the iodine-127.

Humans↗

PubMed1986

Effects of the affinity ligands 14-beta-chloroacetylnaltrexone and 14-beta-bromoacetamidomorphine on [3H]-dihydromorphine binding sites in rat brain.

The aim of the present study was to examine the inhibitory effects in vitro of the affinity ligands 14-beta-chloroacetylnaltrexone (CAN) and 14-beta-bromoacetamidomorphine (BAM) to characterize the pharmacological specificity of the ligands for high and low affinity opioid binding sites. Rat brain membranes were incubated with 2.0 microM BAM or CAN, or their parent compounds (morphine and naltrexone, respectively) at 37 degrees for 45 min, and the membranes were washed extensively to remove the unbound ligand. The specific binding of 0.3 nM [3H]dihydromorphine ([3H]DHM) was reduced 32 +/- 7% in membranes treated with CAN and BAM, whereas specific binding in preparations treated with morphine and naltrexone was not significantly different from controls. An increased affinity of BAM and CAN relative to morphine and naltrexone could not account for the observed irreversible inhibition, since the relative affinity of CAN was similar to that of naltrexone and that of BAM was 10-fold less active than morphine. Saturation binding assays revealed that the affinity ligands selectively abolished a high affinity binding site (Kd = 0.3 nM, Bmax 95 fmoles/mg protein), which comprised approximately one-third of the total number of sites. The affinity of the remaining site (Kd = 4.0 nM) was not altered significantly. The results indicate that the inhibition caused by the affinity ligands is irreversible and represents inactivation of high affinity opioid binding sites in a relatively selective manner.

Animals↗

PubMed1980

Localization of naloxone-sensitive [3H]dihydromorphine binding sites within the hippocampus of the rat.

In vitro radioautographic experiments were performed on coronal rat brain slices to determine the precise localization of [3H]dihydromorphine binding sites sensitive to naloxone, within the hippocampus. Binding was observed in all cell fields and in dentate gyrus (DG) in the order CA2 greater than CA1 greater than CA3 greater than DG. Within each cell field the density of receptors was greatest in the stratum pyramidale, which in field CA2 was 77% as dense as the striatum. The existence of a dense population of opiate binding sites within the hippocampus is consistent with the view that this structure is involved in opiate actions.

Animals↗

PubMed1983

Morphine tolerance is associated with elevated levels of an uncharacterized endorphin (peak B) in mouse brain with no change in 3H-dihydromorphine binding.

A partially characterized mouse brain endorphin was shown to be elevated (p 0.01 U-Test) in ICR strain mice that had been made tolerant but not dependent upon morphine (5 mg/kg sc., given for 32 days). The animals were tolerant to the antinociceptive effect of morphine as judged by the tail immersion assay (48 degrees C) but showed no detectable dependence or withdrawal syndrome effects following the administration of naloxone (writhing, jumping, diarrhea or hypermotility) on day 33. No significant changes were seen in any other mouse brain endorphins (p 0.05 U-Test). Also there was no apparent change in the number of binding properties of 3H-dihydromorphine (3H-DHM) receptors (mu-receptors) in chronic morphine (CM) treated, as compared with chronic saline (CS) treated animals.

Animals↗

PubMed1996

Characterization of the genetic polymorphism of dihydrocodeine O-demethylation in man via analysis of urinary dihydrocodeine and dihydromorphine by micellar electrokinetic capillary chromatography.

The genetic polymorphism of dihydrocodeine O-demethylation in man via analysis of urinary dihydrocodeine (DHC) and dihydromorphine (DHM) by micellar electrokinetic capillary chromatography is described. Ten healthy subjects which are known to be extensive metabolizers for debrisoquine ingested 60 mg of DHC and collected their 0-12 h urines. In these samples, about 1% of the administered DHC equivalents are shown to be excreted as DHM. Premedication of 50 mg quinidine sulfate to the same subjects is demonstrated to significantly reduce (3-4 fold) the amount of O-demethylation of DHC, a metabolic step which is thereby demonstrated to co-segregate with the hydroxylation of debrisoquine. Thus, in analogy to codeine and other substrates, extensive and poor metabolizer phenotypes for DHC can be distinguished. Using the urinary DHC/DHM metabolic ratio to characterize the extent of O-demethylation, the metabolic ratio ranges of extensive and poor metabolizers in a frequency histogram are shown to partially overlap. Thus, classification of borderline values is not unequivocal and DHC should therefore not be employed for routine pharmacogenetic screening purposes. Nevertheless, the method is valuable for metabolic research and preliminary data demonstrate that the same assay could also be used to explore the metabolism of codeine.

Codeine↗