Morphine-6-glucuronide, a potent mu agonist

The 3- and the 6-glucuronides of morphine have been examined in binding studies and in vivo. The 3-glucuronide had poor affinity in all binding studies whereas the 6-glucuronide potently labeled mu, but not delta or kappa receptors with affinities similar to morphine. Microinjections of the 3-glucuronide directly into the periaqueductal gray were without effect. The 6-glucuronide, on the other hand, was up to 20-fold more potent than morphine following microinjections in the same region. High doses of the 6-glucuronide produced profound seizure activity. All 6-glucuronide actions were sensitive to the opiate antagonist naloxone.     

Potentiation of morphine analgesia by BQ123, an endothelin antagonist

Several neurotransmitter mechanisms have been proposed to play a role in the actions of morphine. The present study is the first to provide evidence that central endothelin (ET) mechanisms are involved in the modulation of pharmacological actions of morphine. The effect of intracerebroventricular (i.c.v.) administration of endothelin-A (ET(A)) antagonist, BQ123, on morphine-induced analgesia, hyperthermia, and catalepsy was determined in the rat. Morphine produced a significant increase in tail-flick latency as compared to control group. Pretreatment with BQ123 significantly potentiated the effect and duration of morphine (2 and 8 mg/kg, s.c.)-induced analgesia as compared to vehicle-pretreated control rats. The hyperthermic effect of morphine was not only significantly greater in BQ123-pretreated rats but also lasted for more than 6 h. ET antagonist, BQ123, did not affect the pharmacological effect of morphine on cataleptic behavior. These studies demonstrate that BQ123, a specific ET(A) receptor antagonist, significantly potentiated morphine-induced analgesia and hyperthermia in rats without affecting morphine-induced cataleptic behavior. [(3)H]-Naloxone binding was carried out to determine the possibility of BQ123 acting on opiate receptors. It was found that morphine could displace [(3)H]-naloxone but BQ123 did not affect [(3)H]-naloxone binding even at 1,000 nM concentration. Therefore, it can be concluded that BQ123 does not act on opioid receptors. This is the first report suggesting that an ET(A) antagonist, BQ123, significantly potentiates the analgesic effect of morphine, possibly through a nonopioid mechanism.     

Identification of a potent and nonpeptidyl ccr3 antagonist

CCR3 is expressed in a variety of leukocyte subsets, especially eosinophils, and may be involved in allergic disorders such as atopic asthma. To clarify the pathophysiological roles of CCR3 in allergic disorders, we developed a nonpeptidyl CCR3 antagonist. This antagonist, which is referred to as "Compound X," that inhibited the binding of [(125)I]Eotaxin to CHO cells transfected with human CCR3 with an IC(50) value of 2.3 nM. In human eosinophils, Compound X also inhibited Eotaxin-induced increases in intracellular Ca(2+) concentrations and chemotaxis. Thus, Compound X appears to be a highly potent CCR3 antagonist. These findings suggest that Compound X may be a useful tool for elucidating the pathophysiological roles of CCR3 in a variety of allergic disorders.     

Pinacidil potentiates morphine analgesia.

The opening of K+ channels in the membrane of target neurons is a key mechanism of the effect of opioids. Here we show that the K+ channel opener, pinacidil, i.c.v. injected at doses of 50, 100 or 150 micrograms/rat, significantly increases and prolongs the effect of morphine on the thermal pain threshold (hot-plate and tail-flick tests). These data may suggest a novel approach to the management of pain.     

3-Phenyl-5-isothiazole carboxamides with potent mGluR1 antagonist activity

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.     

Pyrrolidino-tetrahydroisoquinolines as potent dual H3 antagonist and serotonin transporter inhibitors

A series of novel and potent pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. A highly regio- and diastereoselective synthesis of the pyrrolidino-tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH(3) was developed. In vitro and in vivo data are discussed.     

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.     

GABA in morphine analgesia and tolerance

Drugs affecting various steps of GABA transmission exhibit analgesia in a variety of experimental models in animals; this analgesic response generally requires high doses of the drugs and does not appear to be opiate-like since the GABAergic analgesia is naloxone-insensitive and lacks dependence liability. The outcome of the analgesia response is variable when opiate and GABAergic drugs are administered together; however, directly acting GABA receptor stimulants and GABA-transaminase inhibitors generally enhance the analgesic effect of opiates. The development of newer GABAergic drugs with greater potency and specificity may offer an alternative to opiate analgesics. The results obtained over the years, on the possible involvement of the GABA system in morphine tolerance and dependence are equivocal. Studies on region-specific changes in opiate-GABA interaction as well as opiate-GABA-benzodiazepine interaction are needed to further elucidate the role of GABA on opiate system.     

THIP analgesia: cross tolerance with morphine

THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridone-3-ol), a direct acting GABA receptor agonist, has been shown to have antinociceptive properties. To determine whether tolerance develops to the analgesic response, mice received multiple injections of THIP for up to 21 days after which analgesia was tested using both tail immersion and hot-plate methods. Both tests indicated a significant reduction in the antinociceptive response to THIP, as well as other GABA agonists, beginning between days 3 and 5 of chronic administration. Moreover, these animals demonstrated a decreased analgesic response to morphine, and morphine tolerant animals were also less responsive to THIP. These data indicate that opiates and GABA agonists induce analgesia by acting through separate but related pathways in the central nervous system.     

ODC-polyamine system is involved in morphine analgesia

alpha-Difluoromethylornithine (DFMO) directly infused into a brain-lateral ventricle (12.5, 25 and 50 micrograms/rat) dose- and time-dependently inhibited brain ODC activity. While having no influence per se on pain threshold, DFMO significantly inhibited the analgesic activity of morphine (15 mg/kg i.p.), this effect being obtained when brain ODC activity was reduced by at least 80%. On the other hand, DFMO had no influence on number and affinity of brain opiate binding sites. Morphine per se neither modified whole brain ODC activity nor significantly affected the ODC inhibitory effect of DFMO. In more discrete brain areas (midbrain, brainstem) morphine actually increased ODC activity. The present results indicate that brain ODC/polyamines system may play a role in the analgesic activity of opioids, probably at a post-receptorial level or through a non-opiate receptor-linked mechanism.     

Bovine endozepine potentiates morphine analgesia in mice

This paper describes the influence of bovine endozepine (BEP) on the analgesic effect of morphine. The intraventricular administration of BEP between doses of 2-4 nmole in mice resulted in the potentiation of the morphine-analgesic effect. The basic pain threshold did not change when BEP was given alone, thus indicating that BEP is unable to elicit analgesic effect alone. Intravenous injection of BEP in the dose range of 5-7.5 mg/kg also potentiated the analgesic effect of morphine. These observations suggest that endozepine can act as a regulator of pain.     

A new highly potent antagonist of bradykinin

We report that the acylation of the N-terminus of [D-Arg0,Hyp3,Thi5,8,D-Phe7]bradykinin, one of the most potent bradykinin antagonists described to date, with 1-adamantane-acetic acid, results in an analogue with more than ten times enhanced potency. The new analogue does not increase the plasma catecholamines, even when administered at doses sufficient to inhibit by more than 90% the vasodepressor response to 250 ng of exogenous bradykinin. This modification suggests new possibilities for the design of even more potent and selective bradykinin antagonists for studying the physiopathology of bradykinin.     

Postoperative analgesia with controlled-release morphine sulphate: comparison with intramuscular morphine.

Fifty patients undergoing hysterectomy or cholecystectomy took part in a trail of postoperative analgesia provided by either intramuscular morphine or controlled-release morphine sulphate tablets orally. Respiratory function and plasma catecholamine concentrations were measured after operation and pain was assessed by using a linear analogue scoring method. Controlled-release morphine sulphate produced comparable pain relief with that of intramuscular morphine, and depression of respiratory function after operation was similar with the two analgesic regimens. The mean total dose of drug per patient given over 48 h to patients undergoing hysterectomy was 115 mg for morphine sulphate and 53 mg for morphine. Patients undergoing cholecystectomy received 130 mg morphine sulphate or 76 mg morphine. There was more sedation after operation in those patients undergoing hysterectomy who received morphine sulphate tablets. Morphine sulphate tablets produced satisfactory postoperative analgesia compared with intramuscular morphine: both regimens were acceptable to the patients.     

DMSO (dimetyl sulfoxide), morphine and analgesia

DMSO was compared to morphine in rats to determine its relative analgesic effects. DMSO produces analgesia that is comparable in magnitude to morphine although its duration (6–7 hrs) is longer than that of morphine (≤ 2 hrs). DMSO apparently produced analgesia both by an action at the site at which it was administered as well as at a site that was remote to the site of administration. The mechanism of action of DMSO is apparently different from that of morphine because naloxone, a specific narcotic antagonist, does not block the analgesic effect of DMSO. However, DMSO has toxic effects such as hematuria (bloody urine). Therefore, the toxicity observed may restrict the clinical usefulness of DMSO as an analgesic drug.     

SR 142801, The first potent non-peptide antagonist of the tachykinin NK3 receptor

SR 142801 is the first potent and selective non-peptide antagonist of the tachykinin NK₃ receptor. It inhibited [MePhe⁷]NKB binding to its receptor from various species, including humans. SR 142801 was a competitive antagonist of [MePhe⁷]NKB-mediated contractions of guinea-pig ileum and inhibited the acetylcholine release following the activation of the guinea-pig ileum tachykinin NK₃ receptor. In vivo, SR 142801 potently inhibited the turning behaviour induced by intrastriatal injection of senktide in gerbils, and appears as a powerful tool for investigation of the physiological and pathological role of NKB and its NK₃ receptor.     

Effect of the new potent LHRH antagonist antide

The ability of the new LHRH antagonist antide to induce a long-term chemical castration in adult male rats and cynomolgus monkeys was investigated. The animals were treated subcutaneously with different doses either once or on 5 consecutive days. The effects on serum concentration of LH (only rat) and testosterone and on the weights of the testes, prostates and seminal vesicles were investigated after different periods of time. Histological evaluation of testes, pituitary and hypothalamus was also performed. In the rat a clear dose-dependent inhibitory effect on the above mentioned parameters was observed whereby long-lasting castration-like effects were achieved at concentrations between 6 (8 weeks) and 15 mg/kg (> 8 weeks). In the cynomolgus monkey a prolonged inhibitory effect was induced only at 15 mg/kg and the duration was only 2–3 weeks. Histologically, no signs indicative of irreversible effects were observed in either species. In conclusion: although species differences became evident in terms of the duration of a long-lasting inhibutory effect on the male reproductive system, antide exhibited such an effect in the rat and the monkey and was able to induce a chemical castration in both species. In addition, using the rat Dunning R 3327 prostatic carcinoma model, 10 mg/kg antide given subcutaneously every 6 weeks for a total period of 26 weeks, had an inhibitory effect on tumor growth identical to that of castration emphasizing the suitability of this compound for treatment of prostatic cancer.     

Delayed onset of single dose tolerance to morphine analgesia

Rats received either 20 mg/Kg of morphine sulfate I.P. or 5 μgm of morphine sulfate microinjected into the periaqueductal gray area of the brain. The analgesic effect of the morphine was determined by comparing pre- and postinjection tailflick latencies. To test for tolerance following a single injection, the procedure was repeated 6, 12 or 24 hours after the first injection and tests. Tolerance was not observed 6 hours after the original injection, tolerance was observed at 12 hours and increased tolerance was present at 24 hours. Single dose tolerance to morphine appears to develop slowly over a period of several hours and during much of this time, the amount of opiate present in the brain was insufficient to produce analgesia. Similarity between central and peripheral administration suggests a central mechanism of single dose tolerance.