Biomedical subjects

P L Tao

Publications and source records attributed to P L Tao.

At least 19 recordsLinked to original sources

PubMed2001

Co-administration of dextromethorphan during pregnancy and throughout lactation significantly decreases the adverse effects associated with chronic morphine administration in rat offspring.

In this study, we have focused our investigation of the facts whether co-administration of a NMDA antagonist dextromethorphan (DM) with morphine during pregnancy and throughout lactation could prevent the adverse effects associated with chronic morphine administration in rat offspring. Adult female Sprague-Dawley rats were randomly separated into four groups and were received subcutaneous injection of either saline, morphine, morphine + dextromethorphan or dextromethorphan twice a day and progressively increased 1 mg/kg at 7-day intervals from a beginning dose of 2 mg/kg for both morphine and dextromethorphan. The rats were mated between days 7 and 8. Administration of drugs was continued during pregnancy. After rat offspring were born, the doses of morphine or dextromethorphan injected into the maternal rats were increased by 1 mg/kg every two weeks till the offspring were 30 day old. The results showed that mortality of morphine group is much higher than control group. The offspring of morphine group weighed significantly less than control group on postnatal day 14 (p14), p30 or p60. The antinociceptive effect of morphine on p14 rats was reduced in the morphine group and indicated the development of morphine tolerance. The hippocampal NMDA receptor densities have been shown decreased on p14 rats. The precipitated withdrawal symptoms were assessed on p7 rats. Rats in morphine group showed greater frequency of abdominal stretch and wet dog shake in 2 hr than control group. On the other hand, co-administration of DM with morphine effectively prevented all these adverse effects of morphine to the offspring rats. DM co-administered with morphine also partially prevented the development of morphine tolerance in maternal rats. If this effect of dextromethorphan is applied to clinical pregnant patients with morphine addiction or chronic pain, it will have a great value for the benefit of their children.

Analgesics, Opioid↗

PubMed2001

Synergistic apoptosis induced by bacterial endotoxin lipopolysaccharide and high glucose in rat microglia.

The present study investigates whether bacterial lipopolysaccharide (LPS) in the presence of increased levels of glucose induced synergistic cytotoxicity in primary cultured microglia. Significant cytotoxicity was only observed while the concentrations of LPS were increased to 10 microg/ml. D-glucose concentration-dependently (25-125 mM) generated cytotoxicity. Synergistic apoptosis of microglia was seen by LPS in the presence of increased levels of D-glucose. This synergistic cytotoxicity was attenuated by the use of superoxide dimutase and catalase, suggesting the involvement of oxidative free radicals. Collectively, the present results suggest that increased ambient levels of glucose rendered microglia vulnerable to LPS insults, and led to a synergistic apoptosis. The findings here may be important in certain patho-physiological implications in which hyperglycemia exacerbated the ambient functions contributed by microglia, and may provide new insight into a novel therapeutic intervention.

Animals↗

PubMed2000

Study the mechanisms of U-50,488 to prevent the development of morphine tolerance in guinea pigs.

Previously we have shown that low dose of [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride] (U-50,488) could prevent the development of morphine tolerance in guinea pigs. In the present study we tried to investigate the role of glutamate and nitric oxide in this process. Male Hartley guinea pigs (200-300 g) were chronically treated s.c. with either saline or morphine (15 mg/kg) or morphine + U-50,488 (0.003 mg/kg) twice a day for 7 days. Antinociceptive activity was assessed by hot-plate test on the first, fourth and seventh day. Spinal cord slices (450 microm) were prepared 30 min after drug treatment on eighth day and [3H] glutamate and nitric oxide (NO) released were determined. We found that coadministration of U-50,488 (0.003 mg/kg) suppressed the development of morphine tolerance to antinociceptive effect as we reported before. The percentage of in vitro spinal release of [3H] glutamate by 100 microM morphine was significantly higher in the chronic morphine group than the control group. On the other hand, coadministration of U-50,488 with morphine for 7 days blocked this effect significantly. The basal NO level released from the spinal cord slices was significantly higher in chronic morphine group but not in chronic (morphine + U-50,488) group. In vitro morphine (100 microM) increased the NO level in control group and chronic (morphine + U-50,488) group and also further increased NO in chronic morphine group. From the NMDA-displaced [3H] glutamate binding in guinea pig spinal cord, we found that the Bmax decreased in chronic morphine group but not in the chronic (morphine + U-50,488) group. In conclusion, chronic morphine treatment may activate the NMDA receptors by increasing the release of glutamate which causes the increase of synthesis and release of NO and following uncertain mechanisms to induce the development of morphine tolerance. And the mechanisms of U-50,488 to prevent the development of morphine tolerance may involve the inhibition of glutamate released by chronic morphine and also the decrease of NO induced by chronic morphine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2000

Prenatal exposure to morphine alters kinetic properties of NMDA receptor-mediated synaptic currents in the hippocampus of rat offspring.

Whole-cell patch-clamp recordings of pharmacologically isolated N-methyl-D-asparate (NMDA) receptor-mediated evoked excitatory postsynaptic currents (EPSCs) were made, to study whether prenatal exposure to morphine affected functional properties of synaptic NMDA receptors in hippocampal slices of 2-week-old rat offspring from morphine-addicted mothers. The saturated amplitude of synaptic NMDA receptor-mediated EPSCs from morphine-treated offspring was about twofold larger than that from vehicle-control offspring. The apparent dissociation constant (Kd) values of NMDA receptors for Mg2+ at 0 mV were 7.5 +/- 1.4 and 7.9 +/- 1.3 mM in slices from vehicle-control and morphine-treated offspring, respectively. In addition, no distinguishable changes in the voltage-dependent nature and the reversal potential of NMDA receptors occurred in morphine-treated offspring, suggesting no alterations of Mg2+ blockade and ion selectivity to NMDA receptors. The 10-90% rise times of NMDA receptor-mediated EPSCs in morphine-treated offspring became longer than those in vehicle-control offspring. The decay of NMDA receptor-mediated EPSCs in both morphine-treated and vehicle-control offspring could be described by the sum of a fast and a slow exponential function. The slow, but not fast, decay times of synaptic NMDA receptor-mediated currents in morphine-treated offspring became slower than those in vehicle-control offspring. Collectively, these results suggest that prenatal exposure to morphine altered kinetic properties of synaptic NMDA receptors in hippocampal CA1 pyramidal neurons of rat offspring during early life. The extended duration of synaptic NMDA receptor-mediated currents presumably provided more Ca2+ entry through NMDA receptors in morphine-treated offspring, and its further prolongation by depolarization in such young offspring strengthened NMDA receptor-dependent functions. Thus, in light of pathophysiological implications within the central nervous system of morphine-treated offspring during early life, the present study may provide important insights and serve as a basis for therapeutic intervention in conditions under which NMDA receptors become abnormal.

Age Factors↗

PubMed2000

Pre-incisional epidural ketamine, morphine and bupivacaine combined with epidural and general anaesthesia provides pre-emptive analgesia for upper abdominal surgery.

BACKGROUND: Previous studies have shown that N-methyl-D-asparate (NMDA) receptor antagonists provide a pre-emptive analgesic effect in humans. This study investigated the benefits of pre-emptive analgesia for upper abdominal surgery, using pre-incisional epidural ketamine + morphine + bupivacaine (K+M+B) treatment for achieving postoperative pain relief. METHODS: Sixty ASA 1-2 patients scheduled for upper abdominal surgery were allocated to three groups in a randomized, single-blinded study. Patients in the control group (I) received general anaesthesia followed by an infusion of normal saline. Group II and III patients received general anaesthesia with a continuous epidural infusion of 2% lidocaine. Thirty minutes after the incision in groups I and II, an epidural pain control regimen was administered using ketamine (10 mg) and morphine (1 mg) in 10 ml of 0.085% bupivacaine (K+M+B). Group III patients also received K+M+B, but it was administered 10 min after the 2% lidocaine injection and 30 min before skin incision. All patients received an epidural pain control regimen (q12 h) for 3 days after their first injection. Patient-controlled analgesia (PCA) with morphine was used to control subsequent postoperative pain. During the 3-day period following surgery, duration to PCA trigger (h), morphine consumption (mg), pain intensity at rest and when coughing/moving, and analgesic-related adverse effects were recorded. The VAS scale (0-10) was used to assess pain intensity. RESULTS: Median times to first PCA trigger were 1.2 (0.5-2.0) h, 3.0 (0.7-4.2) h, and 4.0 (2.5-7.5) h for groups I, II, and III, respectively. Both the incident and resting pain scores were consistently lower for group III patients than groups I and II. The number of PCA triggers (all attempts/successful triggers) during the day following surgery were 14.0 (3-30)/8.0 (3-24) times, 10.0 (3-23)/6.0 (2-20) times, and 7.0 (3-12)/4.5 (1-10) times for groups I, II, and III. Total morphine consumption for the 3-day observation period was 12.5 (3-42) mg, 10.5 (2-29) mg, and 6.0 (1-20) for groups I, II, and III, respectively. CONCLUSION: Pre-incisional epidural K+M+B treatment combined with continuous epidural anaesthesia and general anaesthesia provides an ideal pre-emptive analgesic therapy, exhibiting better postoperative pain relief than general anaesthesia and post-incisional K+M+B treatment.

Abdomen↗

PubMed2000

Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord.

N-Methyl-D-aspartate (NMDA) receptor antagonists and nitric oxide synthase (NOS) inhibitors inhibit morphine tolerance. In the present study, a lumbar subarachnoid polyethylene (PE10) catheter was implanted for drug administration to study alterations in NMDA receptor activity and NOS protein expression in a morphine-tolerant rat spinal model. Antinociceptive tolerance was induced by intrathecal (i.t.) morphine infusion (10 micrograms h-1) for 5 days. Co-administered (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (10 micrograms h-1 i.t.) with morphine was used to inhibit the development of morphine tolerance. Lumbar spinal cord segments were removed and prepared for [3H]MK-801 binding assays and NOS western blotting. The binding affinity of [3H]MK-801 was higher in spinal cords of morphine-tolerant rats (mean (SEM) KD = 0.41 (0.09) nM) than in control rats (1.50 (0.13) nM). There was no difference in Bmax. Western blot analysis showed that constitutive expression of neuronal NOS (nNOS) protein in the morphine-tolerant group was twice that in the control group. This up-regulation was partially prevented by MK-801. The results suggest that morphine tolerance affects NMDA receptor binding activity and increases nNOS expression in the rat spinal cord.

Analgesics, Opioid↗

PubMed2000

Immunohistochemical study of opioid receptors after chronic morphine treatment in rats.

Previously, we have used the biochemical receptor binding method to investigate whether down-regulation of the opioid receptor is a mechanism for morphine tolerance, and we were led to a negative conclusion. In the current study, we further used immunohistochemistry to reinvestigate this issue. Male Sprague-Dawley rats (250-300 g) were chronically treated with morphine s.c. for 2, 4 or 6 days, using an escalating dosage paradigm (5-45 mg), which resulted in a 1.8 to 4.0-fold increase in AD50. Rat brains were removed, frozen, coronally sectioned (14 microm) and processed for mu- or delta-opioid receptor immunohistochemistry using the Avidin-Biotin Complex (ABC) method. No significant decrease in mu-opioid receptor (MOR) immunodensity was found in most of the brain regions, which were enriched with MOR after chronic treatment with morphine except for the anteroventral thalamic nucleus in the ventrolateral part (AVVL). No significant change in delta-opioid receptor (DOR) immunodensity after chronic treatment with morphine was found either. Therefore, our conclusion is that down regulation of opioid receptors may not be an important mechanism for morphine tolerance.

Animals↗

PubMed1999

The role of nitric oxide in the development of morphine tolerance in rat hippocampal slices.

In the present study, we investigated the effects of a nitric oxide (NO) precursor, L-arginine, on the effect of different drugs, [trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e hydrochloride] (U-50,488, a kappa-opioid receptor agonist); dPTyr(Me)AVP (a vasopressin receptor antagonist); dizocilpine (MK-801, a N-methyl-D-aspartate (NMDA) receptor antagonist), to block the development of morphine tolerance or NO release in Sprague-Dawley rat hippocampal slices (450 microm). Slices were continuously superfused with artificial cerebrospinal fluid (ACSF) or drugs at 1 ml/min. Nichrome wire electrodes were placed in the Schaffer-collateral pathway and used to deliver biphasic 0.2-ms pulses of 5-30 V (0.033 Hz). A glass microelectrode was placed in the CA1 area to record population spikes. The amount of NO released in the superfusate was measured as nitrite formation. When the slices were superfused with 10 microM morphine, the amplitude of population spikes increased 200%-300% in 30-40 min. However, this effect of morphine decreased, i.e., tolerance developed, after continuous superfusion of morphine for 2-6 h. On the other hand, the nitrite level was increased about 250% of the control level through 6 h of morphine superfusion. Co-superfusion of L-arginine with morphine could further increase the nitrite level and also facilitate the development of morphine tolerance. On the other hand, 3-Br-7-nitroindazole (a neuronal NO synthase inhibitor) decreased the nitrite level significantly and blocked the development of morphine tolerance. When either U-50,488 (200 nM) or dPTyr(Me)AVP (500 pM) or MK-801 (500 pM) was co-superfused with morphine (10 microM), the development of morphine tolerance was blocked significantly and the nitrite level decreased to 100%-150% of the control level. L-arginine (500 nM) significantly reversed the effect of these drugs to block the development of morphine tolerance or to decrease the nitrite level through 6 h of superfusion. These data suggest that NO may play a key role in the development of morphine tolerance. Drugs which suppress the synthesis or release of NO would be expected to block the development of morphine tolerance.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Preincisional dextromethorphan decreases postoperative pain and opioid requirement after modified radical mastectomy.

PURPOSE: To examine whether preincisional dextromethorphan (DM) improved analgesia after modified radical mastectomy (MRM). METHODS: Sixty patients (ASA I-II) scheduled for MRM were included and randomly allocated into two groups. Patients in the treatment group (DM) received 40 mg DM and 20 mg chlorpheniramine maleate (CPM) i.m., and those in the control group received 20 mg CPM i.m. alone 30 min before skin incision. Meperidine, 1 mg x kg(-1) i.m., was given for postoperative pain relief as required. The time to first meperidine injection, total meperidine consumption, worst pain score, bed-rest time, and side effects were recorded every 24 hr for 48 hr after surgery by a resident anesthesiologist on a double-blind basis. RESULTS: A longer time to first meperidine injection (19.2 +/- 1.6 vs 1.5 +/- 0.23 hr, P < 0.001) and lower meperidine consumption (0[10] vs 75[50] mg, median [interquartile range], P < 0.001) were observed in the DM group than in the control group. The bed-rest time was shorter in the DM than in the control group (18.0[4] vs 23.0[19] hr, P < 0.001). No difference was noted in worst VAS pain score. Meperidine-related side effects (nausea, vomiting, pruritus, dizziness, headache) were more frequent in the control (10/30) than in the DM group (3/30, P < 0.05). The number of patients who required meperidine injection for pain relief was lower in the DM (7/30) than in the control group (25/30, P < 0.005). No DM- or CPM-associated side effects were observed. CONCLUSION: Preincisional IM. DM treatment decreased postoperative pain and opioid requirement after MRM surgery.

Analgesics, Opioid↗

PubMed1998

Alteration in transcripting the gene encoding the delta-opioid receptor in rat brain is not underlying the development of tolerance to [D-Ala2,D-Leu5] enkephalin.

Previous study has demonstrated that chronic treatment of [D-Ala2,D-Leu5] enkephalin (DADLE) induces profound down-regulation of delta opioid receptor in rat brain. We further examined whether this down-regulation of receptor was due to a decrease in the transcription of gene encoding delta-opioid receptor (DOR-1). Rats received daily i.c.v. injection of DADLE for 1, 3, or 5 days and developed significant tolerance to the antinociceptive effect of DADLE after one-day treatment. We measured the level of mRNA in rat brain tissues using in situ hybridization. No significant changes in the mRNA levels of the cortex, striatum, hippocampus, and thalamus on any examined days were found as compared to those of rats received sham operation only. There is only a transient decrease of DOR-1 mRNA level in midbrain region that occurred after a three-day treatment. Thus, the result of this study did not suggest that alteration in transcription of gene-encoding delta-opioid receptor was responsible for the down-regulation of delta-opioid receptor associated with the development of tolerance to DADLE.

Animals↗

PubMed1998

Studies on quinazolines and 1,2,4-benzothiadiazine 1,1-dioxides. 8.1, 2 synthesis and pharmacological evaluation of tricyclic fused quinazolines and 1,2,4-benzothiadiazine 1,1-dioxides as potential alpha1-adrenoceptor antagonists.

A series of 2-substituted methyl 2,3-dihydroimidazo[1, 2-c]quinazolin-5(6H)-ones (4), 3-substituted methyl 2, 3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-ones (15a,b), 3-substituted methyl 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones (16a,b), 3-substituted methyl 2,3-dihydro-1H-imidazo[1,2-b][1,2, 4]benzothiadiazine 5,5-dioxides (33a,b), 2-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (42-45a,b), 3-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (50-53a,b), 3-substituted methyl 5H-thiazolo[2,3-b]quinazolin-5-ones (55-56a,b), and 3-substituted methyl 5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (57) were synthesized as compound 1conformational rigid congeners for pharmacological evaluation as potential alpha1-adrenoceptor antagonists. Compounds 4, 5, 33a,b, 44a,b, 45a,b, 52a,b, 53a,b, and 57 were found to possess high affinity for the alpha1-adrenoceptor. Compounds 5 and 57 were the most highly selective and potent alpha1 antagonists with Ki = 0.21 +/- 0.02 and 0.90 +/- 0.08 nM, respectively. The S-enantiomers of these two compounds (Ki = 0.13 +/- 0.01 nM for (S)-(-)-5; Ki = 1.0 +/- 0.2 nM for (S)-(+)-57) were 144-200-fold more potent than the R-enantiomers (Ki = 26 +/- 8 nM for (R)-(+)-5; Ki = 144 +/- 23 nM for (R)-(-)-57). Compound 4 showed 8-fold higher affinity to alpha1A-AR better than alpha1B-AR. These compounds possessed weak to no activity against the 5-HT1A receptor.

Adrenergic alpha-Agonists↗

PubMed1998

C-alkylated spiro[benzofuran-3(2H),4'-1'-methyl-piperidine-7-ols] as potent opioids: a conformation-activity study.

Among a series of C-alkylated analogs of the weak mu opioid ligand spiro[benzofuran-3(2H),4'-1'-methylpiperidine-7-ol] (1), the 2-methyl, 2-ethyl, and cis 3'-methyl analogs, namely compounds (+/-)2, (+/-)-3, and (+/-)-4, showed much enhanced mu-affinities, with (+/-)-4 being almost as potent as (-)-morphine; while the trans 3'-methyl analog (+/-)-5 remained a weak mu-binder. Energy calculations and nmr data indicated that compounds 2-4 favor phenyl-axial conformations, while compounds 1 and 5 favor phenyl-equatorial conformations.

Magnetic Resonance Spectroscopy↗

PubMed1998

Immunohistochemical evidence of down-regulation of mu-opioid receptor after chronic PL-017 in rats.

In a previous study, mu-opioid receptor binding was decreased by chronic treatment of rats with a mu-opioid receptor-selective agonist [CH3Phe3, D-Pro4]morphiceptin (PL-017) [Tao, P.L., Lee, H.Y., Chang, L.R., Loh, H.H., 1990. Decrease in mu-opioid receptor binding capacity in rat brain after chronic PL-017 treatment. Brain Res. 526, 270-275]. However, there was a lack of correlation between the time course of receptor down-regulation and the loss of pharmacological effects of the drug. In the current study, we used immunohistochemistry to reinvestigate this issue. Male Sprague-Dawley rats were chronically treated with PL-017 i.c.v. for 1, 3 or 5 days, using an escalating dosage paradigm (0.75-6.0 microg), which resulted in a 1.4 to 32-fold increase in the AD50. Rat brains were removed, frozen, coronally sectioned (14 microm) and processed for mu-, delta- or kappa-opioid receptor immunohistochemistry by the avidin-biotin complex (ABC) method. Significant decreases in OP3 immunodensity were found in many brain regions which are enriched with OP3 after chronic treatment of PL-017. Time-dependent decreases in OP3 were detected and reached a plateau around 3 days of PL-017 treatment. No significant change in OP1 or OP2 immunodensity after chronic treatment with PL-017 was found. Our conclusion is that chronic treatment with PL-017 of rats selectively down-regulates mu-opioid receptors in the brain. This may be an important mechanism for PL-017 tolerance.

Animals↗

PubMed1998

Blockade of the development of morphine tolerance by U-50,488, an AVP antagonist or MK-801 in the rat hippocampal slice.

1. In this study, we investigated the effects of different drugs (a kappa-opioid receptor agonist U-50,488, a vasopressin receptor antagonist dPTyr(Me)AVP or an N-methyl-D-aspartate (NMDA) receptor antagonist MK-801) on the development of morphine tolerance in rat hippocampal slices. 2. Hippocampal slices (450 microm) of Sprague-Dawley rats (250-300 g) were used. Slices were continuously superfused with artificial CSF or drugs at 1 ml min(-1). Nichrome wire electrodes were placed in the Schaffer-collateral pathway and used to deliver biphasic 0.2 ms pulses of 5-30 V (0.033 Hz). A glass microelectrode was placed in the CA1 area to record population spikes. 3. When the slices were superfused with 10 microM morphine, the amplitude of population spikes increased 2-3 fold in 30-40 min. However, this effect of morphine decreased, i.e. tolerance developed after continuous superfusion of morphine for 2-6 h. 4. When either U-50,488 (200 nM) or dPTyr(Me) AVP (500 pM) or MK-801 (500 pM) was co-superfused with morphine (10 microM), it significantly blocked the development of morphine tolerance. Nor-BNI (a kappa-opioid receptor antagonist, 200 nM) significantly reversed the inhibitory effect of U-50,488 but not those of dPTyr(Me)AVP or MK-801 on the development of morphine tolerance. 5. These data indicate that kappa-opioid receptors, AVP receptors and NMDA receptors are all involved in the development of morphine tolerance. The suppression of kappa-opioid receptor activity after chronic morphine may occur before the activation of AVP receptors or NMDA receptors during the development of morphine tolerance.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1997

The role of vasopressin on the effect of U-50,488 to block the development of morphine tolerance and physical dependence.

U-50,488, a selective kappa-opioid receptor agonist, has been reported to inhibit the development of antinociceptive tolerance to morphine in mice, rats and guinea pigs, but the mechanism involved in this action remains unknown. Since U-50,488 has been reported to suppress the plasma vasopressin level, we investigated the role of vasopressin with U-50,488 in the male Sprague Dawley rat in this study. Animals (230-270 g) were chronically treated with morphine (10 mg/kg, i.p.) twice a day for 6 days in order to induce tolerance to antinociceptive effect measured by tail-flick test. Withdrawal symptoms were precipitated by naloxone (10 mg/kg, i.p.) on day 7. U-50,488 (i.p.) or AVP (i.p. or i.c.v.) or U-50,488 and AVP was (were) coadministered with chronic morphine to investigate their effects on morphine tolerance and dependence. We found that coadministration of 8 mg/kg U-50,488 (i.p.) with morphine almost completely block morphine tolerance and partially block withdrawal symptoms. In contrast, coadministration of AVP (0.3 microgram/kg, i.p., or 0.01 microgram, i.c.v.) with morphine and U-50,488, the effects of U-50,488 to block morphine tolerance and dependence were reversed. In addition, treatment of AVP antagonist (dPTyr(Me)AVP, 0.5 microgram/kg, i.p. or 0.5 microgram, i.c.v.) has the similar effect as U-50,488 to block morphine tolerance. In summary, the effect of U-50,488 to block morphine tolerance and dependence may relate to its inhibitory effect on AVP release.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1997

Nalbuphine coadministered with morphine prevents tolerance and dependence.

Nalbuphine, an opioid mixed agonist-antagonist, prevents many morphine-related side effects. In this study, we compared the effects of nalbuphine versus naloxone on the prevention of morphine tolerance and dependence in Sprague-Dawley rats. Group 1 received a morphine 5 mg/kg intraperitoneal (I.P.) injection. Groups 2 and 3 received single doses of nalbuphine (0.01 to 5 mg/kg I.P.) or naloxone (1 to 500 microg/kg I.P.) coadministered with morphine (5 mg/kg I.P.), respectively. Group 4 received a saline I.P. injection. Treatments were continued for 4 days. The occurrence of tolerance was estimated by comparing the antinociceptive effect of morphine on Day 1 (Group 1) and Day 5 (each group). The severity of dependence was determined by precipitated withdrawal signs (incidence of diarrhea and teeth chattering) induced by naloxone (10 mg/kg I.P.). We found that coadministration of nalbuphine or naloxone with morphine dose-dependently blocked the development of morphine tolerance and dependence. However, unlike naloxone, nalbuphine did not attenuate the antinociceptive effect of morphine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1997

Synthesis and structure-opioid activity relationships of trans-(+/-)-3,4-dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides.

To explore the effects of attaching a hydroxy function to the cyclohexane ring of kappa-selective opioid N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamides, trans-(+/-)-3,4-dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides (1-4) and their benzoates (5-8) have been synthesized in a divergent and stereoselective manner. When compared with the parent compound U-50488, hydroxy derivatives 1-4 maintained high selectivity towards the kappa-opioid receptor (mu/kappa ratio = 24 to > 91); while displaying significant reduction in binding affinity (Ki,kappa = 75-218 nM). The lowest kappa-affinity was observed with compound 4, where the hydroxy group is attached at the 5-axial or 5-beta position. Further reduction in kappa-affinity was observed when the hydroxy function was benzoylated. However, the 4 beta, 5 alpha, and 5 beta isomers (6-8) maintained varying degrees of kappa-selectivity; the 4 alpha-isomer compound 5, with its benzoate moiety situated at the 4-axial position is now a moderately potent mu-selective opioid (Ki,mu = 168 nM, mu/kappa = 0.076). The result suggest the importance of lipophilicity in binding to opioid receptors and the presence of a specific lipophilic binding site on the mu-opioid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1996

Chronic intrathecal morphine treatment does not cause down-regulation of spinal adenosine A1 receptors in rats.

We have shown previously that systemic chronic morphine treatment causes down-regulation of spinal adenosine A1 receptors in rats. Recently, we have found that chronic supraspinal morphine treatment also causes this effect. In the present study, we investigated whether chronic spinal morphine treatment has the same effect of down-regulation of spinal adenosine A1 receptors. Adult male Sprague-Dawley rats were rendered tolerant to morphine either by multiple intrathecal (i.t.) injections or continuous i.t. infusion by osmotic pump administration for 2 or 4 days. Spinal A1-adenosine receptor binding activity was measured by using the selective A1 adenosine agonist [3H]cyclohexyladenosine. No significant decrease in [3H]cyclohexyladenosine binding was found in the spinal cord after 2 or 4 days of multiple i.t. injections of morphine. There was also no significant change in the amount of spinal [3H]cyclohexyladenosine bound after 4 days of continuous i.t. infusion of morphine by osmotic pump. From these and our previous results, it is concluded that only supraspinal chronic morphine treatment down regulates the spinal A1 adenosine receptor and this may play a role in the mechanism of supraspinal morphine tolerance but not spinal morphine tolerance.

Adenosine↗