In order to identify ceftriaxone and its analogs whether has the function of anti-tolerance of morphine and study the dose-effect relation of ceftriaxone in mice, hot plate method to measure pain threshold of mouse and naloxone withdrawal models were carried out and compared with normal saline group. Ceftriaxone and cefotaxime had the effect of anti-tolerance and anti-dependence of morphine notably. And ceftriaxone has the effect of anti-tolerance of morphine in a dose dependent manner.
Animals ; Anti-Bacterial Agents ; pharmacology ; Cefotaxime ; pharmacology ; Ceftriaxone ; pharmacology ; Dose-Response Relationship, Drug ; Drug Tolerance ; Female ; Mice ; Morphine ; pharmacology ; Morphine Dependence ; prevention & control ; Pain Threshold ; drug effects ; Random Allocation ; Substance Withdrawal Syndrome ; physiopathology

AIMTo investigate the effects of intragastric administration of thenorphine (Then) on behavioral sensitization to morphine (Mor) in mice.

METHODSLocomotor activity was detected after intragastric administration of thenorphine or co-administration of thenorphine with Mor in mice. Mice were induced to be behaviorally sensitive to Mor, and were given the combination of Mor and thenorphine to observe the effects of thenorphine on the development, transfer and expression of Mor-induced behavioral sensitization.

RESULTSA single intragastric administration of thenorphine (1.25 - 5.0 mg x kg(-1)) dose-dependently inhibited the locomotor activity in mice (P < 0.01) and the effects of thenorphine on locomotor activity developed tolerance after repeated administration. Co-administration of thenorphine effectively inhibited Mor-induced hyperactivity (P < 0.05) and the development, transfer, expression of Mor-induced behavioral sensitization in mice (P < 0.05 or P < 0.01).

CONCLUSIONThenorphine was shown to suppress the central nervous system and may be effective against the abuse and addiction to opioids.

Animals ; Behavior, Animal ; drug effects ; Buprenorphine ; analogs & derivatives ; pharmacology ; Central Nervous System Depressants ; pharmacology ; Dose-Response Relationship, Drug ; Drug Tolerance ; Female ; Male ; Mice ; Morphine ; antagonists & inhibitors ; Motor Activity ; drug effects ; Random Allocation

Human rhinoviruses (HRVs) are the causative pathogens in more than half of viral upper respiratory tract infections. Currently, no antiviral agents that are active against HRVs are available for clinical use. Because only higher primates are susceptible to HRVs, the screening of new drug is most commonly based on the cell line model. In this study, isolated rabbit airway smooth muscles (ASM) tissue model has been established, and the airway responsiveness with different treatment has been examined. Relative to control tissues, the maximal constrictor (Tmax) response to ACh increased significantly 150% in ASM inoculated with HRV, and relaxation to isoproterenol has been attenuated to 63%. And the abnormal responsiveness can be inhibited in presence of pretreatment with several new compounds which have been exhibited effective anti-HRV activity on cell lines. The results demonstrate that the established ASM model will be applied to screening the anti-HRVs drugs.
Acetylcholine ; pharmacology ; Animals ; Antiviral Agents ; pharmacology ; Cytopathogenic Effect, Viral ; drug effects ; HeLa Cells ; Humans ; Isoproterenol ; pharmacology ; Muscle Contraction ; drug effects ; Muscle Relaxation ; drug effects ; Muscle, Smooth ; drug effects ; physiopathology ; virology ; Piperidines ; pharmacology ; Pyridazines ; pharmacology ; Rabbits ; Rhinovirus ; Trachea ; drug effects ; physiopathology ; virology

Natural product seselin and related derivatives with an angular pyranocoumarin skeleton were synthesized from 8-acetyl-7-hydroxycoumarins by condensation with acetone, reduction, and dehydration successively under mild conditions with total yield of > 50%. Twelve seselin derivatives were tested by the writhing response assay induced by acetic acid at a dose of 40 mg x kg(-1). Seselin (4a) and 4,8,8-trimethyl-9,9-dihydro-pyran[2,3-f] chromene-2,10-dione (2b) showed obviously antinociceptive activity with inhibitory effect of 85% and 50%, respectively, more or quite potent than aspirin in the same assay, suggesting that seselin derivatives could be a novel kind of potential antinociceptive agents.
Analgesics ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Chromones ; chemical synthesis ; chemistry ; pharmacology ; Coumarins ; chemical synthesis ; chemistry ; pharmacology ; Female ; Male ; Mice ; Molecular Structure ; Pain Measurement ; drug effects

Thienorphine is a chemically-new opioid developed in Beijing Institute of Pharmacology and Toxicology. To elucidate the chemical basis for the unique pharmacological effects of thienorphine, 15 derivatives were synthesized according to combinatorial chemistry and the structure-activity relationships of these compounds were studied. It is demonstrated that thienorphine is a potent long-acting partial agonist. N-Cyclopropylmethyl is responsible for the antagonist effect of thienorphine. More importantly, thiophene at the end of side chain is most likely the pharmacophore accounts for the long-lasting effect of thienorphine. Change of the connection of thiophene and the side chain does not result in changes in the antinociceptive activity.
Animals ; Buprenorphine ; analogs & derivatives ; pharmacokinetics ; pharmacology ; Combinatorial Chemistry Techniques ; Dose-Response Relationship, Drug ; Female ; Male ; Mice ; Mice, Inbred Strains ; Morphine ; pharmacology ; Rats ; Rats, Wistar ; Receptors, Opioid ; agonists ; Structure-Activity Relationship

OBJECTIVE The present study was aimed to investigate the role of Wnt/β-catenin sig-naling in spinal VGLUT2 regulation and neuropathic pain. METHODS To elucidate the association be-tween VGLUT2 and neuropathic pain,we determined the expression and distribution characteristics of VGLUT2 in mice subjected to spared nerve injury(SNI),and then observed the effects of two VGLUT2 targeting shRNAs on mechanical allodynia and glutamate release.The effects of Wnt/β-catenin signal-ing on VGLUT2 expression and pain behavior were investigated by using Wnt agonist,Wnt1,and Wnt/β-catenin pathway inhibitor XAV939 in SNI mice.RESULTS SNI surgery induced significant up-regula-tion of VGLUT2 on postoperative days 7,14,and 21.Double immunofluorescence labeling of VGLUT2 with NeuN,MAP2,Iba-1,or GFAP showed that VGLUT2 was mainly expressed in neurons in the dor-sal horn of the spinal cord after SNI(NeuN,MAP2).Intrathecal administration of VGLUT2 shRNAs be-fore or after SNI surgery significantly decreased mechanical allodynia and glutamate release. Mean-while,Wnt1/β-catenin signaling increased significantly after SNI surgery.Over-expression of β-catenin in PC12 cells increased VGLUT2 protein level,intrathecal administration of Wnt agonist or Wnt1 signifi-cantly increased VGLUT2 protein expression in spinal cord, while Wnt/β-catenin pathway inhibitor XAV939 decreased VGLUT2 expression in PC12 cells and spinal cord.Additionally,intrathecal admin-istration of XAV939 7 days after SNI significantly attenuated mechanical allodynia in mice, which was in accordance with down-regulation of VGLUT2 protein levels.VGLUT2 shRNAs significantly attenuat-ed Wnt agonist or Wnt1 induced mechanical allodynia. CONCLUSION Wnt1/β-catenin signaling path-way up-regu-lates the spinal VGLUT2 expression,and this regulation is involved in neuropathic pain behavior.

Schizophrenia, described as the worst disease affecting mankind, is a severe and disabling mental disorder. Schizophrenia is characterized by complicated symptoms and still lacks a diagnostic neuropathology, so developing schizophrenia animal models which have quantifiable measures tested in a similar fashion in both humans and animals will play a key role in new therapeutic approaches. According to the symptoms of cognitive impairment and emotional disorder, the N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 was applied to induce schizophrenia-like behavior in mice. Locomotor activity and prepulse inhibition (PPI) were selected as indices and the effect of clozapine was also investigated in this model. The results showed that compared with the normal group, MK-801-treated mice exhibited significantly increased locomotor activity and impaired PPI, and pre-exposure to clozapine could ameliorate the abnormality and make it back to normal level. These findings suggest that the model we established could be a useful tool for antipsychotic drug screening.
Animals ; Antipsychotic Agents ; pharmacology ; Clozapine ; pharmacology ; Disease Models, Animal ; Dizocilpine Maleate ; Inhibition (Psychology) ; Male ; Mice ; Motor Activity ; drug effects ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Schizophrenia ; chemically induced ; physiopathology

In order to investigate the role of spinal glutamate transporter 1 (GLT-1) in the neuropathic pain and morphine tolerance, rat chronic constriction injury (CCI) of sciatic nerve was performed, and the mechanical allodynia was evaluated by mechanical withdrawal threshold (MWT), the expression of GLT-1 was measured by real-time PCR and Western blotting analysis. The results showed that compared to sham group, the MWT of CCI group had decreased approximately 80%. Administration of morphine alone could develop tolerance rapidly in initial two days, and then had no significant difference with CCI group, the expression of GLT-1 was down-regulated. Ceftriaxone sodium alone could improve mechanical allodynia. Co-administration of ceftriaxone sodium with morphine attenuated morphine tolerance and up-regulated GLT-1 expression, and the MWT remained at high level after 6 days. In conclusion, change of spinal GLT-1 expression and function has close correlation with the development of neuropathic pain and morphine tolerance.
Animals ; Drug Tolerance ; Excitatory Amino Acid Transporter 2 ; metabolism ; pharmacology ; Female ; Male ; Morphine ; pharmacology ; Radiculopathy ; metabolism ; pathology ; Rats ; Rats, Wistar ; Sciatic Nerve ; pathology ; Sciatic Neuropathy ; metabolism ; pathology ; Spinal Cord ; drug effects ; metabolism

AIMTo compare the antagonistic effects of 6 beta-naltrexol and naltrexone against morphine analgesia.

METHODSThe effects of 6 beta-naltrexol and naltrexone against morphine analgesia were observed in mouse heat radiant tail-flick assay and in mouse (55 +/- 1) degrees C hot plate test. The displacement of 6 beta-naltrexol and naltrexone on binding to CHO-mu receptor was observed by radioligand binding study.

RESULTS6 beta-naltrexol antagonized morphine analgesia but the potency was (6.1 +/- 1.7)% that of naltrexone. The effective duration of 6 beta-naltrexol was 3-4 times that of naltrexone and the peak time of the response was about 0.5-1 h after s.c. equivalent efficacy dose (ED95) in two models. Like naltrexone, 6 beta-naltrexol was effective by oral administration and the potency ratio of p.o./s.c. was 1/3. As an antagonist to opioid receptor, the displacement of 6 beta-naltrexol was about 12.5% that of naltrexone, which was almost in agreement with the efficacies against morphine analgesia in mouse.

CONCLUSIONCompared with naltrexone, 6 beta-naltrexol was less potent but duration was longer.

Analgesia ; Analgesics, Opioid ; antagonists & inhibitors ; Animals ; Female ; Male ; Mice ; Morphine ; antagonists & inhibitors ; Naltrexone ; analogs & derivatives ; pharmacology ; Narcotic Antagonists ; pharmacology ; Pain Threshold ; drug effects ; Receptors, Opioid, mu ; metabolism

This study investigates whether kappa-opioid receptor and ORL1 receptor may interact to form a heterodimer. In immunofluorescence and co-immunoprecipitation experiments, differentially epitope-tagged receptors, colocalization and heterodimerization of kappa-opioid receptor and ORL1 receptor were used and examined in primary culturing rat neurons, Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. The results show that fluorescence of both kappa-opioid receptor and ORL1 receptor were overlapping in primary culturing hippocampal and cortical neurons. Similarly in co-expressing CHO or HEK293 cells, HA-KOR and Myc-ORL1 were almost exclusively confined to the membranes, revealing extensive colocalization. When Flag-KOR and Myc-ORL1 were co-expressing in CHO cells, heterodimerization was identified to have the ability to co-immunoprecipitate ORL1-receptors with kappa-opioid receptor and vice versa. In the current study, further evidence was provided for the direct interaction of two subtypes of opioid receptors, kappa-opioid receptor and ORL1-receptor, to form the heterodimerization. The finding represents the novel pharmacological mechanism for modulation of opioid receptor function as well as diversity of G protein-coupled receptors.
Animals ; CHO Cells ; Cells, Cultured ; Cerebral Cortex ; cytology ; metabolism ; Cricetinae ; Cricetulus ; Dimerization ; Female ; HEK293 Cells ; Hippocampus ; cytology ; metabolism ; Humans ; Immunoprecipitation ; Male ; Neurons ; cytology ; metabolism ; Rats ; Rats, Wistar ; Receptors, Opioid ; metabolism ; Receptors, Opioid, kappa ; metabolism