Opioids: a review.
Analgesics; Animals; Clinical Trials as Topic; Drug Tolerance; Humans; mu/drug effects/genetics/physiology; Opioid; Opioid/*drug effects/genetics/physiology; Opioid/adverse effects/*therapeutic use; Pain/*drug therapy/physiopathology; Receptors; Trans-Activators/genetics
Recent discoveries in opioid pharmacology help explain the enormous variability in clinical responses to these powerful analgesics. Although there is only one m opioid receptor gene, splice variants of that gene's expression result in a panoply of different functioning receptors. Other sources of variable response include polymorphisms in the m opioid receptor regulatory region, and pharmacokinetic differences because of cytochrome P-450 mono-oxygenase heterogeneity. Analgesic tolerance is likely the key phenomenon limiting the benefit of opioids. A plethora of intracellular pathways affects this. Among them are the N-methyl-D-aspartate receptor, protein kinase C gamma activity, nitric oxide synthase, and GM1 ganglioside content of the neuronal membrane. Clinical studies undercut the routine use of meperidine in most settings. Other studies have shown better ways to diminish opioid side effects.
Chevlen Eric
Current pain and headache reports
2003
2003-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s11916-003-0005-5" target="_blank" rel="noreferrer noopener">10.1007/s11916-003-0005-5</a>
Ethanol-produced interoceptive stimuli are time dependent in selectively bred HAS and LAS rats.
*Discrimination Learning; Animals; Dose-Response Relationship; Drug; Drug Tolerance; Ethanol/administration & dosage/*pharmacology; Male; Rats; Time Factors
Fourteenth generation high alcohol-sensitive (HAS) and low alcohol-sensitive (LAS) rats were trained to discriminate the effects of 600 mg/kg intraperitoneally administered ethanol from its vehicle at 6 and 30 min postadministration. Each of the earlier- and later-trained animals were given lower doses of ethanol and ED50 values at their trained postadministration interval were found to be nonsignificantly different. Thus, there was no difference between HAS and LAS animals as to their sensitivity to the discriminative effects of ethanol. Phase-generalization studies, where rats trained at 6 min postadministration were tested with the drug at 30 min postadministration were shown not to generalize, whereas the animals trained at 30 min postadministration and tested at 6 min postinjection were shown to readily discriminate the discriminative stimuli. This asymmetrical generalization lends evidence to the biphasic action of ethanol, and suggests that the earlier phase is quantitatively different than the latter phase. The similarity in sensitivity of the LAS and HAS animals, furthermore, suggests that the discrimination of ethanol is not based on its hypnotic effects.
Schechter M D
Alcohol (Fayetteville, N.Y.)
1992
1992-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0741-8329(92)90021-2" target="_blank" rel="noreferrer noopener">10.1016/0741-8329(92)90021-2</a>
Antitumor efficacy and tolerability of systemically administered gallium acetylacetonate-loaded gelucire-stabilized nanoparticles.
*Lethal Dose 50; Adenocarcinoma/*drug therapy/pathology; Animals; Antineoplastic Agents/administration & dosage/pharmacokinetics/toxicity; Cell Line; Dose-Response Relationship; Drug; Drug Stability; Drug Tolerance; Gallium/*administration & dosage/pharmacokinetics/*toxicity; Humans; Metabolic Clearance Rate; Mice; Nanocapsules/*administration & dosage/chemistry/*toxicity; Nude; Organ Specificity; Tissue Distribution; Treatment Outcome; Triglycerides/chemistry; Tumor
The widespread clinical success with most gallium compounds in cancer therapy is markedly hampered by lack of tumor specific accumulation, poor tumor permeability and undesirable toxicity to healthy tissues. The aim of this work was to investigate for the first time antitumor mechanism of a new gallium compound (gallium acetylacetonate; GaAcAc) while assessing effectiveness of gelucire-stabilized nanoparticles (NPs) for potential application in gallium-based lung cancer therapy. NPs loaded with GaAcAc (Ga-NPs) were prepared using mixtures of cetyl alcohol with Gelucire 44/14 (Ga-NP-1) or Gelucire 53/13 (Ga-NP-2) as matrix materials. Of special note from this work is the direct evidence of involvement of microtubule disruption in antitumor effects of GaAcAc on human lung adenocarcinoma (A549). In-vivo tolerability studies were based on plasma ALT, creatinine levels and histopathological examination of tissues. The superior in-vivo antitumor efficacy of Ga-NPs over GaAcAc was depicted in marked reduction of tumor weight and tumor volume as well as histological assessment of excised tumors. Compared to free GaAcAc, Ga-NPs showed a 3-fold increase in tumor-to-blood gallium concentrations with minimized overall exposure to healthy tissues. Overall, enhancement of antitumor effects of GaAcAc by gelucire-stabilized NPs coupled with reduced exposure of healthy tissues to gallium would likely ensure desired therapeutic outcomes and safety of gallium-based cancer treatment.
Wehrung Daniel; Bi Lipeng; Geldenhuys Werner J; Oyewumi Moses O
Journal of biomedical nanotechnology
2013
2013-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jbn.2013.1598" target="_blank" rel="noreferrer noopener">10.1166/jbn.2013.1598</a>
Discriminative stimulus properties of (+)cathine, an alkaloid of the khat plant.
Male; Animals; Rats; Drug Administration Schedule; Drug Tolerance; Psychotropic Drugs/*pharmacology; Haloperidol/pharmacology; Alkaloids/*pharmacology; *Discrimination (Psychology)/drug effects; Catha; Domperidone/pharmacology; Phenylpropanolamine/antagonists & inhibitors/*pharmacology; Plant Extracts/analysis; Inbred Strains
The effects of the psychostimulant (+)cathine (norpseudoephedrine) were examined in a two-choice, food-motivated, drug-discrimination paradigm. Rats were able to discriminate cathine from vehicle and this effect was dose- and time-dependent. Prior administration of cathine resulted in a diminished response (tolerance) to subsequent cathine and this effect developed and dissipated rapidly. Thus, different dose-response curves were generated depending upon whether cathine or vehicle was administered the day before testing. The development of tolerance also shortened cathine's time course of action and enhanced the ability of haloperidol to antagonize the cathine cue. These results suggest caution in interpreting effects produced by intermittent drug injection schedules.
Pehek E A; Schechter M D
Pharmacology, biochemistry, and behavior
1990
1990-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(90)90402-4" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(90)90402-4</a>
Advantages and disadvantages of a rapid method to train drug discrimination.
Male; Animals; Rats; Drug Tolerance; Methods; Discrimination Learning/*drug effects; Amphetamines/*pharmacology; Dose-Response Relationship; Drug; 3; N-Methyl-3; 4-methylenedioxyamphetamine; 4-Methylenedioxyamphetamine/analogs & derivatives/*pharmacology
In an effort to reduce the often extensive period of time needed to train rats to discriminate between a drugged and nondrugged state, a fast training regimen was employed with 1.5 mg/kg 3,4-methylenedioxymethamphetamine (MDMA) used as the training drug in ten rats. This protocol consisted of one to three training sessions per day and it was compared to the more conventional method of once-per-day training in an equal number of rats. Results indicate that the fast-trained rats learned the discrimination in significantly fewer sessions than the slowly-trained rats. However, the subsequent dose-response experiments indicate that when the fast-trained rats are tested with various doses of MDMA, without prior vehicle treatment, their sensitivity to the drug is less than that of the slowly-trained rats. When a vehicle session is presented prior to drug dose-response testing, both groups perform similarly. It appears that the preceding vehicle sessions function as a reference point for the fast-trained rats and, although the more rapid training regimen allows for faster learning, these treatment regimens should be employed with caution when subsequent dose-response tests and generalization tests with other drugs are conducted.
Schechter M D
Pharmacology, biochemistry, and behavior
1988
1988-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(88)90340-1" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(88)90340-1</a>
Dopaminergic nature of acute cathine tolerance.
Male; Animals; Rats; Drug Tolerance; Dopamine/*physiology; Discrimination (Psychology)/drug effects; Discrimination Learning/drug effects; Alkaloids/pharmacology; Thiazepines/pharmacology; Antipsychotic Agents/pharmacology; Appetite Depressants/*pharmacology; Phenylpropanolamine/*pharmacology; Generalization (Psychology)/drug effects; Dose-Response Relationship; Drug; Inbred Strains
Cathine is a psychoactive constituent in the leaves of the Khat shrub which are habitually ingested for their stimulatory effects in many parts of the world. Rats were trained to discriminate the stimulus effect of intraperitoneally administered 4.8 mg/kg d-cathine and, once trained, administration of another Khat constituent, cathinone, was shown to produce cathine-like effects. This generalization to cathinone was dose-responsive when testing occurred 24 hr after vehicle administration, whereas prior administration of cathine resulted in a diminished discriminative response to subsequent cathinone administration possibly as a result of the development of acute tolerance. CGS 10746B, a compound that blocks presynaptic release of dopamine, significantly decreased rats' ability to discriminate cathine when it was administered 25 min prior to cathine testing and it reversed the acute tolerance observed when cathine was tested 24 hr after cathine administration. These results indicate that a previously reported acute tolerance effect to cathine after cathinone administration in cathinone-trained rats appears to be symmetrical in that there is acute tolerance to cathinone after cathine in these cathine-trained rats. The results with CGS 10746B would suggest that both the cathine-induced discriminative cue and cathine's ability to produce acute tolerance are mediated by presynaptic dopamine release.
Schechter M D
Pharmacology, biochemistry, and behavior
1990
1990-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(90)90083-t" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(90)90083-t</a>
Rats become acutely tolerant to cathine after amphetamine or cathinone administration.
Male; Animals; Rats; Drug Tolerance; Discrimination (Psychology)/drug effects; Psychotropic Drugs/*pharmacology; Thiazepines/pharmacology; Antipsychotic Agents/pharmacology; Alkaloids/*pharmacology; Amphetamine/*pharmacology; Phenylpropanolamine/*pharmacology; Dose-Response Relationship; Drug; Inbred Strains
The drug discrimination paradigm was used to evaluate in rats the ability of the discriminate response to either 0.8 mg/kg d-amphetamine or 0.8 mg/kg l-cathinone to generalize to 2.4-6.0 mg/kg of the active cathinone metabolite d-norpseudoephedrine, also known as cathine. When tested 24 h after vehicle administration, cathine generalized in a dose-related fashion in rats (n = 6) trained with cathinone (ED50 = 3.03 mg/kg) and in rats (n = 8) trained with amphetamine (ED50 = 2.93 mg/kg). In contrast, when cathine was tested 24 h after the administration of either amphetamine or cathinone, it produced significantly decreased discriminative performance. The possibility that this acute tolerance may have been produced by release, and subsequent depletion, of brain dopamine was tested by pretreating rats with the dopamine release inhibitor CGS 10746B. When CGS 10746B was administered prior to cathinone it significantly decreased cathinone discrimination. In addition, acute tolerance to cathine at 24 h after vehicle-cathinone co-administration was reversed when cathine was tested 24 h after CGS 10746B-cathinone co-administration. The results suggest that cathinone-produced discriminative stimulus, as well as the acute tolerance to cathine, may be dopaminergically mediated.
Schechter M D
Psychopharmacology
1990
1905-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/bf02253729" target="_blank" rel="noreferrer noopener">10.1007/bf02253729</a>
Stability of the stimulus properties of drugs over time.
Animals; Rats; Ethanol/*pharmacology; *Discrimination (Psychology); Drug Tolerance; Piperazines/*pharmacology; Dextroamphetamine/*pharmacology; Dose-Response Relationship; Drug; Inbred Strains
Three separate groups of rats were trained to discriminate the stimulus effects of either 600 mg/kg ethanol (n = 5), 0.8 mg/kg d-amphetamine (n = 8) or 1.0 mg/kg
Schechter M D; Signs S A; Boja J W
Pharmacology, biochemistry, and behavior
1989
1989-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(89)90256-6" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(89)90256-6</a>