Ibogaine is a plant-derived alkaloid with putative ‘anti-addictive’ properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an
N-methyl-
...d-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (
N=6–8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.
A structurally novel opioid δ receptor selective antagonist has been identified. This compound, ...(+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo3.3.1non-7-yl-(1-phenyl-1-cyclopentane)carboxamide (+)-KF4, (+)-4, showed a K e value of 0.15 nM in the 35SGTPγS functional assay. (+)-KF4 is also a δ inverse agonist with an IC50 value of 1.8 nM. To our knowledge, this is the first potent and selective δ opioid receptor antagonist from the 5-phenylmorphan class of opioids.
Chronic morphine treatment results in functional uncoupling of the mu opioid receptor and its G protein in both cell culture and animal models. In the present study, Chinese hamster ovary (CHO) cells ...stably expressing the cloned human mu opioid receptor (hMOR‐CHO cells) were incubated with 1 μM of morphine (or no drug) for 20 h. Subsequently, we assessed DAMGO‐ and morphine‐stimulated 35S‐GTP‐γ‐S binding and agonist‐mediated inhibition of forskolin‐stimulated cAMP accumulation. Using a single concentration of 35S‐GTP‐γ‐S (0.05 nM), chronic morphine treatment did not significantly change basal 35S‐GTP‐γ‐S binding, shifted the morphine EC50 from 59 nM to 146 nM, and decreased the maximal stimulation (Emax) from 201% to 177%. Similar results were observed with DAMGO. Binding surface analysis resolved two 35S‐GTP‐γ‐S binding sites (high‐affinity and low‐affinity sites). In control cells, morphine stimulated 35S‐GTP‐γ‐S binding by increasing the Bmax of the high‐affinity site. In morphine‐treated cells, morphine stimulated 35S‐GTP‐γ‐S binding by decreasing the high‐affinity Kd without changing the Bmax. Morphine treatment increased the EC50 (5–11‐fold) for agonist‐mediated inhibition of forskolin‐stimulated cAMP accumulation. These changes were not observed in cells expressing a mutant mu opioid receptor which does not develop morphine tolerance, suggesting that the changes in 35S‐GTP‐γ‐S binding observed in hMOR‐CHO cells result from the development of morphine tolerance. Synapse 47:1–9, 2003. Published 2002 Wiley‐Liss, Inc.
Sixty osteoarthritic patients undergoing primary uncemented total hip arthroplasty were matched for age and weight and randomized into one of four groups with respect to implant coating and ...postoperative protected weight-bearing status: group 1, hydroxyapatite, 12 weeks; group 2, uncoated, 12 weeks; group 3, hydroxyapatite, 6 weeks; group 4, uncoated, 6 weeks. Tantalum spheres were implanted periprosthetically into the femur at the time of arthroplasty, thus providing constant references for stereoscopic radiographs. Patients were then evaluated over a 1-year period with clinical examination, plain radiography, and roentgen stereophotogrammetric analysis (RSA). Clinical evaluation using Charnley scoring showed no significant preoperative or postoperative intergroup differences, whereas visual analog testing noted less thigh pain with hydroxyapatite-coated stems at 12 weeks and 6 months follow-up. Plain radiographic analysis produced no significant differences, with no instability detected and bony ingrowth noted uniformly in all groups. The preliminary stereographic evaluation showed migration in all groups, but there were no significant differences between coated and uncoated stems or 6-week and 12-week partial weightbearing protocols. The Charnley, plain radiographic, and preliminary stereogrammetric evaluations all suggest that migration is unaltered by enhanced surfaces and that early unprotected weightbearing does not jeopardize implant fixation regardless of coating design. The lower incidence of visual analog thigh pain with the hydroxyapatite-coated stems, however, may be a reflection of bony ingrowth and as such add some validity to the theoretical advantages of enhanced surface prostheses.
To obtain data on the degree to which the opioid system is changed in cholestasis, endogenous opioid activity in plasma of rats with acute cholestasis was determined 5 days after bile duct resection. ...Total plasma opioid activity was determined using a radioreceptor technique that measured the displacement of the opiate receptor ligand 3H-DAMGO from lysed synaptosomal fractions of normal rat brain. Plasma total opioid activity was threefold greater in bile duct-resected rats than in sham-operated and unoperated controls (P less than or equal to 0.05). Plasma levels of the individual endogenous opioid, methionine-enkephalin, were determined using a sensitive radioimmunoassay, and the specificity of the assay was confirmed using high-performance liquid chromatography. In cholestatic rats, plasma methionine-enkephalin levels were more than six-fold greater than in sham-operated controls (P less than or equal to 0.001) and more than 17-fold greater than in unoperated controls (P less than or equal to 0.001). However, plasma methionine-enkephalin levels accounted for less than 5% of total plasma opioid activity after bile duct resection. Plasma methionine-enkephalin levels in both cholestatic plasma and plasma from sham-operated animals were stable when incubated in vitro despite the presence of undiminished activity of the major enkephalin-degrading enzymes. Thus, protection of methionine-enkephalin from degradation may be a factor contributing to the elevated plasma levels of methionine-enkephalin found in cholestasis. The magnitude of the increase in plasma endogenous opioid activity in bile duct-resected rats provides support for the hypothesis that endogenous opioids contribute to the pathophysiology of cholestasis.
A series of naltrexone-derived pyridomorphinans possessing various substituents at the 5′-position on the pyridine ring were synthesized and evaluated for opioid receptor binding in rodent brain ...membranes and functional activity in smooth muscle preparations. While the introduction of aromatic 1-pyrrolyl group (
6h) improved the δ affinity and δ antagonist potency of the parent compound (
3), the introduction of guanidine group (
6i) transformed it to a κ selective ligand in opioid receptor binding and
35SGTP-γ-S functional assays.
A series of 5′-substituted analogues of
3 were synthesized and evaluated. While a pyrrole substituent (
6h) improved the δ selectivity and antagonist potency of
3, a guanidine group (
6i) transformed it to a κ selective antagonist.
Abstract Background : We examined risk of multiple myeloma (MM) associated with variants in genes involved in metabolism and response to exogenous chemicals cytochrome P450 enzymes ( CYP1B1 , CYP2C9 ...), epoxide hydrolase ( EPHX1 ), paraoxonase 1 ( PON1 ), arylhydrocarbon hydroxylase receptor ( AHR ), and NAD(P)H:quinone oxidoreductase ( NQO1 ). Methods : This study included 279 MM cases and 782 controls in a pooled analysis of two population-based case–control studies. One common variant from each candidate gene was genotyped using DNA from blood or buccal cells. We estimated risk of MM associated with each genotype, controlling for race, gender, study site, and age, using odds ratios (OR) and 95% confidence intervals (CI). Results : Evaluations of the CYP1B1 V432L variant (rs1056836) suggested increased risk of MM among persons with the CG and GG genotypes compared to the CC genotype OR (95% CI) = 1.4 (1.0–2.0). Similar results were seen in analyses stratified by race and gender. We did not find any associations between MM and the CYP2C9 , EPHX1 , NQO1 , or PON1 genes. Conclusions : CYP1B1 activates chemicals such as polycyclic aromatic hydrocarbons and dioxins to create oxidized, reactive intermediates, and higher gene activity has been shown for the G allele. We conducted the largest analysis to date on MM and these genetic variants and our results provide preliminary evidence that variation in CYP1B1 may influence susceptibility to MM.
: Methamphetamine (METH) abuse is a growing health problem, and no treatments for METH dependence have been identified. The powerful addictive properties of METH are mediated by release of dopamine ...(DA) from nerve terminals in mesolimbic reward pathways. METH stimulates DA release by acting as a substrate for DA transporter (DAT) proteins, thereby triggering efflux of DA from cells into the synapse. We have shown that blocking DAT activity with high‐affinity DA uptake inhibitors, like GBR12909, can substantially reduce METH‐evoked DA release in vitro, suggesting GBR12909 may have potential as a pharmacotherapy for METH dependence. The purpose of the present study was to examine the neurobiological effects of a long‐acting oil‐soluble preparation of GBR12909 (1‐2‐bis(4‐fluorophenyl)methoxyethyl‐4‐(3‐hydroxy‐3‐phenylpropyl) piperazinyl decanoate, or GBR‐decanoate). Male rats received GBR‐decanoate (480 mg/kg, i.m.) or its oil vehicle, and were tested using a variety of methods one and two weeks later. Ex vivo autoradiography showed that GBR‐decanoate decreases DAT binding in DA‐rich brain regions. In vivo microdialysis in the nucleus accumbens revealed that GBR‐decanoate elevates baseline levels of extracellular DA and antagonizes the ability of METH to evoke DA release. The dopaminergic effects of GBR‐decanoate were sustained, lasting for at least two weeks. Rats pretreated with GBR‐decanoate displayed enhanced locomotor responses to novelty at one week, but not two weeks, postinjection. Administration of the D2/D3 receptor agonist quinpirole (10 and 100 μg/kg, s.c.) decreased locomotor activity and suppressed plasma prolactin levels; quinpirole‐induced responses were not altered by GBR‐decanoate. Thus, GBR‐decanoate is able to elevate basal synaptic DA levels and block METH‐evoked DA release in a persistent manner, without significant perturbation of DA receptor function. The findings suggest that GBR‐decanoate, or similar long‐acting agents, should be evaluated further as potential treatment adjuncts in the management of METH addiction in humans.
We determined if men with prostate pain syndromes have petechiae in the bladder after hydrodistension.
A total of 60 men with the diagnosis of prostate pain and without bacteriuria underwent ...cystoscopy and hydrodistension under a general or regional anesthetic.
Of the 60 men 35 (58%) had moderate to severe petechiae similar in appearance to women with interstitial cystitis after hydrodistension. Men with moderate to severe bladder petechiae had fewer leukocytes in expressed prostatic secretions, smaller bladder capacities and less often testicular pain than men with more normal appearing bladders after hydrodistension. Symptomatic improvement 2 to 6 weeks after hydrodistension was more common in men with moderate to severe petechiae than in those with fewer petechiae. Absence of rectal pain predicted symptomatic improvement after hydrodistension.
We suggest that bladder petechiae, and possibly interstitial cystitis or a related condition, may be more frequently associated with prostate pain syndromes in men than previously appreciated.
Recent clinical reports indicate that combined administration of phentermine and fenfluramine may have useful effects in the treatment of drug abuse. The present study was designed to evaluate the ...subjective and mood-altering effects of these drugs, alone and in combination, in normal healthy volunteers. Seven male and five female volunteers participated in an eight-session, double-blind study in which each subject received each of the following drug conditions: d-amphetamine (10 and 20 mg), phentermine (30 mg), fenfluramine (40 and 80 mg), phentermine (30 mg) with fenfluramine (40 mg), phentermine (30 mg) with fenfluramine (80 mg), and placebo. Sessions were conducted in a laboratory setting two or three days a week. Subjects completed standardized self-report questionnaires and psychomotor tests before and at regular intervals after each drug administration. Phentermine produced effects that were similar to those of d-amphetamine, whereas fenfluramine produced different and apparently aversive effects (e.g., it increased measures of anxiety and confusion). Phentermine reduced the apparently aversive effects of fenfluramine when the two drugs were given together. These results suggest that the combination of phentermine and fenfluramine would have a low potential for abuse.
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