电针治疗阿片类依赖稽延性戒断症状的临床研究

为了控制阿片类依赖的稽延性戒断症状，又避免使用阻断剂的毒副作用，对５６例治疗后期有稽延性戒断症状的病人在某些穴位上施加特定频率及强度的电刺激，结果发现其疗效优于可乐定，尤其对失眠、疼痛及焦虑烦躁更有效，并可减少合并用药的不良反应，为今后的戒毒治疗开辟了又一途径。     

The clinical relevance of opiate receptor research

Recent progress in opiate receptor research of particular relevance to clinicians is discussed. A simple binding assay, which in itself is valuable in allowing rapid screening of new compounds for opiate activity, has been the basis of these studies. Extensive mapping of opiate receptors in subcortical brain regions has provided important insights into the neuronal pathways involved in analgesia, while physical and chemical characterization of these receptors has led to a simple means of distinguishing agonists from antagonists. The existence of multiple receptors suggests that the analgetic effects of the opiates may be dissociated from other effects, and studies of tolerance and dependence indicate that they too may be dissociable from analgesia. Purification of the receptors, at last a reasonable possibility, may lead to new ways to promote or inhibit analgesia.     

Suicidal Ideation in Veterans Receiving Treatment for Opiate Dependence

Abstract

Persons with opiate use disorders, especially veterans. have a number of both chronic and acute indicators of risk for suicide, but are not typically screened for suicidal ideation on a routine basis, beyond initial evaluations. One hundred one veterans receiving treatment for opiate dependence at an urban VA medical center were screened for suicidal ideation. Over 24% reported some suicidal ideation. Current ideation was associated with severe chronic pain, ongoing problems with street drugs. firearm ownership, and with having recently enrolled in treatment. It was also associated with a variety of recent negative life events and mental health issues, especially depression, recurring troubling thoughts, hallucinations, loss of jobs, and conflicts with family members. Two veterans endorsing suicidal ideation required immediate hospitalization. The implications of these findings are discussed, and frequent screening for suicidal ideation among patients receiving treatment for opiate dependence is recommended.     

Age-related differences in the effect of chronic administration of naloxone on opiate binding in rat brain

Infant and adult rats were injected chronically with either naloxone or saline for 21 consecutive days. At various intervals after cessation of the pretreatment with naloxone, animals were sacrificed and assessed for specific binding of [3H]naloxone in different regions of the CNS. Infants displayed an increase in opiate binding in the spinal cord, hypothalamus, striatum and cortex one day after cessation of the pretreatment with naloxone, but the increase in opiate binding was dissipated within one week after cessation of the pretreatment. The increase in opiate binding in infants was accompanied by an increase in the antinociceptive efficacy of morphine. In contrast to infants, adults failed to display any alteration in opiate binding following the chronic pretreatment with naloxone. Infants may be especially susceptible to naloxone-induced receptor supersensitivity because infants excrete naloxone more slowly than adults, and thus their opiate receptors may be blocked for a longer duration following an injection of naloxone.     

Synthesis and receptor binding characteristics of [d-Ala2, cysteamine5]enkephalin,a thiol-containing probe for structural elements of opiate receptors

For the elucidation of structural elements in the opiate receptors, a thiol-containing enkephalin analog, [d -Ala², cysteamine⁵]enkephalin, and its dimeric analog were synthesized and evaluated in the radio-ligand receptor binding assays using rat brain membranes. The dimeric analog was very potent in both delta and mu assays. Comparison of receptor affinities of the thiol-containing enkephalin with those of standard mu or delta receptor specific ligands suggested that the mu receptor contains an essential thiol group which may interact with the thiol group at the C-terminus of the enkephalin analog. It also appears that no metal-ion site, postulated for the delta receptors, is present in the delta binding site.     

Assessment of the potential agonistic and antagonistic properties of ketamine at opiate receptors in the guinea-pig ileum

The anesthetic agent ketamine was studied for its ability to interact with opiate receptors in the longitudinal smooth muscle-myenteric plexus preparation of the guinea-pig ileum. The drug was found to possess agonistic, but not antagonistic, activity on opiate receptors. Naloxone antagonized the effect of ketamine although to a lesser degree than the antagonism exhibited toward morphine. In addition to the opiate action, ketamine also produced a depression of the contractile responses of the ileal smooth muscle to acetylcholine and histamine. The concentrations of ketamine that produced this non-specific depression were generally higher than those needed to demonstrate the opiate effect. However, some overlap in the concentration ranges for the two actions were observed. Although the nature of the opiate action of ketamine suggested that it interacts with opiate receptors or sub-types of these differently than does morphine, the non-specific action of the drug on the ileal smooth muscle precluded a definitive analysis of differences in the opiate receptor preferences of the drug.     

Inhibition of Enkephalin Binding to Opiate Receptors by Zinc Ions: Possible Physiological Importance in the Brain

Abstract: Zinc ions can totally block stereospecific binding of ³H-met-enkephalinamide (2-D-ala-5-L-methionine) to opiate receptor sites in synaptic membranes of the hippocampus, the cerebral cortex and the basal ganglia of the rat brain. Analysis of binding isotherms indicates that this inhibitory effect involves a decrease in both receptor affinity and the number of binding sites. Our data also suggest that the zinc ions react with essential SH-groups of the opiate receptor. The endogenous concentrations of zinc ions in the hippocampus, the cerebral cortex and the basal ganglia are compatible with the concentrations needed to inhibit opiate receptor binding in vitro. Especially the hippocampus contains a high concentration of zinc ions, which are localized exclusively in the giant boutons of the mossy fibers. Further, the hippocampal distribution of enkephalin and zinc ions is identical and confined to the mossy fiber zone. Hence, zinc ions may represent important modulators of opiate receptor binding in the central nervous system, particularly in the hippocampal mossy fiber zone.     

ISOLATION OF OPIATE RECEPTOR LIGANDS IN COFFEE

1. We have reported previously that instant coffee contains ligands for opiate receptors with characteristics similar to those of opiate antagonists. 2. A concentrate of receptor-active ligands from instant coffee was prepared by serial treatments involving Amberlite XAD-2, flash chromatography and gel permeation chromatography. 3. Examination of the final concentrate by GC-MS showed the presence of a number of isomeric (iso)feruloylquinic acid lactones. 4. It is suggested that the synthesis and biological testing of each quinide isomer will establish which is responsible for the opiate receptor activity of instant coffee.     

Thailand: Southeast Asia's Marketplace for Opiates

Abstract

This article presents a historical discussion of disease models of opiate addiction in the United States in the twentieth century. First, several approaches to defining disease arc discussed. Then, the shifts in formulations of opiate addiction as a disease in the twentieth century in the U.S. are analysed in light of the preceding theoretical discussion. The period before 1920 is described as heterodox, as researchers auempted to develop scientific models of opiate addiction, while various medically legitimate and quasi-legitimate treatment approaches flourished in an unregulated marketplace. After 1920, a stigmatizing disease model of opiate addiction was based on a psychiatric formulation that linked chronic addiction with psychoneurotic deficits in certain individuals. After 1940, this model dominated medical and scientific thinking about opiate addiction for several decades. After 1970, enormous changes in the demographics of drug use forced changes to the prevailing model of addiction. A new focus on behavioral aspects of addiction allowed the creation of a nonstigmatizing Parson ian disease model.     

Interaction of dopamine receptor ligands with subtypes of the opiate receptor

There are currently several studies in which individual dopamine receptor ligands have been reported to bind with relatively low affinity to opiate receptors. To extend these studies, and to examine the opiate receptor subclass selectivity of such agents, we have examined the ability of six dopamine receptor ligands (prochlorperazine, chlorpromazine, haloperidol, bromocriptine, pimozide and metoclopramide) to compete with four tritiated tracers - [3H]naloxone, [3H][D-Ala2,D-Leu5]enkephalin, [3H]morphine and [3H]ethylketocyclazocine - for binding to rat brain membrane opiate receptors. The dopamine receptor ligands displaced the labelled opiates in a dose-dependent manner, with ED50 values of 3 microM to 3 mM. Pimozide was consistently the most potent (ED50 3-14 microM), and metoclopramide the least potent (ED50 35 microM to 3.5 mM). Dopamine receptor agonists and antagonists thus interact with opiate receptors with no clear subclass selectivity, and with similar hierarchies of inhibitory potency in each of the various opiate receptor systems.     

Antagonism by phenoxybenzamine and pentazocine of the antinociceptive effects of morphine in the spinal cord

In contrast to morphine, intrathecally administered phenoxybenzamine (PBX: 0.1–400 μg) or pentazocine (1–400 μg) had no effect on the rat hot plate or tail flick response. The failure to observe any effect of either drug on the hot plate or tail flick response, or on the locomotor behavior of the animals rules out a local anesthetic effect of these agents given intrathecally under the present conditions. Pretreatment with intrathecal PBX or pentazocine, however, antagonized the antinociceptive effects of a large (15 μg), but not a small (3 μg) dose of morphine. The antagonism was observed to occur only with small intrathecal doses of PBX (1–10 μg) and pentazocine (10–30 μg) with the PBX being approx. 10 times more potent than pentazocine in its ability to antagonize. At higher dose levels of either agent, neither antagonism nor enhancement of the morphine effect was observed. Phentolamine (1–200 μg) had no effect on the antinociceptive effects of intrathecal morphine. The failure of intrathecal pentazocine and PBX to produce a change in the hot plate response latency suggests that they do not act as full agonists upon the category of receptor acted upon by morphine and that the antinociceptive effects produced by systemically administered pentazocine and PBX must be mediated by an agonist action upon a different receptor population located within supraspinal structures. The biphasic activity described for the interaction of partial opiate agonists with full agonists is similar to that observed in the present experiments and leads to the conclusion that both pentazocine and the α-adrenergic antagonist, PBX, can serve as partial agonists of the spinal opiate receptor.     

Conformation and electrostatic potential surfaces of opiates: Relationship to µ- and λ-site binding

Molecular mechanics energy minimization and electrostatic potential surface calculations have been used to examine a series of opioid compounds that interact with the µ opoid receptor and a recently discovered high-affinity naloxone binding site (the site). The compounds studied include members of the morphinan, 4,5-epoxymorphinan, and benzomorphan families. All compounds bind with a high affinity at the µ opiate receptor site, but only the 4,5-epoxymorphinans bind tightly at the site. The results suggest that conformational differences in the various families do not satisfactorily explain the observed trends in binding affinity at the site. However, electrostatic potential surfaces for a representative subset of these opioids exhibit patterns that allow us to classify members as high-affinity or low-affinity -site ligands in good agreement with the experimental results. The procedures used in this work may be useful in defining characteristics that impart selectivity for opiate receptor subtypes such as the µ, , and receptors.     

3H]etorphine binding in rat striatum following lesions of the raphe nuclei

Following 5,7-dihydroxytryptamine lesions of the rat raphe nuclei a significant reduction in striatal serotonin concentrations was observed. However, with [3H]etorphine as ligand no change in opiate receptor binding was observed in striatal membranes. Moreover, when [3H]etorphine binding was resolved into its mu- and delta + kappa-components no change in either component was observed compared with controls. It is concluded that opiate receptors are not on striatal serotonergic nerve terminals whose cell bodies are located in the raphe nuclei.     

Nociceptin, endomorphin-1 and -2 do not interact with invertebrate immune and neural mu 3 opiate receptor

AIM: To determine if endomorphin-1, -2 and nociceptin (orphanin FQ) bind to the mu 3 opiate receptor subtype or release nitric oxide as mu 3 selective ligands do. METHODS: These opioid peptides were examined for their ability to displace [3H]dihydromorphine (DHM) binding from the invertebrate (immunocytes and pedal ganglia) mu 3 opiate receptor in membrane homogenates. The ligands were also tested for their ability to release nitric oxide from the same intact tissues utilizing an amperometric probe that measures nitric oxide in real-time. RESULTS: Endomorphin-1, -2 and nociceptin do not displace [3H]DHM binding from immunocyte or pedal ganglia membrane homogenates nor do they release nitric oxide from these tissues. CONCLUSION: Since these newly discovered opioid peptides do not interact with the mu 3 opiate receptor subtype, endogenous morphine's significance is enhanced because it appears to be the only naturally occurring opiate ligand for the receptor. Furthermore, since this study involves invertebrate tissues, this signal system had to evolve early during evolution.     

Binding of β-Carbolines and Tetrahydroisoquinolines by Opiate Receptors of the δ-Type

Abstract: Effects of various β-carbolines (BC's) and two tetrahydroisoquinolines (TIQ's) on the specific binding of a natural opiate δ-receptor ligand, leucine enkephalin, have been studied in rat synaptosomal membranes, and compared with the effects on the binding of mu-receptor ligands dihydromorphine and naloxone. Harmaline (7-MeO-1-Me-dihydro-BC) was the most potent compound studied (Ki value 3.5 μM), while the two TIQ's (salsolinol and salsolidine) were less potent than BC's (Ki> 100 μM) in inhibiting the binding of δ-receptors. In general, BC's showed more affinity for δ-receptors than for μ-receptors; salsolinol was more potent against the binding of μ-receptors. Inhibition of binding was generally of the competitive type: Kd values increased and Bmax values were not altered. The Na dependence suggests that BC's and salsolinol are antagonists or partial agonists of opioids. Since the binding affinity of BC's and TIQ's was on the micromolar level only, the opiate receptors do not appear to be the major sites of action for BC's or TIQ's.     

Non-peptide opioid receptor ligands - recent advances. Part I - agonists

Developments in the domain of non-peptide opioid receptor agonists, beginning from the first evidence of opiate binding to definite receptors, are briefly summarized. The recent achievements are in a more detailed way depicted and discussed. Novel agonists for each of three opioid receptor basic types (delta, kappa and micro) are presented with the special emphasis on one-type-selective ligands. Such selective or even specific agonists have been synthesized with a moderate success. Considerably more serious difficulties concern searching for selective ligands for opioid receptor subtypes (micro(1), micro(2), delta(1), delta(2, kappasub>1), kappasub>2, kappasub>3) which may be connected with the fact that dissimiliarities observed in vivo result from postbinding processes (signaling). For the large number of opioid receptor ligands, their structural diversity and relative easiness of generating them from combinatorial libraries (not comparable even with that of orphanine receptors) it is justified to consider the plasticity of opioid receptors (micro-receptor especially). This remark, in conjunction with the existence of opioid receptor types and subtypes, may enable to create new drugs with significantly reduced side-effects. The above facts and brand new reports about highly-active opioid agonists possessing no moieties thought to be essential for agonist activity make the need of reevaluation of classical opioid receptor pharmacophore model extremely important. In general, research results suggest that selective agonists of opioid receptors can be found both in morphine type of ligands and new structures like pyrido-acridine derivatives (COMP1) or diphenylmethylpiperazine derivatives (SNC 80). Better understanding of the structural prerequisites of the opioid receptors binding domains will certainly lead to even more potent and more selective ligands in a near future.     

Dynorphin-(1–13).

Dynorphin-(1–13) (Dyn-(1–13)) and its analogs substituted by single introduction of Ala in positions 1–11 were synthesized by the solid-phase method and purified by high pressure liquid chromatography. Relative potencies of the synthetic compounds were determined by their ability to inhibit electrically-evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with [³H]-etorphine for opiate receptors in rat brain homogenates. Introduction of Ala in positions 1 and 4 of Dyn-(1–13) provoked most important decreases in the activity of the molecule in the three assays (relative potency of 0.2% or less). Substitution of Ala in positions 2 or 5, but not 3, also severely decreased the potency of the peptide in the smooth muscle preparations (0.6–5.0% activity). However, the opiate receptor binding assay was less sensitive to the replacement of residue in position 2 (20% activity) than that in positions 3 or 5 (12% and 6% relative potencies, respectively). In the GPI assay and the opiate binding test, the other substitutions which greatly lowered the potency of the molecule were seen in positions 6, 7, 9 and 11, four basic residues. Among these, Arg⁶ and Arg⁷ were demonstrated to be the most important in the three biological tests. Finally, the replacement of Ile⁸ by Ala increased the relative potency of Dyn-(1–13) up to 191% and 900% in the MVD and the opiate binding tests, respectively.     

Opiate receptors in brain labelled in vivo with [3H]lofentanil

The in vivo binding of [³H]lofentanil was studied in various regions of the brain in rat. After intravenous injection of [³H]lofentanil the disposition of the labelled drug in the brain paralleled exactly the regional distribution of opiate receptors measured in in vitro binding assays. The labelling was saturable and could be prevented by naloxone when given before [³H]lofentanil, in all the regions except in the cerebellum. The long-lasting occurrence of the specific labelling was entirely compatible with the extremely slow dissociation rate of lofentanil and its long duration of action. This explains why [³H]lofentanil is not displaceable by naloxone in vivo. Subcellular fractionation experiments revealed that all the labelling in the frontal cortex but not in the cerebellum was particulate-bound and entirely displaceable by naloxone.The advantages of [³H]lofentanil in vivo are its extremely low non-specific binding and its ability to reveal very low occupancy of opiate receptors in brain.     

Interactions between delta opioid receptors and alpha-adrenoceptors

1. Several studies have reported functional interactions between different subtypes of opioid and alpha2A-adrenoceptors in the induction of spinal cord analgesia. The mechanisms underlying this phenomenon are not well characterized. We propose that direct receptor-receptor associations could account for some of the observed functional interactions. In the present study, we examined the presence of delta opioid receptors and alpha2A-adrenoceptors in interacting complexes and the functional implications of such interactions on receptor activity. 2. Using the proximity based bioluminescence resonance energy transfer (BRET) assay, we found that the delta opioid receptors and alpha2A-adrenoceptors are in close enough proximity (< 100 A) in live cells that can foster physical interactions. 3. Using coimmunoprecipitation of differentially epitope-tagged receptors, we found that delta opiate receptors exist in interacting complexes with alpha2A-adrenoceptors in heterologous cells. 4. Finally, using receptor activity mediated neurite outgrowth in Neuro 2A cells as a physiological readout, we found that interactions between delta opiate receptors and alpha2A-adrenoceptors have functional consequences. The expression of alpha2A-adrenoceptors is sufficient to promote delta opiate receptor-mediated neurite outgrowth, suggesting that the presence of inactive alpha2A-adrenoceptors can enhance delta opiate receptor-mediated signalling. 5. Taken together, these findings suggest that modulation of receptor function as a result of physical associations between delta opiate receptors and alpha2A-adrenoceptors may account for the observed synergy between opiate and adrenergic agonists in spinal analgesia.