Search PubMed⌕ Search

Biomedical subjects

A Herz

Publications and source records attributed to A Herz.

At least 19 recordsLinked to original sources
PubMed1998

Opioid reward mechanisms: a key role in drug abuse?

There is increasing evidence to implicate the mesolimbic dopamine system in the rewarding effects of drugs of abuse such as opioids, psychostimulants, and alcohol, and in addition endogenous opioids may play a key role in the underlying adaptive mechanisms. Opioid agonists with affinity for mu and delta opioid receptors are rewarding, whereas opioid agonists with affinity for kappa receptors are aversive. These opposing motivational effects are paralleled by an increase and decrease, respectively, of dopamine release in the nucleus accumbens. Opposite effects are induced in response to selective antagonists for these different receptor types, pointing to tonically active endogenous opioid reward mechanisms. Withdrawal from chronic morphine results in sensitization for opioid reward; an effect that is counteracted by kappa opioid agonists. The rewarding effects of psychostimulants such as cocaine and amphetamine, mediated by the mesolimbic dopamine pathway, are modulated by opioid mechanisms in both directions: sensitization by morphine pretreatment, inhibition by kappa receptor agonists. A modulatory role of endogenous opioids is also suggested from biochemical data, showing increased dynorphin and kappa receptor expression after chronic cocaine treatment. Alcohol reward involves the mesolimbic reward system also, and opioids modulate this behaviour. Naltrexone as well as selective mu and delta opioid receptor antagonists decrease alcohol consumption in operant conditioning models. Biochemical approaches point to a functional deficit of endogenous opioids in genetic models exhibiting high prevalence for alcohol intake. The therapeutic implications of these data are discussed.

Alcohols↗
PubMed1997

Endogenous opioid systems and alcohol addiction.

Alcohol exerts numerous pharmacological effects through its interaction with various neurotransmitters and neuromodulators. Among the latter, the endogenous opioids play a key role in the rewarding (addictive) properties of ethanol. Three types of opioid receptors (mu, delta and kappa) represent the respective targets of the major opioid peptides (beta-endorphin, enkephalins and dynorphins, respectively). The rewarding (reinforcing) properties of mu- and delta-receptor ligands are brought by activation of the mesolimbic dopamine system which ascends from the ventral tegmentum of the midbrain (VTA) to rostral structures; of these, the nucleus accumbens (NAC) is of particular importance in drug addiction. In contrast, dysphoria results from activation of kappa-receptors. The neurochemical manifestations of these opposing effects are, respectively, increases and decreases in dopamine release in the NAC. Several lines of evidence indicate that alcohol interferes with endogenous opioid mechanisms which are closely linked with dopamine transmission in the mesolimbic pathway. The view that condensation products of dopamine and alcohol-derived aldehyde (tetrahydroisoquinolines) play a role remains controversial. There is, however, much information on the direct (acute and chronic) effects of alcohol on the binding properties of opioid receptors, as well as modulation of opioid peptide synthesis and secretion (e.g. a suggested increase in beta-endorphin release). In view of the reinforcing properties of alcohol, it is relevant to consider behavioural studies involving alcohol self-administration in rodents and primates. Low doses of morphine have been found to increase, and higher doses of the opiate to decrease, alcohol consumption. Conversely, opioid antagonists such as naloxone and naltrexone (which bind to non-selectively opioid receptors) have been shown to decrease alcohol consumption under various experimental conditions. Similar results have been reported when selective mu- or delta-receptor antagonists are administered. Results obtained in genetic models of high preference for alcohol also support the view that alcohol intake depends on the activity of the endogenous opioid reward system and that alcohol consumption may serve to compensate for inherent deficits in this system. One hypothetical model proposes that reward results from activation of mu-opioid receptors in the VTA and/or delta-receptor in the NAC; both these nuclei are targets of endogenous beta-endorphin. It is suggested that alcohol interferes with this reward pathway either directly or indirectly. The available experimental data accord well with those obtained from clinical studies which opioid antagonists have been used to prevent relapse in alcoholics. Conceptual considerations concerning communalities between various forms of addictions are also discussed in this review.

Alcohol Drinking↗
PubMed1995

Role of immune processes in peripheral opioid analgesia.

The experimental data clearly demonstrate that opioids (alkaloids as well as peptides) are able to inhibit nociception arising from inflamed tissue by a local peripheral action. mu- and delta- as well as kappa-opioid receptor ligands are effective by interaction with the respective opioid receptors presumably located in the terminal region of the sensory nerves. Similar effects are obtained when endogenous opioid peptides are released under stress conditions from immune cells present in the inflamed tissue. Immunoreactive beta-EP and enkephalins, processed in these cells, seem to be the relevant peptides in this respect. Although the mechanism of stress-induced release of opioid peptides from the immunocytes is presently not clear, there is indication that this process involves cytokines and CRF. Apart from immunological processes, inflammation-induced changes also take place at the level of the opioid receptors and are of significance in the manifestation of peripheral opioid antinociception; in particular the "activation" of these receptors apparently occurs at the early stages of inflammation when the infiltration of the tissue with immunocompetent cells is just beginning. There is increasing evidence for a therapeutic relevance of opioid-induced analgesia at peripheral sites of inflammation.

Analgesics, Opioid↗
PubMed1995

[Neurobiological principles of drug dependence. Exemplified by opioids and psychostimulants].

New insights into the neurobiological mechanisms underlying drug addition have become available with recent advances in experimental research. This is particularly true for the opioids and psychostimulants: behavioural and biochemical studies have revealed that activation of the mesolimbic "reward pathways", involving the release of dopamine, which acts upon D1 receptors, plays a critical part in the development of addictive behaviour. In the case of the opioids, the differentiation of various types of receptors (and of the corresponding endogenous ligands, the endorphins) revealed a bidirectional role of opioid receptors in this process: stimulation of the reward system, mediated by mu- and delta-opioid receptors, and inhibition of the reward pathways, mediated by the activation of chi-receptors. Thus, a functional equilibrium between these tonically active opioidergic systems appears to provide a neutral motivational state. During drug withdrawal, the decrease in dopamine release most probably reflects a disturbance of this equilibrium. There is increasing evidence that endogenous opioidergic mechanisms also modulate addictive behaviour caused by psychostimulants and other drugs of abuse. This article discusses the implications of these new findings in the context of pharmacotherapeutic strategies in the treatment of addictive behaviours.

Amphetamines↗
PubMed1994

The diagnosis of pulmonary tuberculosis by gaschromatographic detection of tuberculostearic acid using flame ionisation detectors.

It has been shown that the detection of tuberculostearic acid (TBSA) with gas chromatography-mass-spectrometry provides a highly specific, sensitive and rapid method for the diagnosis of various forms of tuberculosis. However, the need for complex and expensive equipment prevented the more widespread use of this method. We report on the application of conventional gas chromatography with flame ionization detectors in the detection of TBSA in sputum samples. TBSA was detected in all patients with proven pulmonary tuberculosis before treatment or under treatment for less than 4 weeks (n = 18). Six of these patients (33%) had a negative microscopy result at the time of the study. Sputum samples from patients under therapy for longer than 4 weeks (n = 20) were TBSA-positive in 15 cases (75%). Only in two cases was the diagnosis by microscopy and/or culture not met by TBSA-detection. All sputa of 20 control patients with lung diseases other than tuberculosis were TBSA negative. Additional analysis of patients' data showed a significant relationship (P < 0.005) between the relative amounts of TBSA detectable in the sputum samples and the duration of therapy. It is concluded that conventional capillary gaschromatography may be sensitive and specific enough to be used for the detection of TBSA in sputum of patients with pulmonary tuberculosis.

Chromatography, Gas↗
PubMed1993

Peripheral mechanisms of opioid antinociception in inflammation: involvement of cytokines.

It has been shown previously that opioids induce antinociceptive effects at peripheral sites in the presence of inflammatory processes. Besides being elicited by local injection of opioids, such effects can also be obtained by activation of intrinsic opioid mechanisms, e.g. following stress. In the present study the possible role of cytokines in this mechanism was investigated. Unilateral inflammation of the hindpaw of rats was induced by local injection of Freund's complete adjuvant. Intraplantar injection of tumor necrosis factor alpha (TNF alpha) or interleukin-6 induced a dose-dependent increase in the threshold in the paw pressure test in the inflamed but not in the non-inflamed paw. This increase was prevented by local injection of naloxone and the mu-opioid receptor specific antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) as well as by 3-E7, an universal opioid peptide antibody. In rats pretreated with cyclosporin A to suppress the immune system, the antinociceptive effect of TNF alpha was completely inhibited. In concert with previous studies these data indicate that the tested cytokines release opioid peptides (e.g. beta-endorphin and/or enkephalins) from immune cells of the inflamed tissue which act on opioid receptors present on sensory nerve terminals, resulting in antinociception.

Amino Acid Sequence↗
PubMed1993

Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue.

The effect of inflammation, induced by unilateral intraplantar injection of Freund's adjuvant, on opioid receptors transported in the sciatic nerve and on opioid receptors present in the paw of the rat was studied by means of in vitro receptor autoradiography using [125I]beta-endorphin (human) as ligand. In the absence of inflammation, human beta-endorphin binding sites accumulated proximally and distally to a ligature placed on the sciatic nerve in a time-dependent manner, indicating bidirectional axonal transport. Some human beta-endorphin binding was also visible in non-inflamed paw tissue. Inflammation of the paw tissue massively increased human beta-endorphin binding on both sides of the sciatic nerve ligature and in the ipsilateral paw tissue. In inflamed paw tissue, beta-endorphin binding accumulated in the cutaneous nerve fibers as well as in the immune cells infiltrating the surrounding tissue. In the sciatic nerve and paw tissue, beta-endorphin binding was displaced by (D-Ala2, N-methyl-Phe4, Gly-ol5)enkephalin and (D-Pen2, D-Pen5)enkephalin, selective mu- and delta-opioid receptor agonists, respectively, and by the universal opioid antagonist naloxone, but not by U-50,488H, a k-selective receptor agonist. Taken together, these data provide neuroanatomical evidence for local inflammation-induced enhanced axonal transport of opioid receptors in rat sciatic nerve and accumulation in paw tissue.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats.

An unbiased conditioned place preference paradigm was used to examine the neuroanatomical substrates mediating the reinforcing and aversive effects of mu and kappa opioid agonists. Unilateral microinjection of the selective mu agonist DAMGO into the ventral tegmental area (VTA), the origin of the mesolimbic and mesocortical dopamine (DA) systems, resulted in dose-dependent preferences for the drug-associated place. Intracranial injections of DAMGO into terminal projection sites of VTA DA neurons, the nucleus accumbens and the medial prefrontal cortex, however, as well as into the lateral hypothalamus, were without effect. In contrast, microinjections of the kappa agonist U50,488H and the dynorphin derivative E-2078 into the VTA produced place aversions. Place aversions were also observed after microinjections of U50,488H and E-2078 into the nucleus accumbens, medial prefrontal cortex and lateral hypothalamus. However, microinjections of mu and kappa agonists into either the origin of the mesostriatal DA system, the substantia nigra or into its major terminal field, the nucleus caudatus-putamen, was without effect. Autoradiographic studies revealed that the substances remained within a restricted area around the injection site, confirming that the effects observed were mediated therein. Thus, these data suggest an important role for the A10 neurons in the VTA in the regulation of both mu and kappa opioid-induced motivational states. The rewarding effects are associated with the activation of mu receptors in the VTA, whereas aversive effects are associated with the activation of kappa receptors in the VTA and its limbic-cortical terminal regions.

Amino Acid Sequence↗
PubMed1993

Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs. D-2 dopamine receptors.

Both the reinforcing and aversive effects of exogenous opioids have been attributed to the activation of opioid receptors within the mesolimbic dopamine (DA) system. At present, however, it is unclear whether the activity of DA neurons projecting to the nucleus accumbens (NAC) is necessary for the expression of these effects. The present study sought to address this issue in rats by examining the influence of 6-hydroxydopamine (6-OHDA) lesions of the NAC and microinjections of selective DA receptor antagonists into this brain area upon the place conditioning produced by systemically administered opioids. The mu-opioid receptor agonist morphine produced dose-related preferences for the drug-paired place in control animals, whereas the kappa-opioid agonist U-69593 produced place aversions. Bilateral 6-OHDA lesions of the NAC abolished the place conditioning produced by both opioids. Lesions of the caudate/putamen or medial prefrontal cortex were, however, without effect. Microinjection of the D-1 DA antagonist SCH-23390 into the NAC, at a dose which was as ineffective as a conditioning stimulus, attenuated the place conditioning produced by low doses of morphine and U-69593. Over the dose range tested, the D-2 DA antagonist (-)-sulpiride was without effect. Neither SCH-23390 nor 6-OHDA lesions of the NAC modified the place conditioning produced by lithium chloride, a drug of a different pharmacological class. These data demonstrate that the rewarding and aversive effects of opioids are dependent on DA neural transmission within the mesolimbic system and suggest a role for NAC D-1 DA receptors in the mediation of both motivational effects.

Animals↗
PubMed1992

Dynorphin, a preferential ligand for kappa-opioid receptors, is present in nerve fibers and immune cells within inflamed tissue of the rat.

Exogenous kappa-opioid agonists have been shown to produce peripheral antinociceptive effects in inflamed tissue. This study sought to determine whether endogenous kappa-receptor ligands are present at the site of inflammation. In Freund's adjuvant-induced hindpaw inflammation in the rat, we show, by immunohistochemistry, that dynorphin is detectable within inflammatory cells and in the cutaneous nerves in a similar distribution as calcitonin gene-related peptide, a specific marker for sensory neurons. These findings extend our previous observations in that not only beta-endorphin and Met-enkephalin (mu- and delta-receptor ligands), but also a preferential kappa-ligand is present within inflamed subcutaneous tissue.

Animals↗
PubMed1992

Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway.

The mesolimbic dopaminergic system has been implicated in mediating the motivational effects of opioids and other drugs of abuse. The site of action of opioids within this system and the role of endogenous opioid peptides in modulating dopamine activity therein remain unknown. Employing the technique of in vivo microdialysis and the administration of highly selective opioid ligands, the present study demonstrates the existence of tonically active and functionally opposing mu and kappa opioid systems that regulate dopamine release in the nucleus accumbens, the major terminal area of A10 dopaminergic neurons. Thus, stimulation of mu-type receptors in the ventral tegmental area, the site of origin of A10 dopaminergic neurons, increases dopamine release whereas the selective blockade of this opioid receptor type results in a significant decrease in basal dopamine release. In contrast, stimulation of kappa-type receptors within the nucleus accumbens decreases dopamine release whereas their selective blockade markedly increases basal dopamine release. These data show that tonic activation of mu and kappa receptors is required for the maintenance of basal dopamine release in the nucleus accumbens. In view of the postulated role of the mesolimbic system in the mediation of drug-induced alterations in mood and affect, such findings may have implications for the treatment of opiate dependence and affective disorders.

Analgesics↗
PubMed1992

Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception.

Our previous studies indicate that endogenous opioids (primarily beta-endorphin) released during stressful stimuli can interact with peripheral opioid receptors to inhibit nociception in inflamed tissue of rats. This study sought to localize opioid precursor mRNAs and opioid peptides deriving therefrom in inflamed tissue, identify opioid containing cells and demonstrate their functional significance in the inhibition of nociception. In rats with Freund's adjuvant-induced unilateral hindpaw inflammation we show that: (i) pro-opiomelanocortin and proenkephalin-mRNAs (but not prodynorphin mRNA) are abundant in cells of inflamed, but absent in non-inflamed tissue; (ii) numerous cells infiltrating the inflamed subcutaneous tissue are stained intensely with beta-endorphin and [Met]enkephalin (but only few scattered cells with dynorphin) antibodies; (iii) beta-endorphin is present in T- and B-lymphocytes, monocytes and macrophages; and (iv) whole-body irradiation suppresses stress-induced antinociception in the inflamed paw. Taken together, these data suggest that endogenous opioid peptides are synthesized and processed within various types of immune cells at the site of inflammation. Immunosuppression abolishes the intrinsic antinociception in inflammatory tissue confirming the functional significance of these cells.

Analysis of Variance↗
PubMed1992

Effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy.

We have investigated the effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy. At the end of surgery, an interpleural catheter was inserted in 17 patients and, in a double-blind and randomized manner, either a bolus of morphine 2.5 mg interpleurally (i.p.) and normal saline i.v. (group I) or, as a control for systemic absorption, morphine 2.5 mg i.v. and i.p. saline (group II) was injected. After the initial bolus, a continuous infusion of morphine 0.5 mg h-1 i.p. and saline i.v. (group I) or morphine 0.5 mg i.v. and saline i.p. (group II) was maintained for 24 h. Postoperative pain was assessed by a visual analogue scale, a numerical rating scale and the McGill Pain Questionnaire. Pulmonary function was assessed by spirometry. Supplementary analgesics, side effects, degree of sedation, vital signs and chest tube drainage were recorded. All variables were assessed on the day before surgery and 1, 2, 3, 4, 5, 6 and 24 h and 7 days after surgery. Supplementary morphine was given upon request. There was no significant difference in any pain measure or postoperative pulmonary function variable between the groups. We conclude that, after thoracotomy, interpleural morphine does not provide superior analgesia or improve pulmonary function compared with systemic morphine.

Forced Expiratory Volume↗
PubMed1992

[Opiate addiction. Pharmacologic and biochemical aspects].

The detailed information now available regarding the neurobiology of opiates (opioids) has contributed greatly to our understanding of opioid addiction. This in turn has permitted a more complete understanding of the processes underlying drug addiction. Opioid agonists with a high affinity for mu- or delta-receptors produce conditioned preferences for an environment previously associated with their administration, whereas kappa-agonists induce place aversions. Studies in which opioids were microinjected into discrete brain areas suggest that these opposing motivational effects are mediated via an interaction with the mesolimbic dopamine (DA) system originating in the midbrain. Microdialysis studies have clearly shown that mu-agonists preferentially increase DA release and metabolism in the Nucleus accumbens, whereas kappa-receptor agonists decrease release. Opposite effects on DA are observed in response to microinjections of selective antagonists for these receptor types, suggesting the existence of tonically active endogenous opioid systems which maintain DA release in the mesolimbic system: a continuous "reward" tone, probably mediated by beta-endorphin in the ventral tegmentum of the midbrain and an "aversive" tone, mediated by dynorphin in the Nucleus accumbens. Aspects of such a bidirectional regulation of the mesolimbic system by endogenous opioids are discussed.

Animals↗
PubMed1992

Paradoxical effect of chronic fentanyl treatment on naltrexone-induced supersensitivity and upregulation.

The present study sought to evaluate the influence of chronic opioid antagonist treatment upon the discriminative stimulus and analgesic effects of the opioid receptor agonist fentanyl. Male Wistar rats were trained to discriminate fentanyl (0.04 mg/kg) from saline in a two-lever food reinforced paradigm. After acquisition of the discrimination, they were implanted with osmotic minipumps which delivered either naltrexone (0.07 mg/h) or distilled water, and the sensitivity of discrimination was assessed at various times after pump removal. The influence of chronic naltrexone treatment upon the antinociceptive effects of fentanyl was assessed in drug-naive (control) rats and in rats which had received fentanyl in the same dosage schedule as those in drug discrimination experiments. Chronic infusion of naltrexone for 7 days did not modify the dose-response curve for the fentanyl vs. saline discrimination. Algesiometric tests revealed a significant increase in the antinociceptive effect of fentanyl in control rats after naltrexone treatment. In contrast, such supersensitivity was not observed in rats which had previously received fentanyl injections. Autoradiographic data revealed a naltrexone-induced upregulation of mu opioid receptors in control animals. Paradoxically, this effect was significantly increased in fentanyl-pretreated rats. These data suggest that prior drug experience can affect the development of antagonist-induced supersensitivity to the behavioral actions of opioid agonists. Furthermore, it would appear that after chronic agonist treatment the phenomena of opioid receptor upregulation and functional supersensitivity are dissociated.

Analgesia↗