Conditioning of opioid reinforcement: neuroanatomical and neurochemical substrates.
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Animals↗
Biomedical subjects
A Herz
Publications and source records attributed to A Herz.
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↗
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↗
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↗
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↗
[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↗
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↗
Prolonged inflammatory pain modifies corticotropin-releasing factor-induced opioid peptide release in the hypothalamus.
The influence of prolonged pain upon hypothalamic opioid peptide release in vitro was examined in rats subjected to Freund's adjuvant (FA)-induced unilateral inflammation of the hindlimb. Basal release of enkephalin (ENK) but not beta-endorphin (END) or dynorphin (DYN) was increased 10 days following FA treatment. Superfusion of corticotropin-releasing factor (CRF; 10(-8) M) stimulated the release of opioid peptides in control hypothalami. CRF, however, failed to modify beta-END and DYN release in hypothalami of FA-treated rats, whereas ENK release was markedly reduced. In contrast, KCl-stimulated opioid peptide release did not differ between FA and control hypothalami. These data demonstrate that prolonged inflammatory pain alters the responsiveness of hypothalamic opioid systems to CRF. It is suggested that this effect is mediated at the level of the CRF neuron or its receptor.
Animals↗
Analgesic effect of intraarticular morphine after arthroscopic knee surgery.
BACKGROUND: Opioids can produce potent antinociceptive effects by interacting with local opioid receptors in inflamed peripheral tissue. In this study we examined the analgesic effects of the intraarticular, as compared with intravenous, administration of morphine after arthroscopic knee surgery. METHODS: In a double-blind, randomized trial, we studied 52 patients who had received one of four injections at the end of surgery. The patients in group 1 (n = 18) received 1 mg of morphine intraarticularly and saline intravenously; those in group 2 (n = 15), saline intraarticularly and 1 mg of morphine intravenously; those in group 3 (n = 10), 0.5 mg of morphine intraarticularly and saline intravenously; and those in group 4 (n = 9), 1 mg of morphine and 0.1 mg of naloxone intraarticularly and saline intravenously. The volume of the intraarticular injections was 40 ml, and that of the intravenous injections was 1 ml. After 1, 2, 3, 4, 6, and 24 hours, postoperative pain was assessed with a visual-analogue scale, a numerical-rating scale, and the McGill pain questionnaire. The need for supplemental analgesic agents, the patients' vital signs, and the occurrence of side effects were monitored. RESULTS: All pain scores were lower in group 1 than in group 2 at all times. The differences were significant (P less than 0.05) at three, four, and six hours (mean [+/- SD] visual-analogue score at six hours, 9 +/- 13 mm vs. 37 +/- 31 mm). The mean (+/- SD) consumption of supplemental analgesic medication per 24 hours was significantly lower in group 1 (36 +/- 51 mg of diclofenac and 1.2 +/- 3.4 mg of meperidine) than in group 2 (75 +/- 42 mg of diclofenac and 14 +/- 18 mg of meperidine, P less than 0.05). The visual-analogue scores in group 3 were slightly but not significantly higher than those in group 1 at all times except 6 and 24 hours after injection. The visual-analogue scores were significantly higher in group 4 than in group 1 one to four hours after injection (P less than 0.05), indicating that the analgesic effect of intraarticular morphine was reversible by naloxone. CONCLUSIONS: Low doses of intraarticular morphine can significantly reduce pain after knee surgery through an action specific to local opioid receptors that reaches its maximal effect three to six hours after injection.
Adult↗
Modulation of the mesolimbic dopaminergic system by beta-endorphin-(1-27) as assessed by microdialysis.
In the present study we used in vivo microdialysis to examine the influence of beta-endorphin-(1-27) (beta-EP-(1-27) upon beta-endorphin (beta-EP)-induced dopamine (DA) release in the nucleus accumbens of anesthetized rats. Microdialysis probes were inserted into the nucleus accumbens and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using a reversed-phase HPLC system with electrochemical detection. Intracerebroventricular (i.c.v.) administration of beta-EP-(1-27) (5-20 micrograms) resulted in a dose-dependent increase in DA release which was smaller than the beta-EP-induced DA release, whereas metabolite levels were not altered. Pretreatment with beta-EP-(1-27) (5-20 micrograms) significantly altered the beta-EP (5 micrograms)-induced increase in DA release. These results indicate that beta-EP-(1-27) antagonizes the beta-EP-induced release of DA in the nucleus accumbens. In addition to its antagonistic properties at the beta-endorphin binding site, beta-EP-(1-27) appears to be a partial agonist, inducing increased DA release. These findings suggest a regulatory function for this naturally occurring beta-EP fragment within the mesolimbic system.
Animals↗
Neuroanatomical substrates mediating the aversive effects of D-1 dopamine receptor antagonists.
An unbiased place preference conditioning procedure was used to examine the secondary reinforcing effects of selective D-1 dopamine (DA) receptor antagonists and the neuroanatomical substrates mediating these effects. Systemic administration of SCH-23390 or the non-benzazepine D-1 receptor antagonist A-69024 produced dose-related conditioned aversions for the drug-associated place. In contrast, the D-2 antagonists spiperone and (-)sulpiride were without effect. SCH-23390-induced place aversions were also observed after intracerebroventricular administration. The minimum dose producing this effect was significantly lower than that after systemic injection. Aversive effects were also observed after microinjection of SCH-23390 into the n. accumbens. In contrast, microinjections of this antagonist into the ventral tegmental area, caudate putamen or medial prefrontal cortex were without effect. These data confirm that the blockade of D-1 but not D-2 DA receptors induces aversive states. Furthermore, they suggest that D-1 receptors in the n. accumbens may play an important role in the regulation of non-drug induced affective states.
Animals↗
Beta-endorphin-induced locomotor stimulation and reinforcement are associated with an increase in dopamine release in the nucleus accumbens.
In vivo microdialysis was used to compare the effects of beta-endorphin upon dopamine (DA) release in the nucleus accumbens (NAC) of anesthetized versus freely moving rats, and to examine the role of the mesolimbic DA system in mediating both the motoric and secondary reinforcing effects of this peptide. Microdialysis probes were inserted into the NAC and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using a reversed phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (ICV) administration of beta-endorphin (2.5 and 5.0 micrograms) increased DA release and metabolites in both freely moving and anesthetized rats. This effect was of greater magnitude and duration in freely moving rats and was accompanied by stimulation of locomotor activity. The 5 micrograms dose also functioned as a secondary reinforcer in a conditioned place preference paradigm. A higher dose of beta-endorphin (7.5 micrograms) stimulated DA release and metabolites in anesthetized rats but failed to affect these parameters in freely moving rats. At this dose, catalepsy and a loss of the reinforcing effects of this peptide were observed. These data demonstrate marked differences in the effects of beta-endorphin upon DA release in the awake versus anesthetized rat. Further, the finding that the reinforcing and locomotor stimulating effects of beta-endorphin only occur at those doses which stimulate DA release suggest that this action is critical for the expression of both behavioral effects.
Anesthesia↗
Influence of chronic lithium treatment upon the motivational effects of opioids: alteration in the effects of mu- but not kappa-opioid receptor ligands.
The influence of chronic lithium (Li) treatment upon the secondary reinforcing effects of opioid agonists and antagonists was examined by use of an unbiased place preference conditioning procedure. Administration of the mu-agonist morphine to control rats resulted in marked preferences for the drug-associated place and a similar effect was observed in response to the psychostimulant d-amphetamine. In contrast, the selective kappa-opioid agonist U-69593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-1(pyrrolidinyl-1-oxaspirol(4,5) dec-8-yl benzeneacetamide)] and the opioid antagonist naloxone produced dose-related place aversions. Chronic administration of a Li-containing diet, which produced serum levels of 0.56 mmol/l, abolished the place preferences induced by morphine but not d-amphetamine. This treatment abolished the aversive effects of naloxone but did not modify those produced by U-69593. These data and those from a previous place conditioning study indicate that Li can function as an antagonist of mu-opioid receptor ligands in vivo and that this action underlies its motivational effects. Furthermore, the inability of chronic Li treatment to modify either the content or basal release of beta-endorphin in various brain regions suggests that this antagonism is mediated directly at the level of the opioid receptor and/or its transducer systems.
Analgesics↗
Identification of the opioid receptor types mediating beta-endorphin-induced alterations in dopamine release in the nucleus accumbens.
In the present study we used in vivo microdialysis to examine the influence of beta-endorphin on dopamine (DA) release in the nucleus accumbens of anesthetized rats and to identify the opioid receptor types mediating its effects. Microdialysis probes were inserted into the nucleus accumbens and perfusates were analysed for DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using a reversed phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (i.c.v.) administration of beta-endorphin resulted in a dose-dependent increase in DA and its metabolites. Pretreatment with the selective delta-antagonist ICI 174,864 significantly attenuated the beta-endorphin-induced increase in DA release and metabolism whereas pretreatment with the selective mu-antagonist CTOP resulted abolition of the beta-endorphin effect. These data demonstrate that the blockade of either mu- or delta-opioid receptors is sufficient to antagonize the stimulatory effects of beta-endorphin on DA release and metabolism. As such, these findings suggest that the concomitant activation of both mu- and delta-receptors underlies the effects of beta-endorphin on DA release in the nucleus accumbens.
Analgesics↗
Nigrostriatal dopamine mediates the stimulatory effects of corticotropin releasing factor on methionine-enkephalin and dynorphin release from the rat neostriatum.
This study examined the effects of corticotropin-releasing factor (CRF) on the in vitro release of methionine-enkephalin (Met-enkephalin) and dynorphin in neostriatal slices taken from rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the nigrostriatal DA pathway. In neostriatal slices from control saline-infused animals and in those from the contralateral hemisphere of 6-OHDA-lesioned animals, CRF (10(-10) M) administered as a 90-min pulse exerted potent stimulatory effects on both Met-enkephalin and dynorphin release. In the neostriatal slices of 6-OHDA-lesioned striata, both the basal release and tissue content of Met-enkephalin were significantly (P less than 0.01) higher (2-fold) than those of control animals and the contralateral hemisphere of 6-OHDA-lesioned animals; however, neither the basal release nor the tissue content of dynorphin in 6-OHDA-lesioned striata was significantly different from control striata. In response to CRF (10(-10) M) the release of both Met-enkephalin and dynorphin were significantly diminished in slices of 6-OHDA-lesioned striata. These data support previous studies suggesting that nigrostriatal DA itself may exert a tonic inhibitory action on the activity of striatal Met-enkephalin neurones; however, DA may not have the same influence on striatal dynorphin neurons. However, the results of this study demonstrate that the action of CRF on Met-enkephalin as well as dynorphin release from the rat neostriatum is DA dependent. The data suggest that CRF receptors in the rat neostriatum may be localized on nigrostriatal/nigropallidal DA terminals/collaterals.
Animals↗
Involvement of central mu and delta opioid receptors in mediating the reinforcing effects of beta-endorphin in the rat.
An unbiased place preference conditioning procedure was used to identify the central opioid receptor types through which the endogenous opioid peptide, beta-endorphin, acts to exert its reinforcing effects in rats in vivo. The intracerebroventricular administration of beta-endorphin, and selective mu (DAGO) or delta (DPDPE) opioid receptor agonists produced marked preferences for the drug-associated place. Intracerebroventricular pretreatment with the selective mu antagonist, CTOP, eliminated the place preference produced by DAGO but not that produced by DPDPE. Pretreatment with the selective delta antagonist, ICI 174,864, abolished the place preference induced by DPDPE. It did not modify the effect of DAGO. In contrast, pretreatment with either ICI 174,864 or CTOP abolished the effects of beta-endorphin. These data demonstrate that both mu and delta receptors are involved in mediating the reinforcing effect of beta-endorphin and indicate that the activation of both receptor types is required for the expression of the motivational effects of beta-endorphin. Further they suggest that beta-endorphin produces its motivational effects via an interaction with an opioid receptor complex composed of both mu and delta receptors.
Amino Acid Sequence↗
Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation.
The effects of capsaicin pretreatment of adult rats was investigated on consequences of unilateral paw inflammation induced by inoculation with Freund's adjuvant. Decrease in mechanical nociceptive threshold in the inflamed paw, as measured by the paw pressure test, was dose-dependently inhibited by capsaicin (20-150 mg/kg s.c.). In control rats, the antinociceptive action of morphine (0.8-1.9 mg/kg s.c.) was greater in the inflamed than in the non-inflamed paw; this difference was absent in capsaicin-treated animals. Increased volume or skin temperature of the inflamed paw was not influenced by capsaicin. It is concluded that capsaicin-sensitive, presumably C-fibre neurones, but not an alteration of the inflammation itself by capsaicin, mediate hyperalgesia and increased morphine antinociception in the rat paw with adjuvant-induced inflammation.
Analgesics↗
Stimulation of hypothalamic opioid peptide release by lithium is mediated by opioid autoreceptors: evidence from a combined in vitro, ex vivo study.
The effect of both chronic and acute lithium treatment on hypothalamic opioid peptides was investigated. Acute treatment with lithium was found to stimulate the release of beta-endorphin, dynorphin and Met-enkephalin from perfused rat hypothalamic slices. Application of tetrodotoxin was found to have no effect upon the stimulation indicating it to be mediated at the nerve terminal level. The release of hypothalamic opioid peptides is known to be under the chronic control of a system of inhibitory autoreceptors. Blockade of these autoreceptors with, for example, the opioid receptor antagonist naloxone causes a release of all three opioid peptides. Simultaneous addition of naloxone and lithium was found to have no additive effect on the release of any opioid, suggesting lithium acts via an inhibition of the inhibitory autoreceptor. Preincubation with pertussis toxin prevented the lithium stimulation of dynorphin and Met-enkephalin, but not beta-endorphin, release, indicating lithium interacts with a G-protein to affect the autoreceptor controlling the release of dynorphin and Met-enkephalin. Chronic treatment with lithium in vivo (10 days) had no effect on the basal release or hypothalamic content of any of the opioids, but prevented the naloxone-stimulated release of dynorphin and Met-enkephalin in vitro. Long-term treatment with lithium would thus appear to inactivate the autoreceptor(s) controlling their release. These data demonstrate a lithium-stimulated release of hypothalamic beta-endorphin, Met-enkephalin and dynorphin, apparently mediated via an inhibition of the autoreceptors controlling their release. Chronic treatment with lithium permanently inactivated the autoreceptor(s) controlling the release of dynorphin and Met-enkephalin but not beta-endorphin. Lithium would appear to mediate its effects upon Met-enkephalin and dynorphin release via an interaction with a pertussis toxin-sensitive G-protein. The mechanisms underlying its release of beta-endorphin are at present uncertain.
Animals↗