Biomedical subjects

T S Shippenberg

Publications and source records attributed to T S Shippenberg.

At least 73 records · Page 4Linked to original sources

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↗

PubMed1991

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↗

PubMed1991

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↗

PubMed1991

Conditioned reinforcing effects of 8-hydroxy-2-(di-N-propylamino) tetralin: involvement of 5-hydroxytryptamine 1A and D1 dopamine receptors.

A conditioned place preference paradigm was used to examine the motivational effects of the putative 5-hydroxytryptamine 1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propyl amino)tetralin (DPAT). Rats exhibited marked preferences for an environment paired with the s.c. injection of DPAT (0.1-0.25 mg/kg): vehicle injections were without effect. Pretreatment with the 5-HT1A/D2 dopamine (DA) receptor antagonist spiperone or the D1 DA receptor antagonist SCH-23390 abolished the DPAT-induced preferences. The D2 antagonist sulpiride was without effect. These data demonstrate that DPAT is an appetitive reinforcer and that this effect results from an interaction with 5-HT1A and D1 DA receptors. They further suggest that 5-HT1A agonists may have potential for abuse.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1991

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↗

PubMed1991

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↗

PubMed1991

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↗

PubMed1990

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↗

PubMed1990

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↗

PubMed1990

The effects of opioid peptides on dopamine release in the nucleus accumbens: an in vivo microdialysis study.

An involvement of the mesolimbic dopamine (DA) system in mediating the motivational effects of opioids has been suggested. Accordingly, the present study employed the technique of in vivo microdialysis to examine the effects of selective mu-, delta-, and kappa- opioids on DA release in the nucleus accumbens (NAC) of anesthetized rats. Microdialysis probes were inserted into the NAC and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DO-PAC) and homovanillic acid (HVA), using a reverse-phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (i.c.v.) administration of selective mu-opioid [D-Ala2, N-methyl-Phe4, Gly5-ol]-enkephalin (DAMGO) or delta-opioid [D-Pen2, D-Pen5]-enkephalin (DPDPE) agonists, at doses that function as positive reinforcers in rats, resulted in an immediate and significant increase in extracellular DA. DOPAC and HVA levels were also significantly increased. The effects of DAMGO were blocked by the selective mu-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) whereas those of DPDPE were blocked by the delta-antagonist allyl2-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864). In contrast to mu- and delta-agonists, the kappa-agonist N-CH3-Tyr-Gly-Gly-Phe-Leu-Arg-N-CH3-Arg-D-Leu-NHC2H5 (E-2078), a dynorphin analog that produces aversive states, decreased DA release in a biphasic manner. Norbinaltorphimine, a selective kappa-antagonist, could block this effect. These results demonstrate that mu-, delta-, and kappa-opioid agonists differentially affect DA release in the NAC and this action is centrally mediated.

Analgesics↗

PubMed1989

Evidence that the aversive effects of opioid antagonists and kappa-agonists are centrally mediated.

The role of central versus peripheral opioid receptors in mediating the aversive effects of opioids was examined by use of an unbiased place preference conditioning procedure in rats. The non-selective opioid antagonist naloxone (NLX) produced conditioned aversions for the drug-associated place after subcutaneous (SC) as well as intracerebroventricular (ICV) administration. Place aversions were also observed in response to the ICV administration of the selective mu-antagonist CTOP. In contrast, the selective delta-antagonist ICI 174,864 and the selective kappa-antagonist norbinaltorphimine (nor-BNI) (ICV) were without effect. Place aversions were also produced by central applications of the selective kappa-agonist U50,488H and the dynorphin derivative E-2078. For those opioid ligands tested, the doses required to produce place aversions were substantially lower following ICV as compared to SC administration. These data confirm that kappa-agonists and opioid antagonists produce aversive states in the drug-naive animal and demonstrate that this effect is centrally mediated. Furthermore, the ability of NLX and CTOP, in contrast to both ICI 174,864 and nor-BNI, to produce place aversions suggests that the aversive effects of opioid antagonists result from the blockade of mu-receptors.

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

PubMed1989

Morphine-induced place conditioning is not confounded by drug-induced alterations in locomotor activity.

The influence of locomotor activity and environmental familiarity upon the reinforcing effects of morphine was examined in an unbiased place preference conditioning procedure. Groups of rats were trained to associate one distinctive environment with morphine and another with saline. One group was made tolerant to the locomotor activity effects of morphine by the SC administration of morphine (5.0 mg/kg/12 hr) for four days prior to conditioning. The other group received injections of saline. Administration of morphine, at doses which decreased locomotor activity, resulted in marked preferences for the drug-associated place in saline-treated rats. In contrast, chronic morphine treatment resulted in tolerance to the sedative effects of morphine and an abolition of the morphine-induced place preference. These results indicate that in the place conditioning procedure, measures of reinforcement are not confounded by drug-induced increases in activity.

Animals↗

PubMed1989

Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors.

This study examined a possible peripheral site of action of opioids in the modulation of the response to noxious pressure on inflamed tissue. Rats developed a unilateral localized inflammation upon injection of Freund's complete adjuvant into one hindpaw. 4-6 days after inoculation, intraplantar administration of mu, delta and kappa selective agonists [D-Ala2,N-methyl-Phe4,Gly-ol5]-en-kephalin (1 micrograms), [D-Pen2,5]-enkephalin (40 micrograms) and U-50, 488H (50 micrograms) produced marked antinociceptive effects in inflamed but not noninflamed paws. Equivalent doses applied systemically (s.c. and i.v.) were without effect. Dose dependency and stereospecificity of these effects were demonstrated using (-)- and (+)-morphine and (-)- and (+)-tifluadom. Furthermore, by use of (-)- and (+)-naloxone, dose-dependent and stereospecific antagonism was shown. Lastly, reversal of effects of [D-Ala2,N-methyl-Phe4,Gly-Ol5]-enkephalin, [D-Pen2,5]-enkephalin and U-50,488H by mu, delta and kappa selective antagonists D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, ICI 174,864 and nor-BNI, respectively, indicated that these agents interact with discriminable populations of receptors. These observations suggest that several selective opioid agonists can modulate responses to noxious pressure through a peripheral opioid receptor-specific site of action in inflammation and that these receptors possess distinguishable pharmacological characteristics resembling those of mu, delta and kappa receptors.

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

PubMed1988

Involvement of beta-endorphin and mu-opioid receptors in mediating the aversive effect of lithium in the rat.

The role of beta-endorphin and mu-opioid receptors in mediating the motivational effect of lithium was examined by use of an unbiased place-preference conditioning procedure. Administration of lithium to drug-naive rats resulted in a dose-related aversion for the drug-associated place. Radiofrequency lesions of the medio-basal arcuate hypothalamus, which markedly reduced the levels of immunoreactive beta-endorphin in the hypothalamus, abolished the lithium-induced aversion. However, suppression of circulating beta-endorphin levels by chronic dexamethasone treatment was without effect. Infusion of the opioid antagonist, naloxone, throughout the conditioning procedure at a dose (0.5 mg/kg per h) that blocks mu- but not kappa-opioid receptors, resulted in the complete abolition of the lithium-induced place aversion. These data demonstrate an involvement of endogenous opioidergic systems in the motivational effect of lithium and indicate that the aversive properties of this drug result from its interactions with beta-endorphin and mu-opioid receptors in the CNS.

Analgesics↗

PubMed1988

Motivational effects of opioids: influence of D-1 versus D-2 receptor antagonists.

An unbiased place preference conditioning procedure was used to: (i) characterize the motivational effects of dopamine (DA)-receptor antagonists and (ii) examine the role of D-1 versus D-2 DA receptors in mediating the reinforcing and aversive properties of opioids. Acute administration of the D-1 antagonist, SCH 23390 (0.001-0.5 mg/kg), produced conditioned place aversions. In contrast, the D-2 antagonists, (-)-sulpiride and spiperone, were motivationally neutral, lacking reinforcing or aversive effects. Chronic infusion of SCH 23390 (1.0 mg/kg per day) during the conditioning sessions abolished the reinforcing effect of the mu-opioid agonist, morphine, and the place aversions produced by the kappa-opioid agonist, U-69593, and the opioid antagonist, naloxone. D-2 antagonists were ineffective in modifying the motivational properties of opioid agonists and naloxone. These data demonstrate the involvement of D-1 but not D-2 receptors in the motivational properties of opioids and suggest that the D-1 receptor is critical for the expression of reinforcing and aversive motivational states.

Animals↗

PubMed1988

Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat.

This study examined a possible peripheral site of action of opiates in the modulation of the response to noxious pressure on inflamed paws. Rats received an injection of Mycobacterium butyricum suspension into one hindpaw which resulted in an ipsilateral inflammatory response (swelling) and decreased threshold to noxious pressure within 1-2 days. Four days post-inoculation direct intraplantar injection of fentanyl resulted in a significant increase of paw pressure thresholds in inflamed, but not in non-inflamed paws. Intraplantar injection of (-)-naloxone but not (+)-naloxone reversed this effect. The action of fentanyl was dose dependent at doses of 0.1-1.2 micrograms. Equal doses of fentanyl given systemically as well as (-)-naloxone or (+)-naloxone given alone were inactive. These data show that fentanyl can modify the response to noxious pressure in inflamed but not non-inflamed paws via a peripheral site of action. Stereospecific reversibility by naloxone as well as dose dependency strongly indicate an opioid mechanism of action. This suggests a possible role for peripherally located opioid receptors in the modulation of nociception in inflamed tissue.

Animals↗

PubMed1988

Beta-endorphin-(1-27) is a naturally occurring antagonist of the reinforcing effects of opioids.

A place preference conditioning procedure was used to characterize the motivational effects of beta-endorphin-(1-27), a naturally occurring fragment of beta-endorphin (beta-EP). The intracerebroventricular (ICV) administration of beta-EP, selective mu-(DAGO) or delta-(DPDPE) opioid receptor agonists to rats produced marked preferences for the drug-associated place, whereas the selective kappa-opioid receptor agonist, U-50488H produced conditioned aversions. ICV injections of the beta-EP-(1-27) (5-20 micrograms), however, resulted in no preference for either the drug- or vehicle-associated place. Pretreatment with beta-EP-(1-27) (10 micrograms) eliminated the place preference produced by beta-EP. It abolished the place preferences induced by both DAGO and DPDPE but did not modify the effects of either U-50488H or the psychostimulant d-amphetamine. These data demonstrate that beta-EP-(1-27) selectively antagonizes the motivational effects of mu- and delta-opioid agonists and suggest that this fragment may function as an endogenous antagonist of the reinforcing effects of opioid agonists in vivo.

Animals↗

PubMed1988

Tolerance and selective cross-tolerance to the motivational effects of opioids.

The issue of whether tolerance develops to the motivational effects of opioids was addressed by use of an unbiased place preference conditioning procedure. Administration of the mu-opioid agonists morphine or fentanyl produced dose-related preferences for the drug-associated place in control rats. In contrast, the kappa-opioid agonist, U-69593 produced conditioned place aversions. Non-contingent administration of morphine (5.0 mg/kg/12 h) for 4 days prior to conditioning resulted in tolerance to its reinforcing effects, and cross-tolerance to the effects of fentanyl. No cross-tolerance to the motivational effects of the psychostimulant d-amphetamine or the kappa-opioid agonist U-69593 was observed. Chronic administration of U-69593 prior to conditioning produced tolerance to its aversive effects. This treatment did not, however, modify the reinforcement produced by morphine. These data demonstrate that tolerance develops to both the reinforcing and aversive properties of opioids and suggest that differential cross-tolerance may provide a useful method for determining the pharmacological basis underlying drug-induced motivational effects.

Analgesics↗