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The Impact of Substance P (SP) N-Terminal Metabolite SP1-7 in Opioid Tolerance and Withdrawal
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The heptapeptide SP1-7, a metabolite of the neuroactive peptide substance P (SP), is suggested to play a role in opioid addiction and memory function. These two dimensions are known to involve dopamine and glutamate transmissions mediated through dopamine receptors and N-methyl-D- aspartate (NNMA) receptors, respectively. Research on interactions between SP1-7 and these two neurotransmitter systems may therefore be of importance to increase our understanding of the mechanisms behind opioid tolerance and dependence as well as memory processes. New knowledge in this area may lead to the discovery of new therapeutic routes for treatment of opioid addiction and other neuropsychiatric disorders, as well.

Studies described in this thesis include investigation of adaptive changes during morphine tolerance and withdrawal in brain levels of SP1-7 and in the activity of substance P endopeptidase (SPE), an enzyme responsible for the generation of this fragment. In morphine tolerant and abstinent rats, the SP1-7 level and SPE activity were significantly increased in discrete areas of the brain, which are crucial for the development of opioid tolerance and dependence. Furthermore, significant correlations between the SPE activity and some morphine withdrawal signs were observed. This finding was indicative of an endogenous modulatory mechanism involving both the enzyme and its active peptide product.

The effects of SP1-7 on the expression of morphine withdrawal and its interaction with dopaminergic pathways were examined in this thesis by behavioural tests, microdialysis as well as Northern blot and autoradiography techniques. Pre-treatment of morphine dependent rats with SP1-7 was found to stimulate dopamine release in nucleus accumbens and to inhibit the intensity of withdrawal behaviours. It was further shown to regulate both the dopamine D2 receptor gene transcript and the density of dopamine receptor proteins in mesolimbic dopamine pathways, confirming an interaction between SP1-7 and the dopamine system.

The influence of SP1-7 on glutamate transmission was investigated in morphine naive rats. The expression of the gene transcripts of the NMDA receptor subunits NR1, NR2A and NR2B was regulated in several brain regions involved in opioid withdrawal reactions and memory functions. The result is consistent with a possible decrease glutamate transmission in these areas.

It was concluded that SP1-7 may function as an endogenous modulator of the expression of opioid withdrawal by influencing both dopaminergic and glutamatergic transmission.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2001. , p. 60
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 260
Keywords [en]
Pharmaceutical biosciences
Keywords [sv]
Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-1551ISBN: 91-554-5174-8 (print)OAI: oai:DiVA.org:uu-1551DiVA, id: diva2:161157
Public defence
2001-12-14, Lecture Hall B42, Uppsala Biomedical Centre, Uppsala, 09:15
Opponent
Available from: 2001-11-22 Created: 2001-11-22 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Alteration in the brain content of substance P (1-7) during withdrawal in morphine-dependent rats
Open this publication in new window or tab >>Alteration in the brain content of substance P (1-7) during withdrawal in morphine-dependent rats
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1998 In: Neuropharmacology, Vol. 37, p. 1545-1552Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89563 (URN)
Available from: 2001-11-22 Created: 2001-11-22Bibliographically approved
2. Substance P endopeptidase-like activity is altered in various regions of the rat central nervous system during morphine tolerance and withdrawal
Open this publication in new window or tab >>Substance P endopeptidase-like activity is altered in various regions of the rat central nervous system during morphine tolerance and withdrawal
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2001 In: Neuropharmacology, Vol. 41, p. 246-253Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89564 (URN)
Available from: 2001-11-22 Created: 2001-11-22Bibliographically approved
3. Intracerebroventricular injection of the N-terminal substance P (SP) fragment SP1-7 regulates the expression of the N-methyl-D-aspartate receptor NR1, NR2A and NR2B subunit mRNAs in the rat brain
Open this publication in new window or tab >>Intracerebroventricular injection of the N-terminal substance P (SP) fragment SP1-7 regulates the expression of the N-methyl-D-aspartate receptor NR1, NR2A and NR2B subunit mRNAs in the rat brain
2000 In: Neurosci Lett, Vol. 291, p. 109-112Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89565 (URN)
Available from: 2001-11-22 Created: 2001-11-22Bibliographically approved
4. Injection of substance P (SP) N-terminal fragment SP1-7 into the ventral tegmental area modulates the levels of nucleus accumbens dopamine and DOPAC in male rats during morphine withdrawal
Open this publication in new window or tab >>Injection of substance P (SP) N-terminal fragment SP1-7 into the ventral tegmental area modulates the levels of nucleus accumbens dopamine and DOPAC in male rats during morphine withdrawal
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-89566 (URN)
Available from: 2001-11-22 Created: 2001-11-22Bibliographically approved
5. The substance P aminoterminal metabolite SP(1-7) affects the expression of the dopamine D2 receptor gene transcript in male rat frontal cortex and nucleus accumbens during morphine withdrawal
Open this publication in new window or tab >>The substance P aminoterminal metabolite SP(1-7) affects the expression of the dopamine D2 receptor gene transcript in male rat frontal cortex and nucleus accumbens during morphine withdrawal
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-89567 (URN)
Available from: 2001-11-22 Created: 2001-11-22Bibliographically approved
6. The substance P (SP) heptapeptide fragment SP1-7 alters the density of dopamine receptors in rat brain mesocorticolimbic structures during morphine withdrawal
Open this publication in new window or tab >>The substance P (SP) heptapeptide fragment SP1-7 alters the density of dopamine receptors in rat brain mesocorticolimbic structures during morphine withdrawal
2004 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 25, no 11, p. 1951-1957Article in journal (Refereed) Published
Abstract [en]

The aminoterminal fragment of substance P (SP), SP(1-7), has been suggested to modulate the expression of opiate tolerance and withdrawal behaviors in rodents. However, the mechanism of this effect is not yet clarified. Using a rat model we have previously demonstrated that SP(1-7) affects dopamine transmission and the expression of the dopamine D2-receptor gene transcript in the nucleus accumbens during naloxone precipitated morphine withdrawal. In the present study, we have applied autoradiography to investigate the effect of the heptapeptide on the binding of dopamine D1- and D2-receptors in mesocorticolimbic brain areas of male rats during morphine withdrawal. Morphine dependent animals were treated with an injection of SP(1-7) into the ventral tegmental area prior to naloxone challenge. The result indicated that the SP fragment elicited a significant decrease in specific binding to D1-like receptors in the caudate putamen, nucleus accumbens shell, nucleus accumbens core, substantia nigra and medial globus pallidus. Radioligand binding to dopamine D2-like receptors was also altered by SP(1-7). The heptapeptide induced a decreased density of these sites in the ventral tegmental area but an increased binding in the substantia nigra and the frontal cortex. The observed alterations in the D1- and D2-like receptor density could reflect activations in dopamine pathways associated with the above-mentioned brain regions. The result provides further evidence for the modulatory effect of SP(1-7) on dopamine systems during opioid withdrawal, suggesting the possible role for the heptapeptide to regulate morphine withdrawal reactions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89568 (URN)10.1016/j.peptides.2004.07.011 (DOI)15501527 (PubMedID)
Available from: 2001-11-22 Created: 2001-11-22 Last updated: 2017-12-14Bibliographically approved

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