<p>The heptapeptide SP<sub>1-7</sub>, 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 SP<sub>1-7</sub> 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. </p><p>Studies described in this thesis include investigation of adaptive changes during morphine tolerance and withdrawal in brain levels of SP<sub>1-7</sub> 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 SP<sub>1-7</sub> 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. </p><p>The effects of SP<sub>1-7</sub> 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 SP<sub>1-7</sub> 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 SP<sub>1-7</sub> and the dopamine system. </p><p>The influence of SP<sub>1-7</sub> 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. </p><p>It was concluded that SP<sub>1-7</sub> may function as an endogenous modulator of the expression of opioid withdrawal by influencing both dopaminergic and glutamatergic transmission. </p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-1551 |
| Date | January 2001 |
| Creators | Zhou, Qin |
| Publisher | Uppsala University, Department of Pharmaceutical Biosciences, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 0282-7484 ; 260 |
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