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Hemorphins and endomorphins
Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
2000 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

In this thesis, two newly discovered endogenous opioid peptide families, the hemorphins and endomorphins, are investigated with emphasis on modulation of pain and inflammation. In addition, the presence of hemorphins in human biological fluids as well as the in vitro and in vivo processing ofLVV-hemorphin-7 in blood and brain is investigated.

Using various chromatographic techniques in combination with radioimmunoassay, several hemorphin-like peptides were detected in cerebrospinal fluid from patients with cerebrovascular bleedings, but only in negligible amounts in control CSF.

Results from in vitro experiments in human plasma showed that LVV-hemorphin-7 was metabolized mainly from the N-terminal end, as determined by RP-HPLC and micro-electrospray mass spectromety. In vivo microdialysis was used to study the processing of LVV-hemorphin-7 in rat striatum and blood. The results demonstrated that the decapeptide was metabolized to form C-terminal fragments, consistent with the results in vitro, however an N-terminal fragment and several internal fragments were also detected.

The modulatory effects of hemorphin-7 and endomorhin-1 (EM-l) on a peripheral inflammatory response were investigated in a blister model in the rat hind paw. The results showed that hemorphin-7 (20µM) and EM-1 (100µM) inhibited the vascular response to electrical stimulation of the sciatic nerve at 20V, 5Hz, 2ms by 54% and 58%, respectively. When exogenously perfused over blisters induced acutely in naive skin, both peptides were shown to attenuate both plasmaextravasation and vasodilatation responses to substance P in a naloxone-revesible manner, suggesting an involvement of opioid receptor(s) in these responses. While hemorphin-7 was shown to modulate the peripheral inflammatory response, in acute injury conditions only, EM-l was able to attenuate this response in acute, as well as recurrent and chronic injury conditions. The results presented support the proposition that different endogenous inhibitory mechanisms operate under different injury conditions.

A rat model with thermal stimulation was used to compare the antinociceptive properties of intrathecally administered EM-l to morphine. I.t. injections of 100 µg of EM-1 resulted in significantly prolonged withdrawal times after 10 and 20 min, indicating an antinociceptive effect of the peptide. The results also showed that EM-l had a shorter duration and lower potency compared to morphine in this preparation.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis , 2000. , s. 70
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 219
Emneord [en]
Pharmaceutical biosciences, Hemorphins, endomorphins, opioid receptors, peptide metabolism, neurogenic inflammation, pain
Emneord [sv]
Farmaceutisk biovetenskap
HSV kategori
Forskningsprogram
biologisk beroendeforskning
Identifikatorer
URN: urn:nbn:se:uu:diva-414ISBN: 91-554-4626-4 (tryckt)OAI: oai:DiVA.org:uu-414DiVA, id: diva2:164298
Disputas
2000-01-07, lecture hall B42, Biomedical Center, Uppsala, Uppsala, 10:15
Tilgjengelig fra: 1999-12-17 Laget: 1999-12-17 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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