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Substance P1-7 induces antihyperalgesia in diabetic mice through a mechanism involving the naloxone-sensitive sigma receptors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2010 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 626, no 2-3, 250-255 p.Article in journal (Refereed) Published
Abstract [en]

We have recently explored the role of the tachykinin substance P neuroactive fragment substance P1-7 in the mediation of anti-inflammatory effects using a blister model in the rat paw (Wiktelius et al., 2006). We observed that this heptapeptide induced a dose-dependent inhibitory effect on the substance P-induced response, which was reversible by the non-selective opioid receptor antagonist naloxone. In the present study, we examined the ability of substance P1-7 to induce antihyperalgesic effects in streptozotocin-induced diabetic mice. We found that the substance P fragment strongly and dose-dependently produced antihyperalgesia in diabetic mice. This effect was reversed by naloxone but not by the selective opioid receptor antagonist beta-funaltrexamine, naltrindole or nor-binaltorphimine. selective for the mu-, delta- or kappa-Opioid receptor, respectively. In addition, the anti hyperalgesic effect induced by substance P1-7 was partly reversed by a sigma(1) receptor agonist (+)-pentazocine. but not a a, receptor antagonist BD1047 ([2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(diamino)ethylamine), suggesting that involvement of the naloxone-sensitive sigma-receptor for the action of the SP related heptapeptides. These results suggest that hyperalgesia in diabetic mice may be, in part, due to the enhanced endogenous sigma(1) receptor systems in the spinal cord.

Place, publisher, year, edition, pages
2010. Vol. 626, no 2-3, 250-255 p.
Keyword [en]
Antihyperalgesia, Substance P fragment substance P1-7, Opioid receptor, Naloxone, Sigma-receptor, Diabetic (mouse)
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-138034DOI: 10.1016/j.ejphar.2009.10.006ISI: 000274090800021PubMedID: 19836387OAI: oai:DiVA.org:uu-138034DiVA: diva2:378787
Available from: 2010-12-16 Created: 2010-12-16 Last updated: 2017-12-11Bibliographically approved
In thesis
1. The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain
Open this publication in new window or tab >>The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is an unmet medical need for the efficient treatment of neuropathic pain, a condition that affects approximately 10% of the population worldwide. Current therapies need to be improved due to the associated side effects and lack of response in many patients. Moreover, neuropathic pain causes great suffering to patients and puts an economical burden on society.

The work presented in this thesis addresses SP1-7, (Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), a major metabolite of the pronociceptive neuropeptide Substance P (SP). SP is released in the spinal cord following a noxious stimulus and binds to the NK1 receptor. In contrast to SP, the degradation fragment SP1-7 is antinociceptive through binding to specific binding sites distinct from the NK1 receptor.

The aim of this thesis was to investigate the impact of SP1-7 on neuropathic pain. To understand how SP1-7 exerts its effect, a series of N-truncated forms of the heptapeptide were biologically evaluated. A set of small high-affinity ligands was evaluated in animal models of neuropathic pain. To confirm a clinical relevance the levels of SP1-7 in human neuropathic pain were assessed incerebrospinal fluid (CSF) collected from neuropathic pain patients.

The results showed that SP1-7 could alleviate thermal as well as mechanical hypersensitivity in three different animal models of neuropathic pain. C-terminal amidation was connected with increased efficacy. N-terminal truncation of SP1-7 indicated a necessity of five amino acids in order to retain biological effect. One small high-affinity ligand showed a significant anti-allodynic effect. CSF levels of SP1-7 in neuropathic pain patients were lower compared to controls. Taken together, these findings demonstrate that the formation of SP1-7 may be attenuated in neuropathic pain. C-terminal amidation and a majority of its amino acids are necessary for stability and permeability. Clearly, SP1-7 and SP1-7 mimetics with high affinity to the SP1-7 binding site ameliorate neuropathic pain-like behaviors in animal models of neuropathic pain. Overall, the findings presented in this thesis contribute to new knowledge regarding the role of SP1-7 and related analogues and fragments in neuropathic pain. In a future perspective, this could be essential for the development of efficient strategies for managing patients with neuropathic pain.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 198
Keyword
neuropathic pain; substance P (SP); SP1-7; bioactive fragments; spared nerve injury; spinal cord injury; streptozotocin-induced diabetes; allodynia; hyperalgesia; peptidomimetics; cerebrospinal fluid; spinal cord stimulation, radioimmunoassay
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-241637 (URN)978-91-554-9206-9 (ISBN)
Public defence
2015-05-08, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2015-04-17 Created: 2015-01-14 Last updated: 2015-07-07

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Hallberg, MathiasNyberg, Fred J

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