uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
N-terminal truncations of substance P1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats
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 Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Show others and affiliations
2014 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 738, 319-325 p.Article in journal (Refereed) Published
Abstract [en]

Central neuropathic pain can arise from injury of the spinal cord and can become chronic. Treatment is difficult and, because complete pain relief is currently very hard to achieve, there is a need for new, more effective treatment options. In this study we used an animal model of spinal cord injury to evaluate the potency of a bioactive fragment of substance P (SP), i.e. SP1-7, in alleviating signs of allodynia and acute pain. SP1-7 is known from earlier studies to possess antinociceptive properties. We also studied the effects of intraperitoneal injection of an amidated analog of this heptapeptide and of its truncated analogs, all of which had high affinity to the SP1-7 binding site, to evaluate the importance of the removed amino acids for the bioclistribution and stability of the peptides. Most of the examined compounds alleviated mechanical alloclynia without any signs of sedation or motor impairment in the rats. In contrast, the response threshold to acute nociceptive stimulation was not affected by arty of the compounds tested. Most of the amino acids in the heptapepticle structure were essential for retaining the biological effect after peripheral injection. These observations suggest that the heptapepticle and its N-Lerminal truncated hexa- and pentapeptide analogs could be of interest for further development of analgesics in the management of mechanical allodynia.

Place, publisher, year, edition, pages
2014. Vol. 738, 319-325 p.
Keyword [en]
Chronic pain, Neuropathic pain, Spinal cord injury, Substance P fragment SP1-7, Anti-allodynia, Substance P-cleaving enzymes
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-230921DOI: 10.1016/j.ejphar.2014.05.060ISI: 000339998000040OAI: oai:DiVA.org:uu-230921DiVA: diva2:743597
Available from: 2014-09-04 Created: 2014-09-01 Last updated: 2015-07-07Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 198
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
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)
Available from: 2015-04-17 Created: 2015-01-14 Last updated: 2015-07-07

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Carlsson-Jonsson, AnnaFransson, RebeccaSandström, AnjaNyberg, Fred
By organisation
Department of Pharmaceutical BiosciencesOrganic Pharmaceutical Chemistry
In the same journal
European Journal of Pharmacology
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 294 hits
ReferencesLink to record
Permanent link

Direct link