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The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Biologisk beroendeforskning)
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 [en]
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: urn:nbn:se:uu:diva-241637ISBN: 978-91-554-9206-9 (print)OAI: oai:DiVA.org:uu-241637DiVA: diva2:796262
Public defence
2015-05-08, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-04-17 Created: 2015-01-14 Last updated: 2015-07-07
List of papers
1. Substance P1-7 induces antihyperalgesia in diabetic mice through a mechanism involving the naloxone-sensitive sigma receptors
Open this publication in new window or tab >>Substance P1-7 induces antihyperalgesia in diabetic mice through a mechanism involving the naloxone-sensitive sigma receptors
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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.

Keyword
Antihyperalgesia, Substance P fragment substance P1-7, Opioid receptor, Naloxone, Sigma-receptor, Diabetic (mouse)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-138034 (URN)10.1016/j.ejphar.2009.10.006 (DOI)000274090800021 ()19836387 (PubMedID)
Available from: 2010-12-16 Created: 2010-12-16 Last updated: 2017-12-11Bibliographically approved
2. The effect of substance P1-7 amide on nociceptive threshold in diabetic mice
Open this publication in new window or tab >>The effect of substance P1-7 amide on nociceptive threshold in diabetic mice
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2011 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 32, no 1, 93-98 p.Article in journal (Refereed) Published
Abstract [en]

We previously demonstrated that intrathecal treatment with substance P metabolite substance P1-7 induced anti-hyperalgesia in diabetic mice. In the present study, we have used a synthetic analog of this peptide, the substance P1-7 amide, showing higher binding affinitiy than the native heptapeptide, for studies of the tail-flick response in diabetic and non-diabetic mice. Intrathecal injection of substance P1-7 amide produced prolongation of the tail-flick latency in both diabetic and non-diabetic mice, an effect that was more pronounced in diabetic mice than non-diabetic mice. Moreover, the observed antinociceptive potency of the substance P1-7 amide was higher in both diabetic and non-diabetic mice in comparison with the native substance P1-7. The antinociceptive effect of substance P1-7 amide 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 antinociceptive effect induced by substance P1-7 amide was partly reversed by the sigma(1) receptor agonist (+)-pentazocine, suggesting a possible involvement of the sigma(1) receptor for the action of this peptide. These results suggest that the actions of substance P1-7 amide mimic the effects of the native substance P fragment but with higher potency and that the mechanisms for its action may involve the sigma(1) receptor system.

Keyword
Antinociception, Diabetes, Substance P fragment substance P1-7, Opioid receptors, Substance P1-7 amide, Sigma receptor
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-147780 (URN)10.1016/j.peptides.2010.09.029 (DOI)000286562300015 ()20933559 (PubMedID)
Available from: 2011-02-28 Created: 2011-02-28 Last updated: 2017-12-11Bibliographically approved
3. N-terminal truncations of substance P1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats
Open this publication in new window or tab >>N-terminal truncations of substance P1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats
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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.

Keyword
Chronic pain, Neuropathic pain, Spinal cord injury, Substance P fragment SP1-7, Anti-allodynia, Substance P-cleaving enzymes
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-230921 (URN)10.1016/j.ejphar.2014.05.060 (DOI)000339998000040 ()
Available from: 2014-09-04 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
4. Small constrained SP1-7 analogues bind to a unique site and promote anti-allodynic effects following systemic injection in mice
Open this publication in new window or tab >>Small constrained SP1-7 analogues bind to a unique site and promote anti-allodynic effects following systemic injection in mice
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2015 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 298, 112-119 p.Article in journal (Refereed) Published
Abstract [en]

Previous results have shown that the substance P (SP) N-terminal fragment SP1–7 may attenuate hyperalgesia and produce anti-allodynia in animals using various experimental models for neuropathic pain. The heptapeptide was found to induce its effects through binding to and activating specific sites apart from any known neurokinin or opioid receptor. Furthermore, we have applied a medicinal chemistry program to develop lead compounds mimicking the effect of SP1–7. The present study was designed to evaluate the pharmacological effect of these compounds using the mouse spared nerve injury (SNI) model of chronic neuropathic pain. Also, as no comprehensive screen with the aim to identify the SP1–7 target has yet been performed we screened our lead compound H-Phe-Phe-NH2 toward a panel of drug targets. The extensive target screen, including 111 targets, did not reveal any hit for the binding site among a number of known receptors or enzymes involved in pain modulation. Our animal studies confirmed that SP1–7, but also synthetic analogs thereof, possesses anti-allodynic effects in the mouse SNI model of neuropathic pain. One of the lead compounds, a constrained H-Phe-Phe-NH2 analog, was shown to exhibit a significant anti-allodynic effect.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-247270 (URN)10.1016/j.neuroscience.2015.04.002 (DOI)000354783300011 ()25862586 (PubMedID)
Available from: 2015-03-16 Created: 2015-03-16 Last updated: 2017-12-04Bibliographically approved
5. Cerebrospinal fluid levels of substance P (SP) N-terminal fragment SP1-7 in patients with chronic neuropathic pain
Open this publication in new window or tab >>Cerebrospinal fluid levels of substance P (SP) N-terminal fragment SP1-7 in patients with chronic neuropathic pain
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(English)Manuscript (preprint) (Other academic)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-247271 (URN)
Available from: 2015-03-16 Created: 2015-03-16 Last updated: 2015-07-07

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