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Protein & Peptide Letters

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ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

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Research Article

Antinociceptive Effects of VV-Hemorphin-5 Peptide Analogues Containing Amino phosphonate Moiety in Mouse Formalin Model of Pain

Author(s): Borislav Assenov, Daniela Pechlivanova*, Elena Dzhambazova, Petia Peneva and Petar Todorov

Volume 28, Issue 4, 2021

Published on: 13 August, 2020

Page: [442 - 449] Pages: 8

DOI: 10.2174/0929866527666200813200714

Price: $65

Abstract

Background: Hemorphins are endogenous hemoglobin-derived peptides that belong to the family of “atypical” opioid peptides with both affinities to opioid receptors and ability to release other endogenous opioid peptides.

Objective: In the present study, peptide analogues of Valorphin (VV-hemorphin-5) containing amino phosphonate moiety synthesized by solid-phase peptide synthesis (Fmoc-strategy) were investigated for their potential antinociceptive activities and compared to the reference VV-H in formalin- induced model of acute and inflammatory pain in mice.

Methods: The hemorphin analogues were prepared by replacement of the one and/or two N-terminal Val in VV-hemorphin5 (VV-H) with ((dimethoxy phosphoryl) methyl)-L-valine and ((dimethoxy phosphoryl) methyl)-L-leucine to obtain the compounds pVV-H, pL-H, and pLV-H. Aiming to additionally prove the importance of amino acid valine, we introduced the ((dimethoxy phosphoryl) methyl)-L-leucine to the N-side of VV-hemorphin-5 (pLVV-H). The experiments were carried out on adult male ICR mice. All peptides were administered intracerebroventricularly at three doses (50, 25 and 12,5 μg/mouse). We have studied the effects of the peptides on acute (1st phase) and inflammatory (2nd phase) pain reaction using un experimental model with intraplantar formalin injection.

Results: VV-H showed a significant antinociceptive effect both in the acute and inflammatory phases of the test. Although Valorphin hexa-, hepta-, and octapeptide analogs demonstrated a significant antinociceptive effect, they showed substantial differences considering their effective dose and the phase of the test as compared to the Valorphin.

Discussion: Data showed that modified heptapeptides pVV-H and pLV-H exerted the same or better antinociception in acute and inflammatory pain, in comparison to the reference peptide, while pL-H and pLVV-H analogues were less effective.

Conclusion: Our study contributes to the elucidation of the role of Valine and the number of amino acid residues in the structure of hemorphin peptide analogs in their effectiveness in suppressing both acute and inflammatory experimental pain.

Keywords: Hemorphin analogues, opioid peptides, analgesic drugs, formalin test, inflammatory pain, mice.

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[1]
Zadina, J.E.; Nilges, M.R.; Morgenweck, J.; Zhang, X.; Hackler, L.; Fasold, M.B. Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine. Neuropharmacology, 2016, 105, 215-227.
[http://dx.doi.org/10.1016/j.neuropharm.2015.12.024] [PMID: 26748051]
[2]
Nyberg, F.; Sanderson, K.; Glämsta, E.L. The hemorphins: a new class of opioid peptides derived from the blood protein hemoglobin. Biopolymers, 1997, 43(2), 147-156.
[http://dx.doi.org/10.1002/(SICI)1097-0282(1997)43:2<147::AID-BIP8>3.0.CO;2-V] [PMID: 9216251]
[3]
Liebmann, C.; Szücs, M.; Neubert, K.; Hartrodt, B.; Arold, H.; Barth, A. Opiate receptor binding affinities of some D-amino acid substituted β-casomorphin analogs. Peptides, 1986, 7(2), 195-199.
[http://dx.doi.org/10.1016/0196-9781(86)90212-3] [PMID: 3016678]
[4]
Zhao, Q.; Piot, J.M.; Sannier, F.; Guillochon, D. Peptic hemoglobin hydrolysis in an ultrafiltration reactor at pilot plant scale generates opioid peptides. Ann. N. Y. Acad. Sci., 1995, 750, 452-458.
[http://dx.doi.org/10.1111/j.1749-6632.1995.tb19995.x] [PMID: 7785876]
[5]
Ivanov, V.T.; Karelin, A.A.; Philippova, M.M.; Nazimov, I.V.; Pletnev, V.Z. Hemoglobin as a source of endogenous bioactive peptides: the concept of tissue-specific peptide pool. Biopolymers, 1997, 43(2), 171-188.
[http://dx.doi.org/10.1002/(SICI)1097-0282(1997)43:2<171::AID-BIP10>3.0.CO;2-O] [PMID: 9216253]
[6]
Brantl, V.; Gramsch, C.; Lottspeich, F.; Mertz, R.; Jaeger, K.H.; Herz, A. Novel opioid peptides derived from hemoglobin: hemorphins. Eur. J. Pharmacol., 1986, 125(2), 309-310.
[http://dx.doi.org/10.1016/0014-2999(86)90044-0] [PMID: 3743640]
[7]
Song, C.Z.; Wang, Q.W.; Song, C.C. Hemorphin as a prognostic biomarker and potential drug for breast cancer? Int. J. Cancer, 2012, 131(4), 1011-1012.
[http://dx.doi.org/10.1002/ijc.26450] [PMID: 21953447]
[8]
Davis, T.P.; Gillespie, T.J.; Porreca, F. Peptide fragments derived from the beta-chain of hemoglobin (hemorphins) are centrally active in vivo. Peptides, 1989, 10(4), 747-751.
[http://dx.doi.org/10.1016/0196-9781(89)90107-1] [PMID: 2587417]
[9]
Maurer, R.; Römer, D.; Büscher, H.H.; Gähwiler, B.H.; Thies, P.W.; David, S. Valorphin: a novel chemical structure with opioid activity. Neuropeptides, 1985, 5(4-6), 387-390.
[http://dx.doi.org/10.1016/0143-4179(85)90035-6] [PMID: 2860596]
[10]
Zadina, J.E.; Kastin, A.J.; Kersh, D.; Wyatt, A. Tyr-MIF-1 and hemorphin can act as opiate agonists as well as antagonists in the guinea pig ileum. Life Sci., 1992, 51(11), 869-885.
[http://dx.doi.org/10.1016/0024-3205(92)90615-V] [PMID: 1355851]
[11]
Domenger, D.; Cudennec, B.; Kouach, M.; Touche, V.; Landry, C.; Lesage, J.; Gosselet, F.; Lestavel, S.; Goossens, J.F.; Dhulster, P.; Ravallec, R. Food-derived hemorphins cross intestinal and blood-brain barriers in vitro. Front. Endocrinol. (Lausanne), 2018, 9, 159.
[http://dx.doi.org/10.3389/fendo.2018.00159] [PMID: 29692758]
[12]
Domenger, D.; Caron, J.; Belguesmia, Y.; Lesage, J.; Dhulster, P.; Ravallec, R.; Cudennec, B. Bioactivities of hemorphins released from bovine haemoglobin gastrointestinal digestion: Dual effects on intestinal hormones and DPP-IV regulations. J. Funct. Foods, 2017, 36, 9-17.
[http://dx.doi.org/10.1016/j.jff.2017.06.047]
[13]
Erchegyi, J.; Kastin, A.J.; Zadina, J.E.; Qiu, X.D. Isolation of a heptapeptide Val-Val-Tyr-Pro-Trp-Thr-Gln (valorphin) with some opiate activity. Int. J. Pept. Protein Res., 1992, 39(6), 477-484.
[http://dx.doi.org/10.1111/j.1399-3011.1992.tb00277.x] [PMID: 1356941]
[14]
Mortensen, U.H.; Raaschou-Nielsen, M.; Breddam, K. Recognition of C-terminal amide groups by (serine) carboxypeptidase Y investigated by site-directed mutagenesis. J. Biol. Chem., 1994, 269(22), 15528-15532.
[PMID: 8195197]
[15]
Pogozheva, I.D.; Przydzial, M.J.; Mosberg, H.I. Homology modeling of opioid receptor-ligand complexes using experimental constraints. AAPS J., 2005, 7(2), E434-E448.
[http://dx.doi.org/10.1208/aapsj070243] [PMID: 16353922]
[16]
Todorov, P.; Peneva, P.; Pechlivanova, D.; Georgieva, S.; Dzhambazova, E. Synthesis, characterization and nociceptive screening of new VV-hemorphin-5 analogues. Bioorg. Med. Chem. Lett., 2018, 28(18), 3073-3079.
[http://dx.doi.org/10.1016/j.bmcl.2018.07.040] [PMID: 30078474]
[17]
Kukhar, V.; Hudson, H. Aminophosphonic and aminophosphinic acids chemistry and biological activity; John Wiley, 2000, pp. 173-203.
[18]
Hariharan, M.; Motekaitis, R.J.; Martell, A.E. Synthesis of dipeptides of aminophosphonic acids. J. Org. Chem., 1975, 40(4), 470-473.
[http://dx.doi.org/10.1021/jo00892a020] [PMID: 1133623]
[19]
Kafarski, P.; Lejczak, B. Synthesis of phosphono- and phosphinopeptides. Aminophosphonic and aminophosphinic acids chemistry and biological activity; Kukhar, V.P.; Hudson, H.R., Eds.; Wiley Chichester, 2000, pp. 173-204.
[20]
Kafarski, P.; Lejczak, B. The biological activity of phosphono and phosphinopeptides. Aminophosphonic and aminophosphinic acids: Chemistry and biological activity; Kukhar, V.P.; Hudson, H.R., Eds.; Wiley Chichester, 2000, pp. 407-442.
[21]
Todorov, P.; Peneva, P.; Tchekalarova, J.; Rangelov, M.; Georgieva, S.; Todorova, N. Synthesis, characterization and anticonvulsant activity of new series of N-modified analogues of VV-hemorphin-5 with aminophosphonate moiety. Amino Acids, 2019, 51(10-12), 1527-1545.
[http://dx.doi.org/10.1007/s00726-019-02789-0] [PMID: 31576456]
[22]
Haley, T.J.; McCormick, W.G. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Br. J. Pharmacol. Chemother., 1957, 12(1), 12-15.
[http://dx.doi.org/10.1111/j.1476-5381.1957.tb01354.x] [PMID: 13413144]
[23]
Zhao, H.; Sugawara, T.; Miura, S.; Iijima, T.; Kashimoto, S. Intrathecal landiolol inhibits nociception and spinal c-Fos expression in the mouse formalin test. Can. J. Anaesth., 2007, 54(3), 201-207.
[http://dx.doi.org/10.1007/BF03022641] [PMID: 17331932]
[24]
Todorov, P.; Rangelov, M.; Peneva, P.; Todorova, N.; Tchekalarova, J. Anticonvulsant evaluation and docking analysis of VV-Hemorphin-5 analogues. Drug Dev. Res., 2019, 80(4), 425-437.
[http://dx.doi.org/10.1002/ddr.21514] [PMID: 30681179]
[25]
Calabrese, E.J. Pain and u-shaped dose responses: occurrence, mechanisms, and clinical implications. Crit. Rev. Toxicol., 2008, 38(7), 579-590.
[http://dx.doi.org/10.1080/10408440802026281] [PMID: 18709566]
[26]
Laulin, J.P.; Maurette, P.; Corcuff, J.B.; Rivat, C.; Chauvin, M.; Simonnet, G. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth. Analg., 2002, 94(5), 1263-1269.
[http://dx.doi.org/10.1097/00000539-200205000-00040] [PMID: 11973202]
[27]
Galeotti, N.; Stefano, G.B.; Guarna, M.; Bianchi, E.; Ghelardini, C. Signaling pathway of morphine induced acute thermal hyperalgesia in mice. Pain, 2006, 123(3), 294-305.
[http://dx.doi.org/10.1016/j.pain.2006.03.008] [PMID: 16650582]
[28]
Rubovitch, V.; Gafni, M.; Sarne, Y. The mu opioid agonist DAMGO stimulates cAMP production in SK-N-SH cells through a PLC-PKC-Ca++ pathway. Brain Res. Mol. Brain Res., 2003, 110(2), 261-266.
[http://dx.doi.org/10.1016/S0169-328X(02)00656-3] [PMID: 12591162]
[29]
Hunskaar, S.; Berge, O.G.; Hole, K. Dissociation between antinociceptive and anti-inflammatory effects of acetylsalicylic acid and indomethacin in the formalin test. Pain, 1986, 25(1), 125-132.
[http://dx.doi.org/10.1016/0304-3959(86)90014-X] [PMID: 3714284]
[30]
Henry, J.L.; Yashpal, K.; Pitcher, G.M.; Coderre, T.J. Physiological evidence that the ‘interphase’ in the formalin test is due to active inhibition. Pain, 1999, 82(1), 57-63.
[http://dx.doi.org/10.1016/S0304-3959(99)00033-0] [PMID: 10422660]
[31]
McNamara, C.R.; Mandel-Brehm, J.; Bautista, D.M.; Siemens, J.; Deranian, K.L.; Zhao, M.; Hayward, N.J.; Chong, J.A.; Julius, D.; Moran, M.M.; Fanger, C.M. TRPA1 mediates formalin-induced pain. Proc. Natl. Acad. Sci. USA, 2007, 104(33), 13525-13530.
[http://dx.doi.org/10.1073/pnas.0705924104] [PMID: 17686976]
[32]
Azhdari-Zarmehri, H.; Haidari-Oranji, N.; Soleimani, N.; Sofiabadi, M. Effects of lidocaine injections into the rostral ventromedial medulla on nociceptive behviours in hot-plate and formalin tests in rats. Koomesh, 2013, 14(4), 490-496.
[33]
Coderre, T.J.; Katz, J.; Vaccarino, A.L.; Melzack, R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain, 1993, 52(3), 259-285.
[http://dx.doi.org/10.1016/0304-3959(93)90161-H] [PMID: 7681556]
[34]
Coderre, T.J.; Yashpal, K. Intracellular messengers contributing to persistent nociception and hyperalgesia induced by L-glutamate and substance P in the rat formalin pain model. Eur. J. Neurosci., 1994, 6(8), 1328-1334.
[http://dx.doi.org/10.1111/j.1460-9568.1994.tb00323.x] [PMID: 7526941]
[35]
Hunskaar, S.; Hole, K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain, 1987, 30(1), 103-114.
[http://dx.doi.org/10.1016/0304-3959(87)90088-1] [PMID: 3614974]
[36]
Dickenson, A.H.; Sullivan, A.F. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain, 1987, 30(3), 349-360.
[http://dx.doi.org/10.1016/0304-3959(87)90023-6] [PMID: 3670880]
[37]
Sevostianova, N.; Zvartau, E.; Bespalov, A.; Danysz, W. Effects of morphine on formalin-induced nociception in rats. Eur. J. Pharmacol., 2003, 462(1-3), 109-113.
[http://dx.doi.org/10.1016/S0014-2999(03)01345-1] [PMID: 12591102]
[38]
Pasquinucci, L.; Turnaturi, R.; Montenegro, L.; Caraci, F.; Chiechio, S.; Parenti, C. Simultaneous targeting of MOR/DOR: A useful strategy for inflammatory pain modulation. Eur. J. Pharmacol., 2019, 847, 97-102.
[http://dx.doi.org/10.1016/j.ejphar.2019.01.031] [PMID: 30690004]

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