The Use of the Selective Imidazoline I1 Receptor Agonist Carbophenyline as a Strategy for Neuropathic Pain Relief: Preclinical Evaluation in a Mouse Model of Oxaliplatin-Induced Neurotoxicity

Abstract

Anti-cancer therapy based on the repeated administration of oxaliplatin is limited by the development of a disabling neuropathic syndrome with detrimental effects on the patient’s quality of life. The lack of effective pharmacological approaches calls for the identification of innovative therapeutic strategies based on new targets. We focused our attention on the imidazoline I1 receptor (I1-R) and in particular on the selective I1-R agonist 2-(1-([1,1′-biphenyl]-2-yl)propan-2-yl)-4,5-dihydro-1H-imidazole) (carbophenyline). The purpose of this work was the preclinical evaluation of the efficacy of carbophenyline on oxaliplatin-induced neuropathic pain in mice. Carbophenyline, acutely per os administered (0.1–10 mg kg−1), induced a dose-dependent anti-hyperalgesic effect that was completely blocked by the pre-treatment with the I1-R antagonist 3 or the I12 receptor antagonist efaroxan, confirming the I1-R-dependent mechanism. Conversely, pre-treatment with the I2-R antagonist BU224 did not block the anti-nociceptive effect evoked by carbophenyline. Repeated oral administrations of carbophenyline (1 mg kg−1) for 14 days, starting from the first day of oxaliplatin injection, counteracted the development of neuropathic pain in all behavioral tests (cold plate, Von Frey, and paw pressure tests) carried out 24 h after the last carbophenyline treatment on days 7 and 14. In the dorsal horn of the spinal cord, carbophenyline significantly decreased the oxaliplatin-induced astrocyte activation detected by immunofluorescence staining by the specific labelling with GFAP antibody. In conclusion, carbophenyline showed anti-neuropathic properties both after acute and chronic treatment with preventive effect against oxaliplatin-induced astrocyte activation in the spinal cord. Therefore, I1-R agonists emerge as a new class of candidates for the management of oxaliplatin-induced neuropathic pain.

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References

  1. 1.

    International Association for the Study of Pain. IASP Taxonomy. Pain terms. Neuropathic pain. Updated 2017. www.iasp-pain.org/Taxonomy#Neuropathicpain

  2. 2.

    André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.

  3. 3.

    Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208–15.

    CAS  PubMed  Google Scholar 

  4. 4.

    Beijers AJM, Mols F, Vreugdenhil G. A systematic review on chronic oxaliplatin-induced peripheral neuropathy and the relation with oxaliplatin administration. Support Care Cancer. 2014;22:1999–2007.

    CAS  PubMed  Google Scholar 

  5. 5.

    Balayssac D, Ferrier J, Descoeur J, et al. Chemotherapy-induced peripheral neuropathies: from clinical relevance to preclinical evidence. Expert Opin Drug Saf. 2011;10:407–17.

    CAS  PubMed  Google Scholar 

  6. 6.

    Kiernan MC. The pain with platinum: oxaliplatin and neuropathy. Eur J Cancer. 2007;43:2631-2633.

    CAS  PubMed  Google Scholar 

  7. 7.

    Argyriou AA, Cavaletti G, Briani C, et al. Clinical pattern and associations of oxaliplatin acute neurotoxicity: a prospective study in 170 patients with colorectal cancer. Cancer. 2013;119(2):438-44.

    CAS  PubMed  Google Scholar 

  8. 8.

    Ta LE, Espeset L, Podratz J, Windebank AJ. Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding. Neurotoxicol. 2006;27:992-1002.

    CAS  Google Scholar 

  9. 9.

    Di Cesare Mannelli L, Pacini A, Bonaccini L, Zanardelli M, Mello T, Ghelardini C. Morphologic features and glial activation in rat oxaliplatin-dependent neuropathic pain. J Pain. 2013;14:1585-600.

    Google Scholar 

  10. 10.

    Di Cesare Mannelli L, Pacini A, Micheli L, Tani A, Zanardelli M, Ghelardini C. Glial role in oxaliplatin-induced neuropathic pain. Exp Neurol. 2014;261:22-33.

    Google Scholar 

  11. 11.

    Di Cesare Mannelli L, Pacini A, Matera C, et al. Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: effects of selective activation. Neuropharmacol. 2014;79:37-48.

    Google Scholar 

  12. 12.

    Di Cesare Mannelli L, Marcoli M, Micheli L, et al. Oxaliplatin evokes P2X7-dependent glutamate release in the cerebral cortex: A pain mechanism mediated by Pannexin 1. Neuropharmacol. 2015;97:133-41.

    Google Scholar 

  13. 13.

    Ibrahim EY, Ehrlich BE. Prevention of chemotherapy-induced peripheral neuropathy: A review of recent findings. Crit Rev Oncol Hematol. 2020;145:102831.

    PubMed  Google Scholar 

  14. 14.

    Hershman DL, Lacchetti C, Loprinzi CL. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2014;10(6):e421-e424.

    PubMed  Google Scholar 

  15. 15.

    Miltenburg NC, Boogerd W. Chemotherapy-induced neuropathy: A comprehensive survey. Cancer Treat Rev. 2014;40(7):872-82.

    CAS  PubMed  Google Scholar 

  16. 16.

    Alemany R, Olmos G, GarciaSevilla JA. Labelling I-2B-imidazoline receptors by [H-3]2-(2-benzofuranyl)-2-imidazoline (2-BFI) in rat brain and liver: characterization, regulation and relation to monoamine oxidase enzymes. Naunyn-Schmied. Arch Pharmacol. 1997;356:39-47.

    CAS  Google Scholar 

  17. 17.

    Gentili F, Cardinaletti C, Carrieri A, et al. Involvement of I2-imidazoline binding sites in positive and negative morphine analgesia modulatory effects. Eur J Pharmacol. 2006;553:73–81.

    CAS  PubMed  Google Scholar 

  18. 18.

    Li JX, Thorn DA, Qiu Y, Peng BW, Zhang Y. Antihyperalgesic effects of imidazoline I2 receptor ligands in rat models of inflammatory and neuropathic pain. Br J Pharmacol. 2014;171:1580-90.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Bektas N, Nemutlu D, Arsla R. The imidazoline receptors and ligands in pain modulation. Indian J Pharmacol. 2015;47:472-478.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Thorn DA, Zhang Y, Li JX. Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I2 receptor agonist phenyzoline in adult male rats. Psychopharmacol. 2017;234:1871-1880.

    CAS  Google Scholar 

  21. 21.

    Nikolic K, Agbaba D. Pharmacophore development and SAR studies of imidazoline receptor ligands. Mini-Rev Med Chem. 2012;12:1542−1555.

    CAS  PubMed  Google Scholar 

  22. 22.

    Cobos-Puc L, Aguayo-Morales H. Cardiovascular Effects Mediated by Imidazoline Drugs: An Update. Cardiovasc Hematol Disord Drug Targets. 2019;19(2):95-108.

    CAS  PubMed  Google Scholar 

  23. 23.

    Head GA, Burke SL. I1 imidazoline receptors in cardiovascular regulation: the place of rilmenidine. Am J Hypertens. 2000;13:89S–98S.

    CAS  PubMed  Google Scholar 

  24. 24.

    Ernsberger P. The I1-imidazoline receptor and its cellular signaling pathways. Ann N Y Acad Sci. 1999;881:35–53.

    CAS  PubMed  Google Scholar 

  25. 25.

    Musgrave IF, Hughes R. 1999. Novel targets and techniques in imidazoline receptor research. Ann N Y Acad Sci. 1999;881:217–228.

    Google Scholar 

  26. 26.

    Greney H, Ronde P, Magnier C, et al. Coupling of I(1) imidazoline receptors to the cAMP pathway: studies with a highly selective ligand, benazoline. Mol Pharmacol. 2000;57:1142–1151.

    CAS  PubMed  Google Scholar 

  27. 27.

    Yoro SG, Urosevic D, Fellmann L, Greney H, Bousquet P, Feldman J. G-protein inwardly rectifying potassium channels are involved in the hypotensive effect of I1-imidazoline receptor selective ligands. J Hypertens. 2008;26:1025–1032.

    Google Scholar 

  28. 28.

    Kim YH, Nam TS, Ahn DS, Chung S. Modulation of N-type Ca(2)(+) currents by moxonidine via imidazoline I(1) receptor activation in rat superior cervical ganglion neurons. Biochem Biophys Res Commun. 2011;409:645–650.

  29. 29.

    Harraz OF, El-Gowelli HM, Mohy El-Din MM, Ghazal AR, El-Mas MM. Adenosinergic modulation of the imidazoline I(1)- receptor-dependent hypotensive effect of ethanol in acute renal failure. Food Chem Toxicol. 2012;50:2622–2628.

    PubMed  Google Scholar 

  30. 30.

    Gentili F, Bousquet P, Carrieri A, et al. Rational design of the new antihypertensive I1-receptor ligand 2-(2-biphenyl-2-yl-1-methyl-ethyl)-4,5-dihydro-1H-imidazole. Lett Drug Des Discov. 2005;2:571-578.

    CAS  Google Scholar 

  31. 31.

    Del Bello F, Bargelli V, Cifani C, et al. Antagonism/agonism modulation to build novel antihypertensives selectively triggering I1-imidazoline receptor activation. ACS Med Chem Lett. 2015;6:496-501.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Gentili F, Bousquet P, Brasili L, et al. Imidazoline Binding Sites (IBS) profile modulation: key role of the bridge in determining I1-IBS or I2-IBS selectivity within a series of 2-phenoxymethylimidazoline analogues. J Med Chem. 2003;46:2169-2176.

    CAS  PubMed  Google Scholar 

  33. 33.

    Eglen RM, Hudson AL, Kendall DA, et al. “Seeing through a glass darkly”: casting light on imidazoline “I” sites. Trends Pharmacol Sci. 1998;19:381-390.

    CAS  PubMed  Google Scholar 

  34. 34.

    Hudson AL, Gough R, Tyacke R, et al. Novel selective compounds for the investigation of imidazoline receptors. Ann N Y Acad Sci. 1999;881:81-91.

    CAS  PubMed  Google Scholar 

  35. 35.

    McGrath JC, Lilley E. Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP. Br J Pharmacol. 2015;172:3189–3193.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Cavaletti GG, Tredici MG, Petruccioli E, et al. Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur. J. Cancer. 2001;37:2457-2463.

    CAS  PubMed  Google Scholar 

  37. 37.

    Micheli L, Di Cesare Mannelli L, Rizzi A, et al. 2015. Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity. Eur J Pharmacol. 2015;766:155-62.

    CAS  PubMed  Google Scholar 

  38. 38.

    Tanabe M, Takasu K, Takeuchi Y, Ono H. Pain relief by gabapentin and pregabalin via supraspinal mechanisms after peripheral nerve injury. J Neurosci Res. 2008;86(15):3258-64.

    CAS  PubMed  Google Scholar 

  39. 39.

    Russo R, D'Agostino G, Mattace Raso G, et al. Central administration of oxytocin reduces hyperalgesia in mice: implication for cannabinoid and opioid systems. Peptides. 2012;38(1):81-8.

    CAS  PubMed  Google Scholar 

  40. 40.

    Baptista-De-Souza D, Di Cesare Mannelli L, Zanardelli M, et al. Serotonergic modulation in neuropathy induced by oxaliplatin: effect on the 5HT2C receptor. Eur J Pharmacol. 2014;735:141-9.

    CAS  PubMed  Google Scholar 

  41. 41.

    Sakurai M, Egashira N, Kawashiri T, Yano T, Ikesue H, Oishi R. Oxaliplatin-induced neuropathy in the rat: involvement of oxalate in cold hyperalgesia but not mechanical allodynia. Pain. 2009;147:165–174.

    CAS  PubMed  Google Scholar 

  42. 42.

    Di Cesare Mannelli L, Micheli L, Maresca M, et al. Anti-neuropathic effects of Rosmarinus officinalis L. terpenoid fraction: relevance of nicotinic receptors. Sci Rep. 2016;6:34832

  43. 43.

    Cardinaletti C, Mattioli L, Ghelfi F, et al. Might adrenergic α2C-agonists/α2A-antagonists become novel therapeutic tools for pain treatment with Morphine? J Med Chem. 2009;52:7319–7322.

    CAS  PubMed  Google Scholar 

  44. 44.

    Del Bello F, Diamanti E, Giannella M, et al. Low doses of allyphenyline and cyclomethyline, effective against morphine dependence, elicit antidepressant-like effect. ACS Med Chem Lett. 2012;3:535-539.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Del Bello F, Giannella M, Piergentili A, Quaglia W. The 2-substituted imidazoline ring linked to an aromatic moiety by a biatomic bridge: a bioversatile scaffold. Glob Drugs Therap. 2016;1:1-4.

    Google Scholar 

  46. 46.

    Giusepponi ME, Cifani C, Micioni Di Bonaventura MV, et al. Combined interactions with I1-, I2-imidazoline binding sites and α2-adrenoceptors to manage opioid addiction. ACS Med Chem Lett. 2016;7:956-961.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Gentili F, Bousquet P, Brasili L, et al. α2-Adrenoreceptors profile modulation and high antinociceptive activity of (S)-(-)-2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole. J Med Chem. 2002;45:32–40.

    CAS  PubMed  Google Scholar 

  48. 48.

    Del Bello F, Cilia A, Carrieri A, et al. The versatile 2-substituted imidazoline nucleus as a structural motif of ligands directed to the serotonin 5-HT1A receptor. Chem Med Chem. 2016;11:2287–98.

    PubMed  Google Scholar 

  49. 49.

    Di Cesare Mannelli L, Ghelardini C, Micheli L, et al. Synergic stimulation of serotonin 5-HT1A receptor and α2-adrenoceptors for neuropathic pain relief: Preclinical effects of 2-substituted imidazoline derivatives. Eur J Med Chem. 2017;810:128-133.

    Google Scholar 

  50. 50.

    Eisenach JC, DuPen S, Dubois M, Miguel R, Allin D. Epidural clonidine analgesia for intractable cancer pain. The Epidural Clonidine Study Group. Pain. 1995;61:391-9.

    CAS  Google Scholar 

  51. 51.

    Pan HL, Chen SR, Eisenach JC. Role of spinal NO in antiallodynic effect of intrathecal clonidine in neuropathic rats. Anesthesiology. 1998;89:1518-23.

    CAS  PubMed  Google Scholar 

  52. 52.

    Szabo B. Imidazoline antihypertensive drugs: a critical review on their mechanism of action. Pharmacol Ther. 2002;93(1):1-35.

    CAS  PubMed  Google Scholar 

  53. 53.

    Wrzosek A, Woron J, Dobrogowski J, Jakowicka-Wordliczek J, Wordliczek J. Topical clonidine for neuropathic pain. Cochrane Database Syst Rev. 2015;318:CD010967.

    Google Scholar 

  54. 54.

    Stone LS, Kitto KF, Eisenach JC, Fairbanks CA, Wilcox GL. ST91 [2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride]-mediated spinal antinociception and synergy with opioids persists in the absence of functional alpha-2A- or alpha-2C-adrenergic receptors. J Pharmacol Exp Ther. 2007;323:899–906.

    CAS  PubMed  Google Scholar 

  55. 55.

    Bousquet P, Hudson A, García-Sevilla JA, Li JX. Imidazoline Receptor System: The Past, the Present, and the Future. Pharmacol Rev. 2020;72:50-79.

    CAS  PubMed  Google Scholar 

  56. 56.

    Ernsberger P, Shen IH. Membrane localization and guanine nucleotide sensitivity of medullary I1-imidazoline binding sites. Neurochem Int. 1997;30:17–23.

  57. 57.

    Edwards L, Ernsberger P. The I(1)-imidazoline receptor in PC12 pheochromocytoma cells reverses NGF-induced ERK activation and induces MKP-2 phosphatase. Brain Res. 2003;980:71–79.

  58. 58.

    Alles SRA, Smith PA. Etiology and Pharmacology of Neuropathic Pain. Pharmacol Rev. 2018;70:315-347.

    CAS  PubMed  Google Scholar 

  59. 59.

    Coppi E, Cherchi F, Fusco I, et al. Adenosine A3 receptor activation inhibits pronociceptive N-type Ca2+ currents and cell excitability in dorsal root ganglion neurons. Pain. 2019;160:1103-1118.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Tanabe M, Kino Y, Honda M, Ono H. Presynaptic I1-imidazoline receptors reduce GABAergic synaptic transmission in striatal medium spiny neurons. J Neurosci. 2006;26:1795–1802.

  61. 61.

    Dixit MP, Upadhya MA, Taksande B, et al. Neuroprotective effect of agmatine in mouse spinal cord injury model: Modulation by imidazoline receptors. J Nat Sci Biol Med. 2018;9:115-120.

    CAS  Google Scholar 

  62. 62.

    Gupta S, Sharma B. Pharmacological benefit of I(1)-imidazoline receptors activation and nuclear factor kappa-B (NF-κB) modulation in experimental Huntington's disease. Brain Res Bull. 2014;102:57-68.

    CAS  PubMed  Google Scholar 

  63. 63.

    Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10(1):23-36.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Von Hehn CA, Baron R, Woolf CJ. Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms. Neuron. 2012;73(4):638–652.

    Google Scholar 

  65. 65.

    Jacob A, Hack B, Chiang E, Garcia JG, Quigg RJ, Alexander JJ. C5a alters blood-brain barrier integrity in experimental lupus. FASEB J. 2010;24(6):1682-8.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Nikolic K, Veljkovic N, Gemovic B, Srdic-Rajic T, Agbaba D. Imidazoline-1 receptor ligands as apoptotic agents: pharmacophore modeling and virtual docking study. Comb Chem High Throughput Screen. 2013;16:298-319

    CAS  PubMed  Google Scholar 

  67. 67.

    Sharma V, Peddibhotla S, Tepe JJ. Sensitization of cancer cells to DNA damaging agents by imidazolines. J Am Chem Soc. 2006;128:9137-43.

    CAS  PubMed  Google Scholar 

  68. 68.

    Seretny M, Currie GL, Sena ES, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014;155:2461–2470.

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Acknowledgments

This research was funded by the Italian Ministry of Instruction, University and Research (MIUR), by the University of Florence and by the University of Camerino (Fondo di Ateneo per la Ricerca 2018).

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Micheli, L., Di Cesare Mannelli, L., Del Bello, F. et al. The Use of the Selective Imidazoline I1 Receptor Agonist Carbophenyline as a Strategy for Neuropathic Pain Relief: Preclinical Evaluation in a Mouse Model of Oxaliplatin-Induced Neurotoxicity. Neurotherapeutics (2020). https://doi.org/10.1007/s13311-020-00873-y

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Key Words

  • Imidazoline I1 receptor agonist
  • oxaliplatin
  • chemotherapy-induced neuropathic pain
  • astrocytes
  • carbophenyline