Abstract
Rationale
Emerging preclinical evidence suggests that imidazoline I2 receptor ligands may be effective analgesics. Quantitative analysis of the combined I2 receptor ligands and opioids is needed for the justification of combination therapy.
Objective
This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats.
Methods
Von Frey filament test was used to examine the anti-hyperalgesic effects of drugs in a rat model of complete Freund’s adjuvant (CFA)-induced inflammatory pain. Schedule-controlled responding was used to assess the rate-altering effects of study drugs. Duration of actions of individual drugs (2-BFI, phenyzoline, and oxycodone) alone or in combination was studied. Dose-addition analysis was employed to assess the anti-hyperalgesic interactions between drugs.
Results
Oxycodone (0.1–3.2 mg/kg, i.p.), 2-BFI (1–17.8 mg/kg, i.p.), and phenyzoline (17.8–56 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and oxycodone produced additive interactions while phenyzoline and oxycodone produced supra-additive interactions under all fixed ratios. The same drug combinations did not alter or significantly reduced the operant responding depending on the ratios of the drug combinations.
Conclusions
Quantitative analysis of the anti-hyperalgesic effects of I2 receptor ligands strongly supports the therapeutic potential of I2 receptor ligands against inflammatory pain. In addition, the data reveal that phenyzoline is superior to the prototypic I2 receptor ligand 2-BFI for the management of pain and warrants further consideration as a novel analgesic.
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References
An XF, Zhang Y, Winter JC, Li JX (2012) Effects of imidazoline I(2) receptor agonists and morphine on schedule-controlled responding in rats. Pharmacol Biochem Behav 101(3):354–359
Berenbaum MC (1989) What is synergy? Pharmacol Rev 41(2):93–141
Boronat MA, Olmos G, Garcia-Sevilla JA (1998) Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands. Br J Pharmacol 125:175–185
Diaz A, Mayet S, Dickenson AH (1997) BU224 produces spinal antinociception as an agonist at imidazoline I2 receptors. Eur J Pharmacol 333:9–15
Escriba PV, Ozaita A, Garcia-Sevilla JA (1999) Pharmacologic characterization of imidazoline receptor proteins identified by immunologic techniques and other methods. Ann N Y Acad Sci 881:8–25
Ferrari F, Fiorentino S, Mennuni L, Garofalo P, Letari O, Mandelli S (2011) Analgesic efficacy of CR4056, a novel imidazoline-2 receptor ligand, in rat models of inflammatory and neuropathic pain. J Pain Res 4:111–125
Gentili F, Cardinaletti C, Carrieri A, Ghelfi F, Mattioli L, Perfumi M, Vesprini C, Pigini M (2006) Involvement of I2-imidazoline binding sites in positive and negative morphine analgesia modulatory effects. Eur J Pharmacol 553(1–3):73–81
Gilron I, Jensen TS, Dickenson AH (2013) Combination pharmacotherapy for management of chronic pain: from bench to bedside. Lancet Neurol 12(11):1084–1095
Institute of Medicine (U.S.) (2011) Relieving pain in America: a blueprint for transforming prevention, care, education and research. National Academies Press, Washington, DC
Ishihara M, Togo H (2007) Direct oxidative conversion of aldehydes and alcohols to 2-imidazolines and 2-oxazolines using molecular iodine. Tetrahedron 63(6):1474–1480
Jarry C, Forfar I, Bosc J, Renard P, Scalbert E, Guardiola B (1997) 5-(Arloxymethyl) oxazoline. US Patent 5,686,477, Adir eCompagnie
Koek W, Mercer SL, Coop A, France CP (2009) Behavioral effects of gamma-hydroxybutyrate, its precursor gamma-butyrolactone, and GABA(B) receptor agonists: time course and differential antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP35348). J Pharmacol Exp Ther 330(3):876–883
Lanza M, Ferrari F, Menghetti I, Tremolada D, Caselli G (2014) Modulation of imidazoline I2 binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats. Br J Pharmacol 171(15):3693–3701
Li JX, Zhang Y (2011) Imidazoline I2 receptors: target for new analgesics? Eur J Pharmacol 658(2–3):49–56
Li JX, Zhang Y (2012) Emerging drug targets for pain treatment. Eur J Pharmacol 681(1–3):1–5
Li JX, Crocker C, Koek W, Rice KC, France CP (2011a) Effects of serotonin 5-HT1A and 5-HT2A receptor agonists on schedule-controlled responding in rats: drug combination studies. Psychopharmacology (Berl) 213(2–3):489–497
Li JX, Zhang Y, Winter JC (2011b) Morphine-induced antinociception in the rat: supra-additive interactions with imidazoline I(2) receptor ligands. Eur J Pharmacol 669(1–3):59–65
Li JX, Thorn DA, Qiu Y, Peng BW, Zhang Y (2014) Anti-hyperalgesic effects of imidazoline I2 receptor ligands in rat models of inflammatory and neuropathic pain. Br J Pharmacol 171(6):1580–1590
Meregalli C, Ceresa C, Canta A, Carozzi VA, Chiorazzi A, Sala B (2012) CR4056, a new analgesic I2 ligand, is highly effective against bortezomib-induced painful neuropathy in rats. J Pain Res 5:151–167
Nagakura Y, Okada M, Kohara A, Kiso T, Toya T, Iwai A (2003) Allodynia and hyperalgesia in adjuvant-induced arthritic rats: time course of progression and efficacy of analgesics. J Pharmacol Exp Ther 306(2):490–497
Nutt DJ, French N, Handley S, Hudson A, Husbands S, Jackson H, Jordan S, Lalies MD, Lewis J, Lione L, Mallard N, Pratt J (1995) Functional studies of specific imidazoline-2 receptor ligands. Ann N Y Acad Sci 763:125–139
Orrù A, Marchese G, Casu G, Casu MA, Kasture S, Cottiglia F et al (2014) Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine. Phytomedicine 21(5):745–752
Qiu Y, He XH, Zhang Y, Li JX (2014) Discriminative stimulus effects of the novel imidazoline I2 receptor ligand CR4056 in rats. Sci Rep 4:6605
Qiu Y, Zhang Y, Li JX (2015) Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats. Eur J Pharmacol 749:133–141
Regunathan S, Reis DJ (1996) Imidazoline receptors and their endogenous ligands. Annu Rev Pharmacol Toxicol 36:511–544
Sampson C, Zhang Y, Del Bello F, Li JX (2012) Effects of imidazoline I2 receptor ligands on acute nociception in rats. Neuroreport 23(2):73–77
Sanchez-Blazquez P, Boronat MA, Olmos G, Garcia-Sevilla JA, Garzon J (2000) Activation of I(2)-imidazoline receptors enhances supraspinal morphine analgesia in mice: a model to detect agonist and antagonist activities at these receptors. Br J Pharmacol 130(1):146–152
Smith HS (2008) Combination opioid analgesics. Pain Physician 11(2):201–214
Tallarida RJ (2000) The composite additive curve. In: drug synergism and dose-effect data analysis. ed Tallarida, R.J.Chapman & Hall/CRC Boca Raton, pp 77–89
Thorn DA, Zhang Y, Peng BW, Winter JC, Li JX (2011) Effects of imidazoline I2 receptor ligands on morphine- and tramadol-induced antinociception in rats. Eur J Pharmacol 670(2–3):435–440
Thorn DA, An XF, Zhang Y, Pigini M, Li JX (2012) Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats. Br J Pharmacol 166(6):1936–1945
Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16(2):109–110
Acknowledgments
This work was supported by the National Institute on Drug Abuse of the National Institutes of Health (Award no. R01DA034806) and by a grant from the National Natural Science Foundation of China (81373390). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Thorn, D.A., Siemian, J.N., Zhang, Y. et al. Anti-hyperalgesic effects of imidazoline I2 receptor ligands in a rat model of inflammatory pain: interactions with oxycodone. Psychopharmacology 232, 3309–3318 (2015). https://doi.org/10.1007/s00213-015-3983-1
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DOI: https://doi.org/10.1007/s00213-015-3983-1