Dose-Dependent Interaction Between Caffeine and Morphine in Analgesia in the Hot-Plate in Mice

Document Type : Original Article

Authors

1 Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran

2 Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

3 Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Pharmacology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

10.34172/ahj.1717

Abstract

Background: Combination analgesic therapy is a widely employed strategy for pain management worldwide. This study investigated the potential synergistic interaction between caffeine and morphine using the hot-plate test and isobolographic analysis in male NMRI mice. The interaction between caffeine and morphine in pain modulation was evaluated, and it was determined whether the combination produces a synergistic effect.
Methods: Mice were treated with morphine (0.135, 1.25, 5, and 20 mg/Kg, s.c.) or caffeine (20, 40, 80, and 160 mg/Kg, i.p.) to obtain the ED50 values of each agent in the hot-plate test, then, an isobolographic analysis was used to evaluate the nature of interaction between the two drugs in mice.
Findings: Morphine significantly increased pain thresholds in a dose-dependent manner (ED₅₀ = 2.49 mg/kg; P < 0.001). Caffeine at a lower dose (46.13 mg/kg) potentiated morphine’s analgesic effect, indicating a synergistic interaction (P < 0.001). In contrast, a higher caffeine dose (138.3 mg/kg) reversed this effect, demonstrating an antagonistic interaction (P < 0.001) in the mouse hot-plate test.
Conclusion: A low dose of caffeine synergistically enhanced morphine-induced analgesia in the mouse hot-plate test; this effect was absent at a higher dose. Consequently, only low-dose caffeine administration effectively reduced the required dosage of morphine for acute pain management in the mouse hot-plate test.

Highlights

Mohammad Reza Jafari(Google Scholar)(Pubmed)

Keywords

References

  1. Cao B, Xu Q, Shi Y, Zhao R, Li H, Zheng J, et al. Pathology of pain and its implications for therapeutic interventions. Signal Transduct Target Ther. 2024;9(1):155. doi: 10.1038/s41392- 024-01845-w
  2. Badshah I, Anwar M, Murtaza B, Khan MI. Molecular mechanisms of morphine tolerance and dependence; novel insights and future perspectives. Mol Cell Biochem. 2024;479(6):1457-85. doi: 10.1007/s11010-023-04810-3
  3. da Fonseca Pacheco D, Klein A, de Castro Perez A, da Fonseca Pacheco CM, de Francischi JN, Duarte ID. The μ‐opioid receptor agonist morphine, but not agonists at δ‐or κ‐opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors. Br J Pharmacol. 2008;154(5):1143-9. doi: 10.1038/bjp.2008.175
  4. Ueda H, Ueda M. Mechanisms underlying morphine analgesic tolerance and dependence. Front Biosci (Landmark Ed). 2009;14(14):5260-72. doi: 10.2741/3596
  5. Ialongo D, Tudino V, Arpacioglu M, Messore A, Patacchini E, Costi R, et al. Synergistic effects of caffeine in combination with conventional drugs: perspectives of a drug that never ages. Pharmaceuticals (Basel). 2023;16(5):730. doi: 10.3390/ ph16050730
  6. Voicu VA, Mircioiu C, Plesa C, Jinga M, Balaban V, Sandulovici R, et al. Effect of a new synergistic combination of low doses of acetylsalicylic acid, caffeine, acetaminophen, and chlorpheniramine in acute low back pain. Front Pharmacol. 2019;10:607. doi: 10.3389/fphar.2019.00607
  7. Tomić MA, Micov AM, Stepanović-Petrović RM. Levetiracetam interacts synergistically with nonsteroidal analgesics and caffeine to produce antihyperalgesia in rats. J Pain. 2013;14(11):1371-82. doi: 10.1016/j.jpain.2013.06.003
  8. Boppana SH, Peterson M, Du AL, Kutikuppala LV, Gabriel RA. Caffeine: what is its role in pain medicine? Cureus. 2022;14(6):e25603. doi: 10.7759/cureus.25603
  9. Person DL, Kissin I, Brown PT, Xavier AV, Vinik HR, Bradley EL. Morphine--caffeine analgesic interaction in rats. Anesth Analg. 1985;64(9):851-6.
  10. Misra AL, Pontani RB, Vadlamani NL. Potentiation of morphine analgesia by caffeine. Br J Pharmacol. 1985;84(4):789-91. doi: 10.1111/j.1476-5381.1985.tb17372.x
  11. Baratloo A, Rouhipour A, Forouzanfar MM, Safari S, Amiri M, Negida A. The role of caffeine in pain management: a brief literature review. Anesth Pain Med. 2016;6(3):e33193. doi: 10.5812/aapm.33193
  12. Khalili M, Semnanian S, Fathollahi Y. Caffeine increases paragigantocellularis neuronal firing rate and induces withdrawal signs in morphine-dependent rats. Eur J Pharmacol. 2001;412(3):239-45. doi: 10.1016/s0014-2999(01)00718-x
  13. Abo-Salem OM, Hayallah AM, Bilkei-Gorzo A, Filipek B, Zimmer A, Müller CE. Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther. 2004;308(1):358-66. doi: 10.1124/jpet.103.056036
  14. Kuribara H, Uchihashi Y. Interactions of opioids with caffeine: evaluation by ambulatory activity in mice. J Pharm Pharmacol. 1994;46(2):141-4. doi: 10.1111/j.2042-7158.1994.tb03758.x
  15. Habibi Asl B, Abdelalipur R, Shahidi M. Effects of caffeine on morphine tolerance and analgesia in mice. Iran J Pharm Sci. 2011;7(2):99-106. doi: 10.22037/ijps.v7.41345
  16. Ahlijanian MK, Takemori AE. The effect of chronic administration of caffeine on morphine-induced analgesia, tolerance and dependence in mice. Eur J Pharmacol. 1986;120(1):25-32. doi: 10.1016/0014-2999(86)90635-7
  17. Eddy NB, Leimbach D. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J Pharmacol Exp Ther. 1953;107(3):385-93.
  18. Schmauss C, Yaksh TL. In vivo studies on spinal opiate receptor systems mediating antinociception. II. Pharmacological profiles suggesting a differential association of mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat. J Pharmacol Exp Ther. 1984;228(1):1-12. doi: 10.1016/s0022-3565(25)21463-x
  19. Savadkoohi H, Vesal N. The analgesic interaction of tramadol and morphine in rats: an isobolographic study. Vet Res Forum. 2019;10(1):31-6. doi: 10.30466/vrf.2010.33108
  20. Khakpai F, Nedaei F, Shahini F, Zarrindast MR. Synergistic analgesic effect of morphine and tramadol in non‑sensitized and morphine‑sensitized mice: an isobolographic study. Acta Neurobiol Exp (Wars). 2021;81(4):350-61.
  21. Gei L, Yan Y, Xing W, Li Q, Chen X, Yan F, et al. Amiloride alleviates morphine tolerance by suppressing ASIC3-dependent neuroinflammation in the spinal cord. Eur J Pharmacol. 2024;963:176173. doi: 10.1016/j.ejphar.2023.176173
  22. Romero A, Miranda HF, Puig MM. Antinociceptive effects of morphine, fentanyl, tramadol and their combination, in morphine-tolerant mice. Pharmacol Biochem Behav. 2010;97(2):363-9. doi: 10.1016/j.pbb.2010.09.005
  23. Miranda HF, Silva E, Pinardi G. Synergy between the antinociceptive effects of morphine and NSAIDs. Can J Physiol Pharmacol. 2004;82(5):331-8. doi: 10.1139/y04-027
  24. Malec D, Michalska E. The effect of methylxanthines on morphine analgesia in mice and rats. Pol J Pharmacol Pharm. 1988;40(3):223-32.
  25. Ghelardini C, Galeotti N, Bartolini A. Caffeine induces central cholinergic analgesia. Naunyn Schmiedebergs Arch Pharmacol. 1997;356(5):590-5. doi: 10.1007/pl00005094
  26. Wu WP, Hao JX, Fredholm BB, Wiesenfeld-Hallin Z, Xu XJ. Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury. Neurosci Lett. 2006;402(1-2):164-6. doi: 10.1016/j.neulet.2006.03.065
  27. Sawynok J, Reid AR, Doak GJ. Caffeine antinociception in the rat hot-plate and formalin tests and locomotor stimulation: involvement of noradrenergic mechanisms. Pain. 1995;61(2):203-13. doi: 10.1016/0304-3959(94)00169-f
  28. Bach-Rojecky L. Analgesic effect of caffeine and clomipramine: a possible interaction between adenosine and serotonin systems. Acta Pharm. 2003;53(1):33-9.
  29. Fan SH, Ali NA, Basri DF. Evaluation of analgesic activity of the methanol extract from the galls of Quercus infectoria (Olivier) in rats. Evid Based Complement Alternat Med. 2014;2014:976764. doi: 10.1155/2014/976764
  30. Gholami M, Saboory E, Mehraban S, Niakani A, Banihabib N, Azad MR, et al. Time dependent antinociceptive effects of morphine and tramadol in the hot plate test: using different methods of drug administration in female rats. Iran J Pharm Res. 2015;14(1):303-11.
  31. Basiri F, Rad A, Mahdian D, Molavi M, Amin B. Effects of glucosamine against morphine-induced antinociceptive tolerance and dependence in mice. J Biomed Sci. 2019;26(1):21. doi: 10.1186/s12929-019-0513-1
  32. Handra C, Ghita I, Georgescu D, Chirila M. The connection between nicotinic and adenosinic system in analgesia. Rom Biotechnol Lett. 2022;27(2):3429-33. doi: 10.25083/ rbl/27.2/3429.3433
  33. Galeotti N, Ghelardini C, Grazioli I, Uslenghi C. Indomethacin, caffeine and prochlorperazine alone and combined revert  hyperalgesia in in vivo models of migraine. Pharmacol Res. 2002;46(3):245-50. doi: 10.1016/s1043-6618(02)00126-3
  1. Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth. 2002;88(2):199-214. doi: 10.1093/bja/88.2.199
  2. Moré AO, Cidral-Filho FJ, Mazzardo-Martins L, Martins DF, Nascimento FP, Li SM, et al. Caffeine at moderate doses can inhibit acupuncture-induced analgesia in a mouse model of postoperative pain. J Caffeine Res. 2013;3(3):143-8. doi: 10.1089/jcr.2013.0014
  3. Díaz-Reval MI, Carrillo-Munguía N, Martínez-Casas M, González-Trujano ME. Tramadol and caffeine produce synergistic interactions on antinociception measured in a formalin model. Pharmacol Biochem Behav. 2010;97(2):357- 62. doi: 10.1016/j.pbb.2010.09.004
  4. Ghassan Ibrahim M, Alabbas NN. The analgesic and anti-inflammatory properties of caffeine co-administration with nefopam in mice. Iraqi J Vet Med. 2024;48(1):48-53. doi: 10.30539/8qhqgn78
  5. Granados-Soto V, Flores-Murrieta FJ, Castañeda-Hernández G, Hong E, López-Muñoz FJ. Comparison of the analgesic effects of ketorolac, morphine and aspirin in the rat. Proc West Pharmacol Soc. 1993;36:245-8.
  6. Granados-Soto V, López-Muñoz FJ, Castañeda-Hernández G, Salazar LA, Villarreal JE, Flores-Murrieta FJ. Characterization of the analgesic effect of paracetamol and caffeine combinations in the pain-induced functional impairment model in the rat. J Pharm Pharmacol. 1993;45(7):627-31. doi: 10.1111/j.2042- 7158.1993.tb05666.x
  7. Díaz-Reval MI, Galván-Orozco R, López-Muñoz FJ, Carrillo- Munguía N. [Synergism of caffeine on antinociceptive effects of metamizole]. Cir Cir. 2008;76(3):241-6. [Spanish].
  8. Sawynok J, Yaksh TL. Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action. Pharmacol Rev. 1993;45(1):43-85.
  9. Sawynok J, Reid AR. Caffeine inhibits antinociception by acetaminophen in the formalin test by inhibiting spinal adenosine A₁ receptors. Eur J Pharmacol. 2012;674(2-3):248- 54. doi: 10.1016/j.ejphar.2011.10.036
  10. Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov. 2006;5(3):247-64. doi: 10.1038/nrd1983
  11. Borea PA, Varani K, Vincenzi F, Baraldi PG, Aghazadeh Tabrizi M, Merighi S, et al. The A3 adenosine receptor: history and perspectives. Pharmacol Rev. 2015;67(1):74-102. doi: 10.1124/pr.113.008540
  12. Sawynok J. Adenosine receptor targets for pain. Neuroscience. 2016;338:1-18. doi: 10.1016/j.neuroscience.2015.10.031
  13. Jacobson KA, Salvemini D. Editorial: small molecules and biologics for future purinergic therapeutics. Purinergic Signal. 2023;19(3):465-6. doi: 10.1007/s11302-023-09964-9
  14. Gomes FI, Cunha FQ, Cunha TM. Peripheral nitric oxide signaling directly blocks inflammatory pain. Biochem Pharmacol. 2020;176:113862. doi: 10.1016/j. bcp.2020.113862
Addiction & Health
Volume 17
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