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Coadministration of Novel Analgesic Isovaline with Tramadol Reduces Inflammatory Pain Response in Rats

Year 2024, Volume: 7 Issue: 2, 52 - 58, 30.06.2024
https://doi.org/10.36516/jocass.1232464

Abstract

Aim: Isovaline is a new and promising analgesic with an antinociceptive effect and, unlike µ-opioid agonists, interacts with aminobutyric acid receptors without causing sedation or respiratory depression. In this study, we compare the effect on thermal hyperalgesia and mechanical allodynia coadministration of subcutaneous isovaline and tramadol with individual administrations in a carrageenan-induced hind paw inflammatory pain model in rats.
Methods: In this study, isovaline, tramadol, and the combination of isovaline and tramadol were subcutaneously administered to rats with carrageenan-induced inflammation of the hind paws. Hyperalgesia in response to thermal stimuli and allodynia in response to mechanic stimuli were assessed by using a thermal plantar test and a dynamic plantar aesthesiometer, respectively.
Results: The administration of subcutaneous isovaline 400mg/kg and tramadol 4mg/ kg combination effect was higher than the other groups on latencies and thresholds (P<0.01). Additionally, isovaline 400 mg/kg administration caused a statistical difference in latencies when compared with carrageenan, isovaline 2mg/kg, and tramadol 2mg/kg groups (P <0.005) and a statistical difference in thresholds when compared with carrageenan, tramadol 2mg/kg and tramadol 4 mg/kg groups (P <0.01). When isovaline 200 mg was used in combination with tramadol 2mg/kg, the latencies and thresholds were significantly higher than either treatment alone tramadol 2mg/kg and carrageenan groups (P≤ 0.001).
Conclusions: The results of this study demonstrated that the subcutaneous administration of isovaline had analgesic efficacy and was effective in combination with tramadol when used for the treatment of inflammatory pain.

Supporting Institution

Kahramanmaras Sutcu Imam University Research Foundation

Project Number

2016/5-74M

Thanks

We thanks to Ph.D. Deniz Özel Erkan for statistical analysis.

References

  • 1. Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth. 2001; 87: 3-11. doi: 10.1093/bja/87.1.3.
  • 2. Brennan TJ. Pathophysiology of postoperative pain. Pain. 2011; 152: 33-40. doi: 10.1016/j.pain.2010.11.005.
  • 3. Dray A. Inflammatory mediators of pain. Br J Anaesth. 1995; 75: 125-31. doi: 10.1093/bja/75.2.125.
  • 4. Cui JG, Holmin S, Mathiesen T, et al. Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy. Pain. 2000; 88: 239-48. doi: 10.1016/S0304-3959(00)00331-6.
  • 5. Ferreira SH. The role of interleukins and nitric oxide in the mediation of inflammatory pain and its control by peripheral analgesics. Drugs. 1993; 46: 1-9. doi: 10.2165/00003495-199300461-00003.
  • 6. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol. 2010; 23: 611-5. doi: 10.1097/ACO.0b013e32833c348b.
  • 7. Carter GT, Duong V, Ho S, et al. Side effects of commonly prescribed analgesic medications. Phys Med Rehabil Clin N Am. 2014; 25: 457–70. doi: 10.1016/j.pmr.2014.01.007.
  • 8. Walsh TD. Prevention of opioid side effects. J Pain Symptom Manage 1990; 5: 362-7. doi: 10.1016/0885-3924(90)90031-e.
  • 9. Vickers MD, O'Flaherty D, Szekely SM, et al. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia. 1992; 47: 291–6. doi: 10.1111/j.1365-2044.1992.tb02166.x.
  • 10. Chrubasik J, Buzina M, Schulte-Mönting J, et al. Intravenous tramadol for postoperative pain comparison of intermittent dose regimens with and without maintenance infusion. Eur J Anaesthesiol. 1992; 9: 23-8.
  • 11. Gerçek A, Eti Z, Gögüs FY, et al. The analgesic and anti-inflammatory effects of subcutaneous bupivacaine, morphine and tramadol in rats. Agri. 2004; 16: 53-8.
  • 12. Mert T, Güneş Y, Guany I. Local analgesic efficacy of tramadol following intraplantar injection. European Journal of Pharmacology. 2007; 558: 68-72. doi: 10.1016/j.ejphar.2006.11.055.
  • 13. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs. 1993; 46: 313–40. doi: 10.2165/00003495-199346020-00008.
  • 14. Cooke JE, Mathers DA, Puil E. Isovaline causes inhibition by increasing potassium conductance in thalamic neurons. Neuroscience. 2009; 164: 1235-43. doi: 10.1016/j.neuroscience.2009.08.045
  • 15. MacLeod BA, Wang JT, Chung CC, et al. Analgesic properties of the novel amino acid, isovaline. Anesth Analg. 2010; 110: 1206-14. doi: 10.1213/ANE.0b013e3181d27da2.
  • 16. Whitehead RA, Schwarz SK, Asiri YI, et al. The Efficacy and Safety of the Novel Peripheral Analgesic Isovaline as an Adjuvant to Propofol for General Anesthesia and Conscious Sedation. Anesthesia & Analgesia. 2015; 121:1481-7. doi: 10.1213/ANE.0000000000000996.
  • 17. Cooke JE, Mathers DA, Puil E. R-isovaline: a subtype specific agonist at GABAB receptors? Neuroscience. 2012; 201: 85-95. doi: 10.1016/j.neuroscience.2011.10.049.
  • 18. Asseri KA, Puil E, Schwarz SKW, et al. Group II metabotropic glutamate receptor antagonism prevents the antiallodynic effects of R-isovaline. Neuroscience. 2015; 293:151–6. doi: 10.1016/j.neuroscience.2015.02.022.
  • 19. Mert T, Sahin E, Yaman S, et al. Pain-Relieving Effectiveness of Co-Treatment with Local Tramadol and Systemic Minocycline in Carrageenan-Induced Inflammatory Pain Model. Inflammation. 2018; 41: 1238-49. doi: 10.1007/s10753-018-0771-1.
  • 20. Martin B. Isovaline: Is It the Next Analgesic? Anesth Analg. 2015; 121:1415-6. doi: 10.1213/ANE.0000000000001024.
  • 21. Whitehead RA, Puil E, Ries CR, et al. GABA(B) receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline. Neuroscience. 2012; 213: 154-60. doi: 10.1016/j.neuroscience.2012.04.026.
  • 22. Fung T, Asiri YI, Wall R, et al. Variations of isovaline structure related to activity in the formalin foot assay in mice. Amino Acids. 2017; 49: 1203-13. doi: 10.1007/s00726-017-2421-6.
  • 23. Cucuiet S, Dogaru G, Nastasa Bild V, et al. Modulation of tramadol antinociception by ketamine and baclofen in mice. Farmacia. 2008; 56: 675-91.
  • 24. Balerio GN, Rubio MC. Baclofen analgesia: involvement of the GABAergic system. Pharmacol Res. 2012; 46: 281-6. doi: 10.1016/s1043-6618(02)00147-0.
  • 25. Schlichter R, Desarmenien M, Li Volsi G, et al. Low concentrations of GABA reduce accommodation in primary afferent neurons by an action at GABAB receptors. Neuroscience. 1987; 20: 385-93. doi: 10.1016/0306-4522(87)90099-6.
  • 26. Desarmenien M, Feltz P, Occhipinti G, et al. Coexistence of GABAA and GABAB receptors on Aδ and C primary afferents. Br J Pharmacol. 1984; 81: 327-33. doi: 10.1111/j.1476-5381.1984.tb10082.x.
  • 27. Dubin AE, Patapoutian A. Nociceptors: the sensors of the in pathway. J Clin Invest. 2010; 120: 3760-72. doi: 10.1172/JCI42843.
  • 28. Tamura S, Watanabe M, Kanbara K, et al. Expression and distribution of GABAergic system in rat knee joint synovial membrane. Histol Histopathol. 2009; 24: 1009-19. doi: 10.14670/HH-24.1009.
  • 29. Turner PV, Brabb T, Pekow C, et al. Administration of substances to laboratory animals: routes of administration and factors to consider. Journal of the American Association for Laboratory Animal Science. JAALAS. 2011; 50: 600–13.
  • 30. Bianchi M, Rossoni G, Sacerdote P, et al. Effects of tramadol on experimental inflammation. Fundam Clin Pharmacol. 1999; 13: 220-5. doi: 10.1111/j.1472-8206.1999.tb00342.x.
  • 31. Driessen B, Reimann W. Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol. 1992; 105: 147-151. doi: 10.1111/j.1476-5381.1992.tb14226.x.

Yeni Analjezik İzovalinin Tramadol ile Birlikte Uygulanması Sıçanlarda İnflamatuar Ağrı Cevabını Azaltır

Year 2024, Volume: 7 Issue: 2, 52 - 58, 30.06.2024
https://doi.org/10.36516/jocass.1232464

Abstract

Amaç: İzovalin, antinosiseptif etkiye sahip yeni ve ümit verici bir analjeziktir ve µ-opioid agonistlerinin aksine, sedasyona veya solunum depresyonuna neden olmadan aminobütirik asit reseptörleri ile etkileşime girer. Bu çalışmada, sıçanlarda karragenan ile indüklenen arka pençe inflamatuar ağrı modelinde subkutan izovalin ve tramadolün termal hiperaljezi ve mekanik allodinia üzerindeki etkisini tek tek uygulamalarla karşılaştırıyoruz.
Yöntem: Bu çalışmada, izovalin, tramadol ve izovalin ve tramadol kombinasyonu, arka ayaklarında karragenan kaynaklı inflamasyon olan sıçanlara deri altından uygulandı. Termal uyaranlara yanıt olarak hiperaljezi ve mekanik uyaranlara yanıt olarak allodini, sırasıyla termal plantar testi ve dinamik plantar esteziyometre kullanılarak değerlendirildi.
Bulgular: Subkutan izovalin 400mg/kg ve tramadol 4mg/kg kombinasyon etkisi latans ve eşikler üzerine diğer gruplara göre daha yüksekti (P<0,001). Ayrıca, izovalin 400 mg/kg uygulaması, karragenan, izovalin 2mg/kg ve tramadol 2mg/kg grupları ile karşılaştırıldığında latanslarda istatistiksel farka (P <0,005) ve karragenan, tramadol 2mg/kg ve tramadol 4 mg/kg grupları ile karşılaştırıldığında eşiklerde istatistiksel farka neden olmuştur. (P <0,001). İzovalin 200 mg, tramadol 2mg/kg ile kombinasyon halinde kullanıldığında, latans ve eşikler, tek başına tramadol 2mg/kg ve karragenan gruplarına göre önemli ölçüde daha yüksek olmuştur (P≤ 0.001).
Sonuç: Bu çalışmanın sonuçları, izovalinin subkutan uygulamasının analjezik etkinliğe sahip olduğunu ve inflamatuar ağrının tedavisi için kullanıldığında tramadol ile kombinasyon halinde etkili olduğunu göstermiştir.

Project Number

2016/5-74M

References

  • 1. Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth. 2001; 87: 3-11. doi: 10.1093/bja/87.1.3.
  • 2. Brennan TJ. Pathophysiology of postoperative pain. Pain. 2011; 152: 33-40. doi: 10.1016/j.pain.2010.11.005.
  • 3. Dray A. Inflammatory mediators of pain. Br J Anaesth. 1995; 75: 125-31. doi: 10.1093/bja/75.2.125.
  • 4. Cui JG, Holmin S, Mathiesen T, et al. Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy. Pain. 2000; 88: 239-48. doi: 10.1016/S0304-3959(00)00331-6.
  • 5. Ferreira SH. The role of interleukins and nitric oxide in the mediation of inflammatory pain and its control by peripheral analgesics. Drugs. 1993; 46: 1-9. doi: 10.2165/00003495-199300461-00003.
  • 6. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol. 2010; 23: 611-5. doi: 10.1097/ACO.0b013e32833c348b.
  • 7. Carter GT, Duong V, Ho S, et al. Side effects of commonly prescribed analgesic medications. Phys Med Rehabil Clin N Am. 2014; 25: 457–70. doi: 10.1016/j.pmr.2014.01.007.
  • 8. Walsh TD. Prevention of opioid side effects. J Pain Symptom Manage 1990; 5: 362-7. doi: 10.1016/0885-3924(90)90031-e.
  • 9. Vickers MD, O'Flaherty D, Szekely SM, et al. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia. 1992; 47: 291–6. doi: 10.1111/j.1365-2044.1992.tb02166.x.
  • 10. Chrubasik J, Buzina M, Schulte-Mönting J, et al. Intravenous tramadol for postoperative pain comparison of intermittent dose regimens with and without maintenance infusion. Eur J Anaesthesiol. 1992; 9: 23-8.
  • 11. Gerçek A, Eti Z, Gögüs FY, et al. The analgesic and anti-inflammatory effects of subcutaneous bupivacaine, morphine and tramadol in rats. Agri. 2004; 16: 53-8.
  • 12. Mert T, Güneş Y, Guany I. Local analgesic efficacy of tramadol following intraplantar injection. European Journal of Pharmacology. 2007; 558: 68-72. doi: 10.1016/j.ejphar.2006.11.055.
  • 13. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs. 1993; 46: 313–40. doi: 10.2165/00003495-199346020-00008.
  • 14. Cooke JE, Mathers DA, Puil E. Isovaline causes inhibition by increasing potassium conductance in thalamic neurons. Neuroscience. 2009; 164: 1235-43. doi: 10.1016/j.neuroscience.2009.08.045
  • 15. MacLeod BA, Wang JT, Chung CC, et al. Analgesic properties of the novel amino acid, isovaline. Anesth Analg. 2010; 110: 1206-14. doi: 10.1213/ANE.0b013e3181d27da2.
  • 16. Whitehead RA, Schwarz SK, Asiri YI, et al. The Efficacy and Safety of the Novel Peripheral Analgesic Isovaline as an Adjuvant to Propofol for General Anesthesia and Conscious Sedation. Anesthesia & Analgesia. 2015; 121:1481-7. doi: 10.1213/ANE.0000000000000996.
  • 17. Cooke JE, Mathers DA, Puil E. R-isovaline: a subtype specific agonist at GABAB receptors? Neuroscience. 2012; 201: 85-95. doi: 10.1016/j.neuroscience.2011.10.049.
  • 18. Asseri KA, Puil E, Schwarz SKW, et al. Group II metabotropic glutamate receptor antagonism prevents the antiallodynic effects of R-isovaline. Neuroscience. 2015; 293:151–6. doi: 10.1016/j.neuroscience.2015.02.022.
  • 19. Mert T, Sahin E, Yaman S, et al. Pain-Relieving Effectiveness of Co-Treatment with Local Tramadol and Systemic Minocycline in Carrageenan-Induced Inflammatory Pain Model. Inflammation. 2018; 41: 1238-49. doi: 10.1007/s10753-018-0771-1.
  • 20. Martin B. Isovaline: Is It the Next Analgesic? Anesth Analg. 2015; 121:1415-6. doi: 10.1213/ANE.0000000000001024.
  • 21. Whitehead RA, Puil E, Ries CR, et al. GABA(B) receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline. Neuroscience. 2012; 213: 154-60. doi: 10.1016/j.neuroscience.2012.04.026.
  • 22. Fung T, Asiri YI, Wall R, et al. Variations of isovaline structure related to activity in the formalin foot assay in mice. Amino Acids. 2017; 49: 1203-13. doi: 10.1007/s00726-017-2421-6.
  • 23. Cucuiet S, Dogaru G, Nastasa Bild V, et al. Modulation of tramadol antinociception by ketamine and baclofen in mice. Farmacia. 2008; 56: 675-91.
  • 24. Balerio GN, Rubio MC. Baclofen analgesia: involvement of the GABAergic system. Pharmacol Res. 2012; 46: 281-6. doi: 10.1016/s1043-6618(02)00147-0.
  • 25. Schlichter R, Desarmenien M, Li Volsi G, et al. Low concentrations of GABA reduce accommodation in primary afferent neurons by an action at GABAB receptors. Neuroscience. 1987; 20: 385-93. doi: 10.1016/0306-4522(87)90099-6.
  • 26. Desarmenien M, Feltz P, Occhipinti G, et al. Coexistence of GABAA and GABAB receptors on Aδ and C primary afferents. Br J Pharmacol. 1984; 81: 327-33. doi: 10.1111/j.1476-5381.1984.tb10082.x.
  • 27. Dubin AE, Patapoutian A. Nociceptors: the sensors of the in pathway. J Clin Invest. 2010; 120: 3760-72. doi: 10.1172/JCI42843.
  • 28. Tamura S, Watanabe M, Kanbara K, et al. Expression and distribution of GABAergic system in rat knee joint synovial membrane. Histol Histopathol. 2009; 24: 1009-19. doi: 10.14670/HH-24.1009.
  • 29. Turner PV, Brabb T, Pekow C, et al. Administration of substances to laboratory animals: routes of administration and factors to consider. Journal of the American Association for Laboratory Animal Science. JAALAS. 2011; 50: 600–13.
  • 30. Bianchi M, Rossoni G, Sacerdote P, et al. Effects of tramadol on experimental inflammation. Fundam Clin Pharmacol. 1999; 13: 220-5. doi: 10.1111/j.1472-8206.1999.tb00342.x.
  • 31. Driessen B, Reimann W. Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol. 1992; 105: 147-151. doi: 10.1111/j.1476-5381.1992.tb14226.x.
There are 31 citations in total.

Details

Primary Language English
Subjects Anaesthesiology
Journal Section Articles
Authors

Gözen Öksüz 0000-0001-5197-8031

Tufan Mert 0000-0002-5926-9210

Selma Yaman 0000-0002-9301-9119

Mahmut Arslan 0000-0002-2820-1547

Metin Kılınç 0000-0002-1623-0201

Nurten Seringeç Akkeçeci 0000-0003-1915-2330

Project Number 2016/5-74M
Publication Date June 30, 2024
Acceptance Date June 26, 2024
Published in Issue Year 2024 Volume: 7 Issue: 2

Cite

APA Öksüz, G., Mert, T., Yaman, S., Arslan, M., et al. (2024). Coadministration of Novel Analgesic Isovaline with Tramadol Reduces Inflammatory Pain Response in Rats. Journal of Cukurova Anesthesia and Surgical Sciences, 7(2), 52-58. https://doi.org/10.36516/jocass.1232464

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