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Role of gabapentin in preventing fentanyl- and morphine-withdrawal-induced hyperalgesia in rats

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Abstract

Purpose

This study was undertaken to examine the effect of gabapentin for preventing hyperalgesia induced by morphine and fentanyl withdrawal in rats.

Methods

To induce hyperalgesia, Sprague Dawley (SD) rats were subcutaneously injected with fentanyl four times at 15-min intervals (60 μg/kg per injection), resulting in total dose of 240 μg/kg over 1 h, and morphine 10 mg/kg twice daily for 7 days. The effect of gabapentin was detected with behavioral tail-flick and paw-withdrawal tests.

Results

Drug termination produced significant decrease in antinociception thresholds (P < 0.05 vs. saline group), indicating that the rats became sensitive to thermal stimuli. In rats that received combined treatment with fentanyl/morphine and gabapentin (25/50 mg/kg), results demonstrated that there were no significant decreases in antinociception thresholds (vs. saline group) after opioid withdrawal. Gabapentin (50 mg/kg) could also prevent morphine tolerance. The 50% effective dose (ED50) value was 12.5 mg/kg in tail-flick and 13.6 mg/kg in paw-withdrawal tests.

Conclusions

The study showed that gabapentin can significantly prevented opioid-induced hyperalgesia (OIH) induced caused by fentanyl and morphine, suggesting a role for the addition of gabapentin in the perioperative period and during chronic pain treatment as an effective drug to prevent OIH.

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References

  1. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104:570–87.

    Article  PubMed  CAS  Google Scholar 

  2. Guntz E, Talla G, Roman A, Dumont H, Segers B, Sosnowski M. Opioid-induced hyperalgesia. Eur J Anaesthesiol. 2007;24:205–7.

    PubMed  Google Scholar 

  3. Li X, Angst MS, Clark JD. A murine model of opioid-induced hyperalgesia. Brain Res Mol Brain Res. 2001;86:56–62.

    Article  PubMed  CAS  Google Scholar 

  4. Okon TR, George ML. Fentanyl-induced neurotoxicity and paradoxic pain. J Pain Symptom Manage. 2008;35:327–33.

    Article  PubMed  CAS  Google Scholar 

  5. Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth. 1999;46:872–5.

    Article  PubMed  CAS  Google Scholar 

  6. Célèrier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000;92:465–72.

    Article  PubMed  Google Scholar 

  7. Waxman AR, Arout C, Caldwell M, Dahan A, Kest B. Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice. Neurosci Lett. 2009;462:68–72.

    Article  PubMed  CAS  Google Scholar 

  8. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995;62:259–74.

    Article  PubMed  CAS  Google Scholar 

  9. Mayer DJ, Mao J, Holt J, Price DD. Cellular mecha–nisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci USA. 1999;96:7731–6.

    Article  PubMed  CAS  Google Scholar 

  10. Field MJ, Holloman EF, McCleary S, Hughes J, Singh L. Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. J Pharmacol Exp Ther. 1997;282:1242–6.

    PubMed  CAS  Google Scholar 

  11. Ross JR, Goller K, Hardy J, Riley J, Broadley K, A’hern R, Williams J. Gabapentin is effective in the treatment of cancer-related neuropathic pain: a prospective, open label study. J Palliat Med. 2005;8:1118–26.

    Article  PubMed  CAS  Google Scholar 

  12. Baillie JK, Power I. The mechanism of action of gabapentin inneuropathic pain. Curr Opin Investig Drugs. 2006;7:33–9.

    PubMed  CAS  Google Scholar 

  13. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem. 1996;271:5768–76.

    Article  PubMed  CAS  Google Scholar 

  14. Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology. 2002;97:560–4.

    Article  PubMed  CAS  Google Scholar 

  15. Van Elstraete AC, Sitbon P, Mazoit JX, Benhamou D. Gabapentin prevents delayed and long-lasting hyperalgesia induced by fentanyl in rats. Anesthesiology. 2008;108:484–94.

    Article  PubMed  Google Scholar 

  16. Raghavendra V, Tanga FY, DeLeo JA. Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology. 2004;29:327–34.

    Article  PubMed  CAS  Google Scholar 

  17. Wong CS, Hsu MM, Chou R, Chou YY, Tung CS. Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats. Br J Anaesth. 2000;85:747–51.

    Article  PubMed  CAS  Google Scholar 

  18. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:77–88.

    Article  PubMed  CAS  Google Scholar 

  19. Rode F, Broløs T, Blackburn-Munro G, Bjerrum OJ. Venlafaxine compromises the antinociceptive actions of gabapentin in rat models of neuropathic and persistent pain. Psychopharmacology (Berl). 2006;187:364–75.

    Article  CAS  Google Scholar 

  20. LaBuda CJ, Little PJ. Pharmacological evaluation of the selective spinal nerve ligation model of neuropathic pain in the rat. J Neurosci Methods. 2005;144:175–81.

    Article  PubMed  CAS  Google Scholar 

  21. Goa KL, Sorkin EM. Gabapentin: a review of its pharmacological properties and clinical potential in epilepsy. Drugs. 1993;46:409–27.

    Article  PubMed  CAS  Google Scholar 

  22. Shy M, Chakrabarti S, Gintzler AR. Plasticity of adenylyl cyclase-related signaling sequelae after long-term morphine treatment. Mol Pharmacol. 2008;73:868–79.

    Article  PubMed  CAS  Google Scholar 

  23. Galeotti N, Stefano GB, Guarna M, Bianchi E, Ghelardini C. Signaling pathway of morphine induced acute thermal hyperalgesia in mice. Pain. 2006;123:294–305.

    Article  PubMed  CAS  Google Scholar 

  24. Mao J, Price DD, Phillips LL, Lu J, Mayer DJ. Increases in protein kinase C gamma immunoreactivity in the spinal cord dorsal horn of rats with painful mononeuropathy. Neurosci Lett. 1995;198:75–8.

    Article  PubMed  CAS  Google Scholar 

  25. Van Elstraete AC, Sitbon P, Mazoit JX, Conti M, Benhamou D. Protective effect of prior administration of magnesium on delayed hyperalgesia induced by fentanyl in rats. Can J Anaesth. 2006;53:1180–5.

    Article  PubMed  Google Scholar 

  26. Yoshikawa M, Nakayama H, Ueno S, Hirano M, Hatanaka H, Furuya H. Chronic fentanyl treatments induce the up-regulation of μ opioid receptor mRNA in rat pheochromocytoma cells. Brain Res. 2000;859:217–23.

    Article  PubMed  CAS  Google Scholar 

  27. Celerier E, Laulin JP, Corcuff JB, Le Moal M, Simonnet G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci. 2001;21:4074–80.

    PubMed  CAS  Google Scholar 

  28. Maneuf YP, McKnight AT. Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase. Br J Pharmacol. 2001;134:237–40.

    Article  PubMed  CAS  Google Scholar 

  29. Shimoyama M, Shimoyama N, Hori Y. Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn. Pain. 2000;85:405–14.

    Article  PubMed  CAS  Google Scholar 

  30. Maneuf YP, McKnight AT. Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase. Br J Pharmacol. 2001;134:237–40.

    Article  PubMed  CAS  Google Scholar 

  31. Singh L, Field MJ, Ferris P, Hunter JC, Oles RJ, Williams RG, Woodruff GN. The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine. Psychopharmacology (Berl). 1996;127:1–9.

    Article  CAS  Google Scholar 

  32. Partridge BJ, Chaplan SR, Sakamoto E, Yaksh TL. Characterization of the effects of gabapentin and 3-isobutyl-gammaaminobutyric acid on substance P-induced thermal hyperalgesia. Anesthesiology. 1998;88:196–205.

    Article  PubMed  CAS  Google Scholar 

  33. Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg. 2000;91:185–91.

    PubMed  CAS  Google Scholar 

  34. Matthews EA, Dickenson AH. A combination of gabapentin and morphine mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model of neuropathy. Anesthesiology. 2002;96:633–40.

    Article  PubMed  CAS  Google Scholar 

  35. De la O-Arciniega M, Díaz-Reval MI, Cortés-Arroyo AR, Domínguez-Ramírez AM, López-Muñoz FJ. Anti-nociceptive synergism of morphine and gabapentin in neuropathic pain induced by chronic constriction injury. Pharmacol Biochem Behav. 2009;92:457–64.

    Article  Google Scholar 

  36. Hansen C, Gilron I, Hong M. The effects of intrathecal gabapentin on spinal morphine tolerance in the rat tail-flick and paw pressure tests. Anesth Analg. 2004;99:1180–4.

    Article  PubMed  CAS  Google Scholar 

  37. Lin JA, Lee MS, Wu CT, Yeh CC, Lin SL, Wen ZH, Wong CS. Attenuation of morphine tolerance by intrathecal gabapentin is associated with suppression of morphine-evoked excitatory amino acid release in the rat spinal cord. Brain Res. 2005;1054:167–73.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The author thanks Mr. Wang-Di and Ms. Wu-Jinjin for the behavioral work. The author also thanks Zhao-Wei and Hu Shan-shan for their technical assistance during this study.

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Authors and Affiliations

  1. Department of Anesthesiology, Anhui Medical University Affiliated Auhui Provincial Hospital, 230001, Hefei, People’s Republic of China

    Xin Wei

  2. Institute of Clinical Pharmacology, Anhui Medical University Key Laboratory of Antiinflammatory and Immunopharmacology, Ministry of Education, 230032, Hefei, People’s Republic of China

    Xin Wei & Wei Wei

  3. Department of Institute of Clinical Pharmacology, Anhui Medical University, No 81 Meishan Road, 230032, Hefei, People’s Republic of China

    Wei Wei

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  1. Xin Wei
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Correspondence to Wei Wei.

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Wei, X., Wei, W. Role of gabapentin in preventing fentanyl- and morphine-withdrawal-induced hyperalgesia in rats. J Anesth 26, 236–241 (2012). https://doi.org/10.1007/s00540-011-1272-7

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  • DOI: https://doi.org/10.1007/s00540-011-1272-7

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