Journal of Anesthesia

, Volume 25, Issue 1, pp 78–86 | Cite as

Antinociceptive action of carbamazepine on thermal hypersensitive pain at spinal level in a rat model of adjuvant-induced chronic inflammation

  • Tatsushige Iwamoto
  • Yoshihiro Takasugi
  • Hideaki Higashino
  • Hiroyuki Ito
  • Yoshihisa Koga
  • Shinichi Nakao
Original Article



Systemic carbamazepine, a voltage-gated sodium channel blocker, has been reported to dose-dependently reduce inflammatory hyperalgesia. However, the antinociceptive effects of carbamazepine on the spinal cord in inflammatory conditions are unclear. The aim of the present study was to evaluate the antinociceptive effects of carbamazepine on the spinal cord in a chronic inflammatory condition.


In Sprague-Dawley rats, a chronic inflammatory condition was induced by complete Freund’s adjuvant (CFA) inoculation into the tail. Tail flick (TF) latencies were measured following intraperitoneal carbamazepine, or intrathecal carbamazepine or tetrodotoxin injection in intact rats and in the chronic inflammatory rats. From the values of TF latency at 60 min after drug injection, the effective dose required to produce 50% response (ED50) of each drug was derived.


Carbamazepine attenuated thermal responses with both systemic and intrathecal administration. The effect was more evident in rats with chronic inflammation than in intact rats; the ED50s of intraperitoneal carbamazepine in intact and inflamed rats were 12.39 and 1.54 mg/kg, and those of intrathecal carbamazepine were 0.311 and 0.048 nmol, respectively. Intrathecal tetrodotoxin also clearly inhibited the response, with ED50s of 1.006 pmol in intact rats and 0.310 pmol in inflamed rats. The relative potencies of intrathecal carbamazepine versus tetrodotoxin for inhibition were approximately 1:150–1:300 in intact and inflamed rats.


These results indicate that the inhibition of voltage-gated sodium channels, at least tetrodotoxin-sensitive channels, may contribute to the antinociceptive effect of carbamazepine on CFA-induced inflammatory pain, since lower doses of intrathecal carbamazepine and tetrodotoxin attenuated thermal responses to a greater extent in inflamed rats than in intact rats.


Chronic inflammatory pain Voltage-gated sodium channel Carbamazepine Tetrodotoxin Complete Freund’s adjuvant 



This study was supported by The Osaka Medical Research Foundation for Incurable Diseases in 2009.


  1. 1.
    Cheng JK, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res. 2008;33:1970–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR. The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain. 2006;7:S1–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev. 2005;(3):CD001133.Google Scholar
  4. 4.
    Bianchi M, Rossoni G, Sacerdote P, Panerai AE, Berti F. Carbamazepine exerts anti-inflammatory effects in the rat. Eur J Pharmacol. 1995;294:71–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Landmark CJ. Targets for antiepileptic drugs in the synapse. Med Sci Monit. 2007;13(1):RA1–7.Google Scholar
  6. 6.
    Stepanović-Petrović RM, Tomić MA, Vucković SM, Kocev N, Ugresić ND, Prostran MS, Bosković B. GABAergic mechanisms are involved in the antihyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory hyperalgesia. Pharmacology. 2008;82:53–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Vucković S, Tomić M, Stepanović-Petrovic R, Ugresic N, Prostran M, Boskovic B. Role of alpha2-adrenoceptors in the local peripheral antinociception by carbamazepine in a rat model of inflammatory mechanical hyperalgesia. Methods Find Exp Clin Pharmacol. 2007;29:689–96.CrossRefPubMedGoogle Scholar
  8. 8.
    Jensen TS, Yaksh TL. Comparison of antinociceptive action of morphine in the periaqueductal gray, medial and paramedial medulla in rat. Brain Res. 1986;363:99–113.CrossRefPubMedGoogle Scholar
  9. 9.
    Takasugi Y, Fuyuta M, Sugiura J, Yabuta K, Iwamoto T, Koga Y. The effect of sub-MAC anesthesia and the radiation setting on repeated tail flick testing in rats. Exp Anim. 2008;57:65–72.CrossRefPubMedGoogle Scholar
  10. 10.
    Chapman V, Dickenson AH. Inflammation reveals inhibition of noxious responses of rat spinal neurons by carbamazepine. Neuroreport. 1997;8:1399–404.CrossRefPubMedGoogle Scholar
  11. 11.
    Chapman V, Suzuki R, Chamarette HL, Rygh LJ, Dickenson AH. Effects of systemic carbamazepine and gabapentin on spinal neuronal responses in spinal nerve ligated rats. Pain. 1998;75:261–72.CrossRefPubMedGoogle Scholar
  12. 12.
    Ardid D, Lamberty Y, Alloui A, Coudore-Civiale MA, Klitgaard H, Eschalier A. Antihyperalgesic effect of levetiracetam in neuropathic pain models in rats. Eur J Pharmacol. 2003;473:27–33.CrossRefPubMedGoogle Scholar
  13. 13.
    Jensen TS. Opioids in the brain: supraspinal mechanisms in pain control. Acta Anaesthesiol Scand. 1997;41:123–32.CrossRefPubMedGoogle Scholar
  14. 14.
    Buvanendran A, Kroin JS, Kerns JM, Nagalla SN, Tuman KJ. Characterization of a new animal model for evaluation of persistent postthoracotomy pain. Anesth Analg. 2004;99:1453–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Sun GC, Werkman TR, Battefeld A, Clare JJ, Wadman WJ. Carbamazepine and topiramate modulation of transient and persistent sodium currents studied in HEK293 cells expressing the Na(v)1.3 alpha-subunit. Epilepsia. 2007;48:774–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Sheets PL, Heers C, Stoehr T, Cummins TR. Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine. J Pharmacol Exp Ther. 2008;326:89–99.CrossRefPubMedGoogle Scholar
  17. 17.
    Hur YK, Choi IS, Cho JH, Park EJ, Choi JK, Choi BJ, Jang IS. Effects of carbamazepine and amitriptyline on tetrodotoxin resistant Na+ channels in immature rat trigeminal ganglion neurons. Arch Pharm Res. 2008;31:178–82.CrossRefPubMedGoogle Scholar
  18. 18.
    Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain. 2004;108:237–47.CrossRefPubMedGoogle Scholar
  19. 19.
    Gould HJ 3rd, England JD, Soignier RD, Nolan P, Minor LD, Liu ZP, Levinson SR, Paul D. Ibuprofen blocks changes in Na v 1.7 and 1.8 sodium channels associated with complete Freund’s adjuvant-induced inflammation in rat. J Pain. 2004;5:270–80.CrossRefPubMedGoogle Scholar
  20. 20.
    Strickland IT, Martindale JC, Woodhams PL, Reeve AJ, Chessell IP, McQueen DS. Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur J Pain. 2008;12:564–72.CrossRefPubMedGoogle Scholar
  21. 21.
    Villarreal CF, Sachs D, Cunha FQ, Parada CA, Ferreira SH. The role of Na(V)1.8 sodium channel in the maintenance of chronic inflammatory hypernociception. Neurosci Lett. 2005;386:72–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Yang YC, Kuo CC. Inhibition of Na(+) current by imipramine and related compounds: different binding kinetics as an inactivation stabilizer and as an open channel blocker. Mol Pharmacol. 2002;62:1228–37.CrossRefPubMedGoogle Scholar
  23. 23.
    Yang YC, Kuo CC. An inactivation stabilizer of the Na+ channel acts as an opportunistic pore blocker modulated by external Na+. J Gen Physiol. 2005;125:465–81.CrossRefPubMedGoogle Scholar
  24. 24.
    Dib-Hajj SD, Binshtok AM, Cummins TR, Jarvis MF, Samad T, Zimmermann K. Voltage-gated sodium channels in pain states: role in pathophysiology and targets for treatment. Brain Res Rev. 2009;60:65–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Benjamin ER, Pruthi F, Olanrewaju S, Ilyin VI, Crumley G, Kutlina E, Valenzano KJ, Woodward RM. State-dependent compound inhibition of Nav1.2 sodium channels using the FLIPR Vm dye: on-target and off-target effects of diverse pharmacological agents. J Biomol Screen. 2006;11:29–39.CrossRefPubMedGoogle Scholar
  26. 26.
    Lingamaneni R, Hemmings HC Jr. Differential interaction of anaesthetics and antiepileptic drugs with neuronal Na+ channels, Ca2 + channels, and GABA(A) receptors. Br J Anaesth. 2003;90:199–211.CrossRefPubMedGoogle Scholar
  27. 27.
    Ostman JA, Nassar MA, Wood JN, Baker MD. GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9. J Physiol. 2008;586:1077–87.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2010

Authors and Affiliations

  • Tatsushige Iwamoto
    • 1
  • Yoshihiro Takasugi
    • 1
  • Hideaki Higashino
    • 2
  • Hiroyuki Ito
    • 3
  • Yoshihisa Koga
    • 1
  • Shinichi Nakao
    • 1
  1. 1.Department of AnesthesiologyKinki University Faculty of MedicineOsaka-sayamaJapan
  2. 2.Department of PharmacologyKinki University Faculty of MedicineOsaka-sayamaJapan
  3. 3.Department of PathologyKinki University Faculty of MedicineOsaka-sayamaJapan

Personalised recommendations