High dose of QX-314 produces anti-nociceptive effect without capsaicin in rats with inflammatory TMJ pain

  • Yang, Kui-Ye (Department of Oral physiology, School of Dentistry, Kyungpook National University) ;
  • Kim, Min-Su (Department of Oral physiology, School of Dentistry, Kyungpook National University) ;
  • Kim, Eun-Kyung (Department of Oral physiology, School of Dentistry, Kyungpook National University) ;
  • Kong, Mi-Sun (Department of Oral physiology, School of Dentistry, Kyungpook National University) ;
  • Ahn, Jong-Soo (Department of Oral physiology, School of Dentistry, Kyungpook National University) ;
  • Lee, Jong-Hun (Department of Oral physiology, School of Dentistry, Kyungpook National University) ;
  • Ju, Jin-Sook (Department of Oral physiology, School of Dentistry, Kyungpook National University) ;
  • Ahn, Dong-Kuk (Department of Oral physiology, School of Dentistry, Kyungpook National University)
  • Received : 2013.09.11
  • Accepted : 2013.12.10
  • Published : 2013.12.31


The present study investigated the effects of QX-314 on inflammatory pain of the temporomandibular joint (TMJ). Experiments were carried out on male Sprague-Dawley rats weighing 220-280 g. Under anesthesia, the TMJ of each animal was injected with $50{\mu}L$ of formalin (5%). The number of noxious behavioral responses, including rubbing or scratching of the facial region including the TMJ area, was recorded over 9 sequential 5 min intervals for each animal. Although 2.5% QX-314 did not affect formalin-induced nociceptive behavior, administration of 5% QX-314 with formalin significantly decreased the number of scratches produced by the formalin injection. Co-administration of capsaicin, a TRPV1 agonist, with 2.5% QX-314 produced significant anti-nociceptive effects whereas 2.5% QX-314 alone did not. However, the co-administration of capsaicin did not enhance the anti-nociceptive effects in the 5% QX-314-treated rats. Moreover, the co-administration of capsazepine, a TRPV1 antagonist, did not attenuate anti-nociceptive effects in the 5% QX-314-treated rats. These findings suggest that TRPV1 is effective in the transport of low but not high doses of QX-314. Moreover, a high dose of QX-314, which is not mediated by peripheral TRPV1 activity, may be viable therapeutic strategy for inflammatory pain in the TMJ.

이상의 실험 결과들을 요약하면, 포르말린을 측두하악관절 내로 주입하여 발생한 염증성 통증 행위반응은 QX-314의 투여로 감소할 수 있었다. 저농도의 QX-314의 진통작용은 TRPV1 통로를 이용하여 세포막 내로 이동하여 작용이 나타났으며 고농도의 QX-314는 TRPV1 통로와 무관하게 진통작용을 나타내었다. 이와 같은 결과는 측두하악관절 장애로 인해 발생되는 염증성 통증에 QX-314가 효과적인 치료제로 사용할 수 있다는 것을 말해주며, 특히 고농도의 QX-314가 세포막을 이동하는 경로에 대한 연구가 더 진행된다면 임상에서 QX-314가 진통제로서 사용할 수 있는 계기가 될 것으로 판단된다.



  1. Butterworth J, Oxford GS. Local anesthetics: a new hydrophilic pathway for the drug-receptor reaction. Anesthesiology. 2009;111:12-14.
  2. Butterworth JF 4th, Strichartz GR. Molecular mechanisms of local anesthesia: a review. Anesthesiology. 1990;72: 711-734.
  3. Frazier DT, Narahashi T, Yamada M. The site of action and active form of local anesthetics. II. Experiments with quaternary compounds. J Pharmacol Exp Ther. 1970; 171:45-51.
  4. Ritchie JM, Ritchie B, Greengard P. The active structure of local anesthetics. J Pharmacol Exp Ther. 1965;150:152-159.
  5. Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature. 2007;449:607-610.
  6. Cairns BE. Pathophysiology of TMD pain--basic mechanisms and their implications for pharmacotherapy. J Oral Rehabil. 2010;37:391-410.
  7. Scrivani SJ, Keith DA, Kaban LB. Temporomandibular disorders. N Engl J Med. 2008;359:2693-2705.
  8. Wadhwa S, Kapila S. TMJ disorders: future innovations in diagnostics and therapeutics. J Dent Educ. 2008; 72:930-947.
  9. Hersh EV, Balasubramaniam R, Pinto A. Pharmacologic management of temporomandibular disorders. Oral Maxillofac Surg Clin North Am. 2008;20:197-210.
  10. Lim TK, Macleod BA, Ries CR, Schwarz SK. The quaternary lidocaine derivative, QX-314, produces longlasting local anesthesia in animal models in vivo. Anesthesiology. 2007;107;305-311.
  11. Abbott FV, Franklin KB, Westbrook RF. The formalin test: scoring properties of the first and second phases of the pain response in rats. Pain. 1995;60:91-102.
  12. Ahn DK, Chae JM, Choi HS, Kyung HM, Kwon OW, Park HS, Youn DH, Bae YC. Central cyclooxygenase inhibitors reduced IL-1beta-induced hyperalgesia in temporomandibular joint of freely moving rats. Pain. 2005;117:204-213.
  13. Choi HS, Ju JS, Lee HJ, Jung CY, Kim BC, Park JS, Ahn DK. Effects of TNF-alpha injected intracisternally on the nociceptive jaw-opening reflex and orofacial formalin test in freely moving rats. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:613-618.
  14. Choi HS, Ju JS, Lee HJ, Kim BC, Park JS, Ahn DK. Effects of intracisternal injection of interleukin-6 on nociceptive jaw opening reflex and orofacial formalin test in freely moving rats. Brain Res Bull. 2003;59:365-370.
  15. Park MK, Song HC, Yang KY, Ju JS, Ahn DK. Participation of peripheral P2X receptors in orofacial inflammatory nociception in rats. Int J Oral Biol. 2011;36:143-148.
  16. Raboisson P, Dallel R. The orofacial formalin test. Neurosci Biobehav Rev. 2004;28;219-226.
  17. Won KA, Kang YM, Lee MK, Park MK, Ju JS, Bae YC, Ahn DK. Participation of microglial p38 MAPK in formalin-induced temporomandibular joint nociception in rats. J Orofac Pain. 2012;26:132-141.
  18. Won KA, Park SH, Kim BK, Baek KS, Yoon DH, Ahn DK. Intracisternal administration of voltage dependent calcium channel blockers attenuates orofacial inflammatory nociceptive behavior in rats. Int J Oral Biol. 2011;36:43-50.
  19. Raboisson P, Dallel R, Clavelou P, Sessle BJ, Woda A. Effects of subcutaneous formalin on the activity of trigeminal brain stem nociceptive neurones in the rat. J Neurophysiol. 1995;73;496-505.
  20. Ahn DK, Choi HS, Yeo SP, Woo YW, Lee MK, Yang GY, Jeon HJ, Park JS, Mokha SS. Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoidinduced antinociceptive effects on inflammatory temporomandibular joint (TMJ) nociception. Pain. 2007; 132:23-32.
  21. Won KA, Lim NH, Lee MK, Park MK, Yang GY, Park YY, Ahn DK, Bae YC. A blockade of the central MAPK pathway attenuates referred pain in rats with complete freund's adjuvant-induced inflammation of the temporomandibular joint. Int J Oral Biol. 2010;35:83-89.
  22. Omana-Zapata I, Khabbaz MA, Hunter JC, Bley KR. QX-314 inhibits ectopic nerve activity associated neuropathic pain. Brain Res. 1997;771:228-237.
  23. Ries CR, Pillai R, Chung CC, Wang JT, MacLeod BA, Schwarz SK. QX-314 produces long-lasting local anesthesia modulated by transient receptor potential vanilloid receptors in mice. Anesthesiology 2009;111:122-126.
  24. Kim HY, Kim K, Li HY, Chung G, Park CK, Kim JS, Jung SJ, Lee MK, Ahn DK, Hwang SJ, Kang Y, Binshtok AM, Bean BP, Woolf CJ, Oh SB. Selectively targeting pain in the trigeminal system. Pain. 2010;150:29-40.
  25. Shen J, Fox LE, Cheng J. Differential effects of peripheral versus central coadministration of QX-314 and capsaicin on neuropathic pain in rats. Anesthesiology. 2012;117:465-480.
  26. LeResche L, Mancl L, Sherman JJ, Gandara B, Dworkin SF. Changes in temporomandibular pain and other symptoms across the menstrual cycle. Pain. 2003;106:253-261.
  27. Gameiro GH, da Silva Andrade A, Nouer DF, Ferraz de Arruda Veiga MC. How may stressful experiences contribute to the development of temporomandibular disorders? Clin Oral Investig. 2006;10:261-268.
  28. Hartwig AC, Mathias SI, Law AS, Gebhart GF. Characterization and opioid modulation of inflammatory temporomandibular joint pain in the rat. J Oral Maxillofac Surg. 2003;61:1302-1309.
  29. Garrett FG, Hawkins JL, Overmyer AE, Hayden JB, Durham PL. Validation of novel rat-holding device for studying heat-and mechanical-evoked trigeminal nocifensive behavioral responses. J Orofac Pain. 2012;26:337-344.
  30. Dionne RA. Pharmacologic treatments for temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:134-142.
  31. Gerner P, Binshtok AM, Wang CF, Hevelone ND, Bean BP, Woolf CJ, Wang GK. Capsaicin combined with local anesthetics preferentially prolongs sensory/nociceptive block in rat sciatic nerve. Anesthesiology. 2008;109; 872-878.
  32. Pelissier T, Pajot J, Dallel R. The orofacial capsaicin test in rats: effects of different capsaicin concentrations and morphine. Pain. 2002;96:81-87.
  33. Novakova-Tousova K, Qyklicky L, Susankova K, Benedikt J, Samad A, Teisinger J, Vlachova V. Functional changes in the vanilloid receptor subtype 1 channel during and after acute desensitization. Neuroscience. 2007;149:144-154.
  34. Binshtok AM, Gerner P, Oh SB, Puopolo M, Suzuki S, Roberson DP, Herbert T, Wang CF, Kim D, Chung G, Mitani AA, Wang GK, Bean BP, Woolf CJ. Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents. Anesthesiology. 2009;111:127-137.
  35. Roberson DP, Binshtok AM, Blasl F, Bean BP, Woolf CJ. Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review. Br J Pharmacol. 2011;164:48-58.