Advances in Clinical and Experimental Medicine
2019, vol. 28, nr 5, May, p. 573–579
Publication type: original article
Study of antinociceptive effect of ketamine in acute and neuropathic pain models in rats
1 Department of Pharmacology and Drug Toxicology, Faculty of Pharmacy, Medical University of Plovdiv, Bulgaria
2 Laboratory of Neuropharmacology, Technological Center for Emergency Medicine (TCEMED), Plovdiv, Bulgaria
3 Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Medical University of Plovdiv, Bulgaria
Background. Glutamate N-methyl-D-aspartate (NMDA) receptors are known for their importance in the perseverance of chronic neuropathic pain. Ketamine, an intravenous anesthetic agent, is a non-competitive blocker of NMDA receptors. Applied in anesthetic doses, ketamine has anti-nociceptive effects in various animal pain models.
Objectives. The objective of this study was to investigate the anti-nociceptive effect of ketamine in acute and neuropathic pain models in rats.
Material and Methods. To study the anti-nociceptive effect of ketamine on acute pain, 40 Wistar rats were divided into 5 groups (n = 8): control, positive control group and 3 experimental groups treated intraperitoneally (ip.) with 30 mg/kg bw, 40 mg/kg bw and 50 mg/kg bw ketamine, respectively. The anti-nociceptive effect was evaluated in hot plate, analgesy-meter and formalin tests. The model of neuropathic pain was induced by left sciatic nerve ligation. Twenty-four Wistar rats were divided into 3 groups (n = 8): sham-control group, model group and ketamine-treated group subsequently tested in hot plate and analgesy-meter tests.
Results. In the hot plate test, the rats treated with ketamine presented increased reaction latency at the 120th min and 180th min compared to the controls. In the analgesy-meter test, ketamine produced an antinociceptive effect at the 60th min compared to the controls. In the formalin test, the paw licking time across the early phase of testing was reduced in the rats treated with the 2 higher doses of ketamine. In a neuropathic pain model, ketamine increased the reaction latency at the 120th min and 180th min compared with the model group in the hot plate test. In the analgesy-meter test, in the ketamine-treated animals the paw withdrawal threshold increased at the 60th min compared with the model group.
Conclusion. Our results suggest that ketamine produces peripheral anti-nociceptive effect in an acute pain model. Also, it relieves thermal and mechanical allodynia after 14 days of treatment in a neuropathic pain model.
ketamine, rats, acute pain, neuropathic pain
- Treede R-D. Chapter 1 Pain and hyperalgesia: Definitions and theories. Handb Clin Neurol. 2006;81:3–10. doi:10.1016/S0072-9752(06)80005-9
- Chizh BA. Low dose ketamine: A therapeutic and research tool to explore N-methyl-D-aspartate (NMDA) receptor-mediated plasticity in pain pathways. J Psychopharmacol. 2007;21(3):259–271. doi:10. 1177/0269881105062484
- Kosson D, Klinowiecka A, Kosson P, et al. Intrathecal antinociceptive interaction between the NMDA antagonist ketamine and the opioids, morphine and biphalin. Eur J Pain. 2008;12(5):611–616. doi:10.1016/j.ejpain.2007.10.005
- Harrison NL, Simmonds MA. Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br J Pharmacol. 1985;84(2):381–391. http://www.ncbi.nlm.nih.gov/pubmed/ 2858237. Accessed July 3, 2017.
- White J, Ryan C. Pharmacological properties of ketamine. Drug Alcohol Rev. 1996;15(2):145–155. doi:10.1080/09595239600185801
- Adams HA. Mechanisms of action of ketamine [in German]. Anaesthesiol Reanim. 1998;23(3):60–63. http://www.ncbi.nlm.nih.gov/pubmed/9707750. Accessed July 3, 2017.
- Kapur S, Seeman P. Ketamine has equal affinity for NMDA receptors and the high-affinity state of the dopamine D2 receptor. Biol Psychiatry. 2001;49(11):954–957. http://www.ncbi.nlm.nih.gov/pubmed/ 11398792. Accessed July 3, 2017.
- Himmelseher S, Durieux ME. Revising a dogma: Ketamine for patients with neurological injury? Anesth Analg. 2005;101(2):524–534. doi:10. 1213/01.ANE.0000160585.43587.5B
- Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87–107. http://www.ncbi.nlm.nih.gov/pubmed/2837713. Accessed July 3, 2017.
- Koizuka S, Obata H, Sasaki M, Saito S, Goto F. Systemic ketamine inhibits hypersensitivity after surgery via descending inhibitory pathways in rats. Can J Anesth. 2005;52(5):498–505. doi:10.1007/BF03016530
- Swartjes M, Morariu A, Niesters M, Aarts L, Dahan A. Nonselective and NR2B-selective N-methyl-d-aspartic acid receptor antagonists produce antinociception and long-term relief of allodynia in acute and neuropathic pain. Anesthesiology. 2011;115(1):165–174. doi:10.1097/ALN.0b013e31821bdb9b
- Romero TR, Duarte ID. Involvement of ATP‐sensitive K+ channels in the peripheral antinociceptive effect induced by ketamine. Vet Anaesth Analg. 2013;40(4):419–424. doi:10.1111/vaa.12024
- Wang N, Fu Y, Ma H, Wang J. Clinical research regarding preemptive analgesic effect of preoperative ketamine after transurethral resection of prostate. Middle East J Anaesthesiol. 2015;23(3):295–300. http://www.ncbi.nlm.nih.gov/pubmed/26860019. Accessed July 3, 2017.
- McNamara CR, Mandel-Brehm J, Bautista DM, et al. TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci. 2007;104(33):13525–13530. doi:10.1073/pnas.0705924104
- Herrero JF, Laird JM, López-García JA. Wind-up of spinal cord neurones and pain sensation: Much ado about something? Prog Neurobiol. 2000;61(2):169–203. http://www.ncbi.nlm.nih.gov/pubmed/ 10704997. Accessed July 3, 2017.
- Bulutcu F, Dogrul A, Güç MO. The involvement of nitric oxide in the analgesic effects of ketamine. Life Sci. 2002;71(7):841–853. http://www.ncbi.nlm.nih.gov/pubmed/12074943. Accessed July 3, 2017.
- Vogelaar CF, Vrinten DH, Hoekman MFM, Brakkee JH, Burbach JPH, Hamers FPT. Sciatic nerve regeneration in mice and rats: Recovery of sensory innervation is followed by a slowly retreating neuropathic pain-like syndrome. Brain Res. 2004;1027(1–2):67–72. doi:10.1016/j.brainres.2004.08.036
- Chizh BA, Headley PM. NMDA antagonists and neuropathic pain – multiple drug targets and multiple uses. Curr Pharm Des. 2005; 11(23):2977–2994. http://www.ncbi.nlm.nih.gov/pubmed/16178757. Accessed July 3, 2017.
- Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-D-aspartate receptor for chronic pain management. Preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage. 2000;20(5):358–373. http://www.ncbi.nlm.nih.gov/pubmed/11068158. Accessed July 3, 2017.
- Coggeshall RE, Carlton SM. Ultrastructural analysis of NMDA, AMPA, and kainate receptors on unmyelinated and myelinated axons in the periphery. J Comp Neurol. 1998;391(1):78–86. doi:10.1002/(SICI)1096–9861(19980202)391:1<78::AID-CNE7>3.0.CO;2-O.
- Du J, Zhou S, Coggeshall RE, Carlton SM. N-methyl-D-aspartate-induced excitation and sensitization of normal and inflamed nociceptors. Neuroscience. 2003;118(2):547–562. http://www.ncbi.nlm.nih.gov/pubmed/12699789. Accessed July 3, 2017.
- Burton AW, Lee DH, Saab C, Chung JM. Preemptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviors in a rat model. Reg Anesth Pain Med. 24(3):208–213. http://www.ncbi.nlm.nih.gov/pubmed/10338169. Accessed July 3, 2017.
- Danysz W, Kozela E, Parsons CG, Sladek M, Bauer T, Popik P. Peripherally acting NMDA receptor/glycine B site receptor antagonists inhibit morphine tolerance. doi:10.1016/j.neuropharm.2004.11.005
- Qian J, Brown SD, Carlton SM. Systemic ketamine attenuates nociceptive behaviors in a rat model of peripheral neuropathy. Brain Res. 1996;715(1–2):51–62. doi:10.1016/0006-8993(95)01452-7.
- Klimscha W, Horváth G, Szikszay M, Dobos I, Benedek G. Antinociceptive effect of the S(+)-enantiomer of ketamine on carrageenan hyperalgesia after intrathecal administration in rats. Anesth Analg. 1998; 86(3):561–565. http://www.ncbi.nlm.nih.gov/pubmed/9495415. Accessed July 3, 2017.
- Kawamata T, Omote K, Sonoda H, Kawamata M, Namiki A. Analgesic mechanisms of ketamine in the presence and absence of peripheral inflammation. Anesthesiology. 2000;93(2):520–528. http://www.ncbi.nlm.nih.gov/pubmed/10910503. Accessed July 3, 2017.
- Näsström J, Karlsson U, Post C. Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice. Eur J Pharmacol. 1992;212(1):21–29. http://www.ncbi.nlm.nih.gov/pubmed/1313371. Accessed July 3, 2017.
- Mei X, Wang W, Wang W, et al. Inhibiting astrocytic activation: A novel analgesic mechanism of ketamine at the spinal level? J Neurochem. 2009;109(6):1691–1700. doi:10.1111/j.1471-4159.2009.06087.x