A comparison of intrathecal magnesium and ketamine in attenuating remifentanil-induced hyperalgesia in rats

Jiehao Sun, Hai Lin, Xiaona Feng, Jiaojiao Dong, Emmanuel Ansong, Xuzhong Xu, Jiehao Sun, Hai Lin, Xiaona Feng, Jiaojiao Dong, Emmanuel Ansong, Xuzhong Xu

Abstract

Background: Activation of NMDA receptors play an important role in the development of remifentanil-induced hyperalgesia. We hypothesized that in addition to ketamine, intrathecal MgSO4 could also relieve thermal and mechanical hyperalgesia in rats.

Methods: Initially, 24 Sprague-Dawley rats were divided into control group, remifentanil group, surgical incision group and remifentanil combined with surgical incision group to create an experimental model. Subsequently, 40 rats were divided into control group, model group, model group plus 100 μg MgSO4, 300 μg MgSO4 and 10 μg ketamine respectively. Paw withdrawal mechanical thresholds and paw withdrawal thermal latency tests were performed at -24 h, 2 h, 6 h, 24 h, 48 h, 72 h and 7 day after the surgical procedure. After behavior assessment on the 7th day, remifentanil was given again to ascertain whether or not NMDA antagonists could suppress the re-exposure of remifentanil-induced hyperalgesia.

Results: Remifentanil administration plus surgical incision induced significant postoperative hyperalgesia, as indicated by decreased paw withdrawal mechanical thresholds and paw withdrawal thermal latency to mechanical and thermal stimulation. In addition to ketamine, intrathecal MgSO4 (100, 300 μg) dose-dependently reduced remifentanil-induced mechanical and thermal hyperalgesia. Ketamine had less mechanical hyperalgesia in 6 h (p = 0.018), 24 h (p = 0.014) and 48 h (p = 0.011) than 300 μg MgSO4. There was no difference in inhibiting thermal hyperalgesia between the group ketamine and group MgSO4 (300 μg). The rats were given remifentanil again 7 days later after the first exposure of remifentanil. The hyperalgesic effect induced by re-exposure of remifentanil was not reversed in any groups of MgSO4 or ketamine.

Conclusions: In addition to ketamine, intrathecal administration of MgSO4 dose-dependently reduced remifentanil-induced hyperalgesia in a surgical incision mode. Re-exposure to remifentanil 1 week later again produced hyperalgesia, and this was not altered by the prior intrathecal treatments in any 4 groups treated with MgSO4 or ketamine.

Keywords: Hyperalgesia; Ketamine; Magnesium; Remifentanil.

Figures

Fig. 1
Fig. 1
a-b Paw withdrawal mechanical threshold (a) and paw withdrawal thermal latency (b) were evaluated at 24 h before incision and 2, 6, 24, 48 and 72 h after remifentanil infusion. Groups allocation: R: Group remifentanil; RI: Group remifentanil + surgical incision; C: Group Control; I: Group surgical incision. Data are expressed as means ± SD. * P < 0.001 compared with Group C, # P < 0.001 compared with Group RI, + P < 0.05 compared with Group R
Fig. 2
Fig. 2
a-b The NMDA antagonist ketamine and MgSO4 were administered intrathecally 30 min before remifentanil infusion and surgical incision. Paw withdrawal mechanical threshold (a) and paw withdrawal thermal latency (b) were evaluated at 24 h before incision and 2, 6, 24, 48, 72 h, 7 days after remifentanil infusion, 6 h after re-exposure of remifentanil 7 days later. Groups allocation: RI: Group remifentanil + surgical incision; C: Group Control; RIK: Group i.t. 10 μg ketamine was given to the group RI; RIMlow: Group i.t. 100 μg MgSO4 was given to the group RI; RIMhigh: Group i.t. 300 μg MgSO4 was given to the group RI. Data are expressed as means ± SD. * P < 0.001 compared with Group C, # P < 0.001 compared with Group RI, + P < 0.01 compared with Group RIMlow, ΔP < 0.05 compared with Group RIMhigh

References

    1. Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Brit J Anaesth. 2014;112:991–1004. doi: 10.1093/bja/aeu137.
    1. Derrode N, Lebrun F, Levron JC, Chauvin M, Debaene B. Influence of perioperative opioid on postoperative pain after major abdominal surgery: sufentanil TCI versus remifentanil TCI. A randomized, controlled study. Brit J Anaesth. 2003;91:842–9. doi: 10.1093/bja/aeg263.
    1. Shin SW, Cho AR, Lee HJ, et al. Maintenance anaesthetics during remifentanil-based anaesthesia might affect postoperative pain control after breast cancer. Brit J Anaesth. 2010;105:661–7. doi: 10.1093/bja/aeq257.
    1. Ana C, David C, Asunción R, Paula GN, Margarita MP. Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice. Eur J Pharmacol. 2011;657:89–96. doi: 10.1016/j.ejphar.2011.01.059.
    1. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103:147–55. doi: 10.1097/00000542-200507000-00022.
    1. Chen L, Huang LY. Protein kinase C reduces Mg2+ block of NMDA receptor channels as a mechanism of modulation. Nature. 1992;9:521–3. doi: 10.1038/356521a0.
    1. Alain C, Van E, Philippe S, Mazoit JX, Marc C, Dan B. Protective effect of prior administration of magnesium on delayed hyperalgesia induced by fentanyl in rats. Can J Anesth. 2006;53:1180–5. doi: 10.1007/BF03021578.
    1. Tufan M, Yasemin G, Dilek O, Ismail G. Magnesium modifies fentanyl-induced local antinociception and hyperalgesia. N-S Arch Pharmacol. 2009;380:415–20. doi: 10.1007/s00210-009-0447-3.
    1. Liu X, Zhang J, Zhao H, Mei H, Lian Q, ShangGuan W. The effect of propofol on intrathecal morphine-induced pruritus and its mechanism. Anesth Analg. 2014;118:303–9. doi: 10.1213/ANE.0000000000000086.
    1. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain. 1996;64:493–501. doi: 10.1016/0304-3959(95)01441-1.
    1. Zhang L, Shu R, Wang H, et al. Hydrogen-rich saline prevents remifentanil induced hyperalgesia and inhibits MnSOD nitration via regulation of NR2B-containing NMDA receptor in rats. Neuroscience. 2014;280:171–80. doi: 10.1016/j.neuroscience.2014.09.024.
    1. Célérier E, González JR, Maldonado R, Cabalvro D, Puig MM. Opioid-induced hyperalgesia in a murine model of postoperative pain: role of nitric oxide generated from the inducible nitric oxide synthase. Anesthesiology. 2006;104:546–55. doi: 10.1097/00000542-200603000-00023.
    1. Célérier 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.
    1. Wang C, Li Y, Wang H, et al. Inhibition of DOR prevents remifentanil induced postoperative hyperalgesia through regulating the trafficking and function of spinal NMDA receptors in vivo and in vitro. Brain Res Bull. 2015;110:30–9. doi: 10.1016/j.brainresbull.2014.12.001.
    1. Juni A, Klein G, Pintar JE, Kest B. Nociception increases during opioid infusion in opioid receptor triple knock-out mice. Neuroscience. 2007;147:439–44. doi: 10.1016/j.neuroscience.2007.04.030.
    1. 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;46:68–72. doi: 10.1016/j.neulet.2009.06.061.
    1. Van Dorp EL, Kest B, Kowalczyk WJ, et al. Morphine-6-β-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology. 2009;110:1356–63. doi: 10.1097/ALN.0b013e3181a105de.
    1. Li Y, Wang H, Xie K, et al. Inhibition of glycogen synthase kinase-3β prevents remifentanil-induced hyperalgesia via regulating the expression and function of spinal N-methyl-D-aspartate receptors in vivo and vitro. PLoS One. 2013;8:e77790. doi: 10.1371/journal.pone.0077790.
    1. Hahnenkamp K, Nollet J, Van Aken HK, et al. Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in Xenopus laevis oocytes. Anesthesiology. 2004;100:1531–7. doi: 10.1097/00000542-200406000-00028.
    1. Guntz E, Dumont H, Roussel C, et al. Effects of remifentanil on N-methyl-d-aspartate receptor: an electrophysiologic study in rat spinal cord. Anesthesiology. 2005;102:1235–41. doi: 10.1097/00000542-200506000-00025.
    1. Celerier E, Simonnet G, Maldonado R. Prevention of fentanyl-induced delayed pronociceptive effects in mice lacking the protein kinase C gene. Neuropharmacology. 2004;46:264–72. doi: 10.1016/j.neuropharm.2003.08.008.
    1. Ram KC, Eisenberg E, Haddad M, Pud D. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - new perspective of opioid- induced hyperalgesia. Pain. 2008;139:431–8. doi: 10.1016/j.pain.2008.05.015.
    1. Bennett AD, Everhart AW, Hulsebosch CE. Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury. Brain Res. 2000;859:72–82. doi: 10.1016/S0006-8993(99)02483-X.
    1. Hama A, Jeung Woon L, Jacqueline S. Differential efficacy of intrathecal NMDA receptor antagonists on inflammatory mechanical and thermal hyperalgesia in rats. Eur J Pharmacol. 2003;459:49–58. doi: 10.1016/S0014-2999(02)02828-5.
    1. Xiao WH, Bennett GJ. Magnesium suppresses neuropathic pain response in rats via a spinal site of action. Brain Res. 1994;666:168–172. doi: 10.1016/0006-8993(94)90768-4.
    1. Van Elstraete AC, Sitbon P, Trabold F, Mazoti JX, Benhamou D. A single dose of intrathecal morphine in rat induces long-lasting hyperalgesia: the protective effect of prior administration of ketamine. Anesth Analg. 2005;101:1750–6. doi: 10.1213/01.ANE.0000184136.08194.9B.
    1. Lim HS, Kim JM, Choi JG, et al. Intrathecal ketamine and pregabalin at sub-effective doses synergistically reduces neuropathic pain without motor dysfunction in mice. Biol Pharm Bull. 2013;36:125–30. doi: 10.1248/bpb.b12-00760.
    1. Yoshito T, Eiru S, Toshihiko K, Isao S. Antihyperalgesic effects of intrathecally administered magnesium sulfate in rats. Pain. 2000;84:175–9. doi: 10.1016/S0304-3959(99)00207-9.
    1. Cheng JK, Lai YJ, Chen CC, Cheng CR, Chiou LC. Magnesium chloride and rutbenium red attenuated the antialldodynic effect of intrathecal gabapentin in a rat model of postoperative pain. Anesthesiology. 2003;98:1472–9. doi: 10.1097/00000542-200306000-00026.
    1. Echevarria G, Elgueta F, Fierro C, et al. Nitrous oxide (N2O) reduces postoperative opioid-induced hyperalgesia after remifentanil propofol anaesthesia in humans. Brit J Anaesth. 2011;107:959–65. doi: 10.1093/bja/aer323.
    1. Cabañero D, Campillo A, Célérier E, Romero A, Puig MM. Pronociceptive effects of remifentanil in a mouse model of postsurgical pain: effect of a second surgery. Anesthesiology. 2009;111:1334–45. doi: 10.1097/ALN.0b013e3181bfab61.
    1. Chen JQ, Wu Z, Wen LY, Miao JZ, Hu YM, Xue R. Preoperative and postoperative analgesic techniques in the treatment of patients undergoing transabdominal hysterectomy: a preliminary randomized trial. BMC Anesthesiol. 2015;15:70. doi: 10.1186/s12871-015-0046-4.
    1. Wilson JA, Garry EM, Anderson HA, et al. NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists. Pain. 2005;117:421–32. doi: 10.1016/j.pain.2005.07.005.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera