CC BY 4.0 · Arq Neuropsiquiatr 2023; 81(03): 233-239
DOI: 10.1055/s-0043-1761491
Original Article

The effect of dexmedetomidine on expression of neuronal nitric oxide synthase in spinal dorsal cord in a rat model with chronic neuropathic pain

O efeito da dexmedetomidina na expressão do óxido nítrico sintase neuronal na medula espinhal dorsal em um modelo rato com dor neuropática crônica
1   Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Department of Anesthesiology, Taiyuan, People's Republic of China.
2   Huazhong University of Science and Technology, Tongji Hospital, Tongji Medical College, Wuhan, People's Republic of China.
,
3   Xuzhou Medical University, The Affiliated Hospital of Xuzhou, Department of Critical Care Medicine, Xuzhou, People's Republic of China.
,
1   Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Department of Anesthesiology, Taiyuan, People's Republic of China.
2   Huazhong University of Science and Technology, Tongji Hospital, Tongji Medical College, Wuhan, People's Republic of China.
,
1   Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Department of Anesthesiology, Taiyuan, People's Republic of China.
2   Huazhong University of Science and Technology, Tongji Hospital, Tongji Medical College, Wuhan, People's Republic of China.
,
1   Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Department of Anesthesiology, Taiyuan, People's Republic of China.
2   Huazhong University of Science and Technology, Tongji Hospital, Tongji Medical College, Wuhan, People's Republic of China.
,
1   Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Department of Anesthesiology, Taiyuan, People's Republic of China.
2   Huazhong University of Science and Technology, Tongji Hospital, Tongji Medical College, Wuhan, People's Republic of China.
,
1   Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Department of Anesthesiology, Taiyuan, People's Republic of China.
2   Huazhong University of Science and Technology, Tongji Hospital, Tongji Medical College, Wuhan, People's Republic of China.
› Author Affiliations

Abstract

Background Neuropathic pain typically refers to the pain caused by somatosensory system injury or diseases, which is usually characterized by ambulatory pain, allodynia, and hyperalgesia. Nitric oxide produced by neuronal nitric oxide synthase (nNOS) in the spinal dorsal cord might serve a predominant role in regulating the algesia of neuropathic pain. The high efficacy and safety, as well as the plausible ability in providing comfort, entitle dexmedetomidine (DEX) to an effective anesthetic adjuvant. The aim of this study was to investigate the effect of DEX on the expression of nNOS in spinal dorsal cord in a rat model with chronic neuropathic pain.

Methods Male Sprague Dawley (SD) rats were randomly assigned into three groups: sham operation group (sham), (of the sciatic nerve) operation (CCI) group, and dexmedetomidine (DEX) group. Chronic neuropathic pain models in the CCI and DEX groups were established by sciatic nerve ligation. The thermal withdrawal latency (TWL) was measured on day 1 before operation and on day 1, 3, 7 and 14 after operation. Six animals were sacrificed after TWL measurement on day 7, and 14 days after operation, in each group, the L4–6 segment of the spinal cords was extracted for determination of nNOS expression by immunohistochemistry.

Results Compared with the sham group, the TWL threshold was significantly decreased and the expression of nNOS was up-regulated after operation in the CCI and DEX groups. Compared with the CCI grou[, the TWL threshold was significantly increased and the expression of nNOS was significantly down-regulated on day 7 and 14 days after operation in the DEX group.

Conclusion Down-regulated nNOS in the spinal dorsal cord is involved in the attenuation of neuropathic pain by DEX.

Resumo

Antecedentes A dor neuropática refere-se tipicamente à dor causada por lesões ou doenças do sistema somatossensorial. De modo geral, é caracterizada por dor à ambulação, alodinia e hiperalgesia. O óxido nítrico produzido pela enzima óxido nítrico sintase neuronal (nNOS) na medula espinhal dorsal pode ter um papel predominante na regulação da dor neuropática. A alta eficácia e segurança, bem como a plausível capacidade de proporcionar conforto, faz com que a dexmedetomidina (DEX) seja um adjuvante anestésico eficaz. O objetivo deste estudo foi investigar o efeito da DEX na expressão de nNOS na medula espinhal dorsal em um modelo de ratos com dor neuropática crônica.

Métodos Ratos Sprague Dawley (SD) machos foram distribuídos aleatoriamente em três grupos: grupo de cirurgia simulada (sham), grupo de cirurgia (do nervo ciático; CCI) e grupo dexmedetomidina (DEX). Os modelos de dor neuropática crônica nos grupos CCI e DEX foram estabelecidos por ligadura do nervo ciático. A latência de retirada térmica (TWL) foi medida no dia 1 antes da cirurgia e nos dias 1, 3, 7 e 14 após o procedimento. Seis animais de cada grupo foram eutanasiados após a medida de TWL nos dias 7 e 14 após a cirurgia e o segmento L4-6 da medula espinhal foi extraído para determinação da expressão de nNOS por imuno-histoquímica.

Resultados Em comparação ao grupo sham, o limiar de TWL diminuiu significativamente e a expressão de nNOS foi regulada de maneira positiva após a cirurgia nos grupos CCI e DEX. Comparado ao grupo CCI, o limiar de TWL aumentou de forma significativa e a expressão de nNOS caiu significativamente diminuída nos dia 7 e 14 após a cirurgia no grupo DEX.

Conclusão A regulação negativa de nNOS na medula espinhal dorsal está envolvida na atenuação da dor neuropática pela DEX.

Authors' Contributions

JP: was the guarantor of integrity of the entire study and helped to prepare and edit the manuscript; JP, SZ: contributed equally to this work; JP, XW: contributed with the study's concept and design; JP, XW, YK: helped with definition of the intellectual content; JP, SZ, ZW, RP: contributed to the literature research; YR, ZW: contributed to experimental studies; ZW, RP: helped with data acquisition; JP, SZ, ZW, PZ: helped with data analysis; XW: helped with manuscript review.




Publication History

Received: 04 July 2022

Accepted: 10 November 2022

Article published online:
14 April 2023

© 2023. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

 
  • References

  • 1 Colloca L, Ludman T, Bouhassira D. et al. Neuropathic pain. Nat Rev Dis Primers 2017; 3: 17002 DOI: 10.1016/S1474-4422(10)70143-5.
  • 2 Zhao Y, He J, Yu N, Jia C, Wang S. Mechanisms of Dexmedetomidine in Neuropathic Pain. Front Neurosci 2020; 14: 330
  • 3 Cízková D, Lukácová N, Marsala M, Marsala J. Neuropathic pain is associated with alterations of nitric oxide synthase immunoreactivity and catalytic activity in dorsal root ganglia and spinal dorsal horn. Brain Res Bull 2002; 58 (02) 161-171 DOI: 10.1016/s0361-9230(02)00761-x.
  • 4 Liang F, Liu M, Fu X, Zhou X, Chen P, Han F. Dexmedetomidine attenuates neuropathic pain in chronic constriction injury by suppressing NR2B, NF-κB, and iNOS activation. Saudi Pharm J 2017; 25 (04) 649-654 DOI: 10.1016/j.jsps.2017.04.039.
  • 5 Xu B, Zhang WS, Yang JL, Xu H, Deng XM, Zhang YQ. Dexmedetomidine blocks thermal hyperalgesia and spinal glial activation in rat model of monoarthritis. Acta Pharmacol Sin 2010; 31 (05) 523-530
  • 6 Shimode N, Fukuoka T, Tanimoto M, Tashiro C, Tokunaga A, Noguchi K. The effects of dexmedetomidine and halothane on Fos expression in the spinal dorsal horn using a rat postoperative pain model. Neurosci Lett 2003; 343 (01) 45-48
  • 7 Kimura M, Saito S, Obata H. Dexmedetomidine decreases hyperalgesia in neuropathic pain by increasing acetylcholine in the spinal cord. Neurosci Lett 2012; 529 (01) 70-74
  • 8 O'Neil T, Rodgers PE, Shultz C. Dexmedetomidine as adjuvant therapy for acute postoperative neuropathic pain crisis. J Palliat Med 2014; 17 (10) 1164-1166
  • 9 Greenberg RG, Wu H, Laughon M. et al. Population Pharmacokinetics of Dexmedetomidine in Infants. J Clin Pharmacol 2017; 57 (09) 1174-1182
  • 10 Mantz J, Josserand J, Hamada S. Dexmedetomidine: new insights. Eur J Anaesthesiol 2011; 28 (01) 3-6 DOI: 10.1097/EJA.0b013e32833e266d.
  • 11 Liu L, Ji F, Liang J, He H, Fu Y, Cao M. Inhibition by dexmedetomidine of the activation of spinal dorsal horn glias and the intracellular ERK signaling pathway induced by nerve injury. Brain Res 2012; 1427: 1-9
  • 12 Andjelković L, Novak-Jankovič V, Požar-Lukanovič N, Bosnić Z, Spindler-Vesel A. Influence of dexmedetomidine and lidocaine on perioperative opioid consumption in laparoscopic intestine resection: a randomized controlled clinical trial. J Int Med Res 2018; 46 (12) 5143-5154 DOI: 10.1177/0300060518792456.
  • 13 Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33 (01) 87-107
  • 14 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 (01) 77-88
  • 15 Tunctan B, Sari AN, Kacan M. et al. NS-398 reverses hypotension in endotoxemic rats: contribution of eicosanoids, NO, and peroxynitrite. Prostaglandins Other Lipid Mediat 2013; 104-105: 93-108 DOI: 10.1016/j.prostaglandins.2012.08.007.
  • 16 Lawler JM, Song W. Specificity of antioxidant enzyme inhibition in skeletal muscle to reactive nitrogen species donors. Biochem Biophys Res Commun 2002; 294 (05) 1093-1100
  • 17 Tejero J, Shiva S, Gladwin MT. Sources of vascular nitric oxide and reactive oxygen species and their regulation. Physiol Rev 2019; 99 (01) 311-379 DOI: 10.1152/physrev.00036.2017.
  • 18 Alvarez S, Boveris A. Mitochondrial nitric oxide metabolism in rat muscle during endotoxemia. Free Radic Biol Med 2004; 37 (09) 1472-1478
  • 19 Han G, Li L, Meng L. Effects of hyperbaric oxygen on NOS system in neuropathic pain rats. Chinese J Pain Medicine 2012; 18: 104-107
  • 20 Nazarian A, Christianson CA, Hua XY, Yaksh TL. Dexmedetomidine and ST-91 analgesia in the formalin model is mediated by alpha2A-adrenoceptors: a mechanism of action distinct from morphine. Br J Pharmacol 2008; 155 (07) 1117-1126 DOI: 10.1038/bjp.2008.341.
  • 21 Zhang J, Wang Z, Wang Y, Zhou G, Li H. The effect of dexmedetomidine on inflammatory response of septic rats. BMC Anesthesiol 2015; 15: 68
  • 22 Iskandar S, Martins MS, Hudson A, Hirsch JG, Jahr JS. Does Dexmedetomidine Improve or Worsen Restless Leg Syndrome under Sedation: A Case Report and Extensive Review. Case Rep Crit Care 2022; 2022: 2447461 DOI: 10.1155/2022/2447461.
  • 23 Li X, Eisenach JC. α2A-adrenoceptor stimulation reduces capsaicin-induced glutamate release from spinal cord synaptosomes. J Pharmacol Exp Ther 2001; 299 (03) 939-944
  • 24 Hashemi M, Karami M, Zarrindast M. The regulatory role of nitric oxide in morphine-induced analgesia in the descending path of pain from the dorsal hippocampus to the dorsolateral periaqueductal gray. Eur J Pain 2022; 26 (04) 888-901 DOI: 10.1002/ejp.1916.
  • 25 Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet 2017; 56 (08) 893-913 DOI: 10.1007/s40262-017-0507-7.