Background & Aims
Remifentanil, characterized by its rapid onset and offset of analgesia, is widely adopted in clinical anesthesia. However, the intraoperative administration of remifentanil can lead to postoperative hyperalgesia, impeding patient recovery. Serving as a relay station for pain signal transmission, the spinal cord receives pain signals from peripheral nociceptors, integrates them, and transmits them to the brain, resulting in the sensation of pain. The response of sensory neurons in the dorsal horn of the spinal cord during remifentanil-induced hyperalgesia remains unclear.
Methods
Male C57BL/6J mice and SST-Cre mice were used in our experiments, we established an incision pain model, and administered remifentanil via subcutaneous infusion. We measured the degree of pain in mice using mechanical and thermal pain thresholds. Immunohistochemistry was used to determine the activation and type of neurons. We employed whole-cell patch-clamp technology to investigate the type of neuronal discharge and utilized optogenetics and chemogenetics for the specific regulation of dorsal spinal cord neurons.
Results
The mechanical pain threshold of the contralateral footpad in mice from the incision pain and remifentanil infusion group (Inci+Remi) significantly decreased compared to the control group. Immunohistochemistry results showed that cFos activation in the dorsal spinal cord layers I/II of the incision pain combined with remifentanil infusion group was significant. Further, we discovered that the activated cFos neurons exhibited high co-staining with the excitatory neuron subtype SST. In vitro whole-cell patch clamp results indicated that the predominant type of neuronal discharge was delayed. We specifically activated dorsal spinal cord SST neurons using either light or chemical activation, which resulted in a significant decrease in the pain threshold of mice. Simultaneously, we employed light or chemical inhibition to specifically suppress dorsal spinal cord SST neurons, significantly alleviating remifentanil-induced hyperalgesia.
Conclusions
Our results elucidate the involvement of the excitatory neuron subtype SST neurons in the dorsal spinal cord in remifentanil-induced hyperalgesia. Specifically regulating these neurons through optogenetics and chemogenetics can alleviate remifentanil-induced hyperalgesia, providing valuable insights and research directions for addressing clinical challenges.
References
[1] Ma J. F., Huang Z. L., Li J., Hu S. J., Lian Q. Q. [Cohort study of remifentanil-induced hyperalgesia in postoperative patients]. Zhonghua Yi Xue Za Zhi. 2011, 91 (14):977-979
[2] Koo C. H., Yoon S., Kim B. R., Cho Y. J., Kim T. K., Jeon Y., Seo J. H. Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial. Br J Anaesth. 2017, 119 (6):1161-1168
[3] Perkins F. M., Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000, 93 (4):1123-1133
[4] Ithnin F. B., Tan D. J. A., Xu X. L., Tan C. H., Sultana R., Sng B. L. Low-dose S+ ketamine in target-controlled intravenous anaesthesia with remifentanil and propofol for open gynaecological surgery: A randomised controlled trial. Indian J Anaesth. 2019, 63 (2):126-133
[5] Wanigasekera V., Lee M. C., Rogers R., Hu P., Tracey I. Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans. J Neurosci. 2011, 31 (8):2835-2842
[6] Zhao M., Joo D. T. Enhancement of spinal N-methyl-D-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance. Anesthesiology. 2008, 109 (2):308-317
[7] Yuan Y., Zhao Y., Shen M., Wang C., Dong B., Xie K., Yu Y., Yu Y. Spinal NLRP3 inflammasome activation mediates IL-1beta release and contributes to remifentanil-induced postoperative hyperalgesia by regulating NMDA receptor NR1 subunit phosphorylation and GLT-1 expression in rats. Mol Pain. 2022, 18 17448069221093016
[8] Fu R., Li S., Li S., Gong X., Zhou G., Wang Y., Ding R., Zhu Z., Zhang L., Li Y. P2X4 receptor in the dorsal horn contributes to BDNF/TrkB and AMPA receptor activation in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats. Neurosci Lett. 2021, 750 135773
[9] Zhang L., Guo S., Zhao Q., Li Y., Song C., Wang C., Yu Y., Wang G. Spinal Protein Kinase Mzeta Regulates alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Trafficking and Dendritic Spine Plasticity via Kalirin-7 in the Pathogenesis of Remifentanil-induced Postincisional Hyperalgesia in Rats. Anesthesiology. 2018, 129 (1):173-186
[10] Santonocito C., Noto A., Crimi C., Sanfilippo F. Remifentanil-induced postoperative hyperalgesia: current perspectives on mechanisms and therapeutic strategies. Local Reg Anesth. 2018, 11 15-23
[11] Zeng J., Li S., Zhang C., Huang G., Yu C. The Mechanism of Hyperalgesia and Anxiety Induced by Remifentanil: Phosphorylation of GluR1 Receptors in the Anterior Cingulate Cortex. J Mol Neurosci. 2018, 65 (1):93-101
[12] Zhao H. Y., Liu L. Y., Cai J., Cui Y. J., Xing G. G. Electroacupuncture Treatment Alleviates the Remifentanil-Induced Hyperalgesia by Regulating the Activities of the Ventral Posterior Lateral Nucleus of the Thalamus Neurons in Rats. Neural Plast. 2018, 2018 6109723
[13] Jin Y., Mao Y., Chen D., Tai Y., Hu R., Yang C. L., Zhou J., Chen L., Liu X., Gu E., Jia C., Zhang Z., Tao W. Thalamocortical circuits drive remifentanil-induced postoperative hyperalgesia. J Clin Invest. 2022, 132 (24):
[14] Wang Q., Zhao X., Li S., Han S., Peng Z., Li J. Phosphorylated CaMKII levels increase in rat central nervous system after large-dose intravenous remifentanil. Med Sci Monit Basic Res. 2013, 19 (4):118-125
[15] Zhou J., Qi F., Hu Z., Zhang L., Li Z., Wang Z. J., Tang H., Chen Z. Dezocine attenuates the remifentanil-induced postoperative hyperalgesia by inhibition of phosphorylation of CaMK?alpha. Eur J Pharmacol. 2020, 869 172882
[16] Mendell L. M. Constructing and deconstructing the gate theory of pain. Pain. 2014, 155 (2):210-216
[17] Light A. R. Normal anatomy and physiology of the spinal cord dorsal horn. Appl Neurophysiol. 1988, 51 (2-5):78-88
[18] Sullivan S. J., Sdrulla A. D. Excitatory and Inhibitory Neurons of the Spinal Cord Superficial Dorsal Horn Diverge in Their Somatosensory Responses and Plasticity in Vivo. J Neurosci. 2022, 42 (10):1958-1973
[19] Abraira V. E., Kuehn E. D., Chirila A. M., Springel M. W., Toliver A. A., Zimmerman A. L., Orefice L. L., Boyle K. A., Bai L., Song B. J., Bashista K. A., O’Neill T. G., Zhuo J., Tsan C., Hoynoski J., Rutlin M., Kus L., Niederkofler V., Watanabe M., Dymecki S. M., Nelson S. B., Heintz N., Hughes D. I., Ginty D. D. The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn. Cell. 2017, 168 (1-2):295-310 e219
[20] Todd A. J. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010, 11 (12):823-836
Presenting Author
Jinjin Zhang
Poster Authors
Jinjin Zhang
PhD
the First Affiliated Hospital, Jiangxi Medical College, Nanchang University
Lead Author
Fei Zeng PhD
Lead Author
Yi Yan PhD
The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, China
Lead Author
Gang Xu
The First Affiliated Hospital of Nanchang University
Lead Author
Xuezhong Cao PhD
The first affiliated hospital, Jiangxi medical college,nanchang university
Lead Author
Tao Liu PhD
The First Affiliated Hospital of Nanchang University
Lead Author
Daying Zhang
The First Affiliated Hospital of Nanchang University
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Post-surgical/Post-traumatic Chronic Pain