The Korean Journal of Pain

The Korean Pain Society (대한통증학회)
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Systemically administered neurotensin receptor agonist produces antinociception through activation of spinally projecting serotonergic neurons in the rostral ventromedial medulla

  • Li, Yaqun (Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School) ;
  • Kang, Dong Ho (Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School) ;
  • Kim, Woong Mo (Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School) ;
  • Lee, Hyung Gon (Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School) ;
  • Kim, Seung Hoon (Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School) ;
  • You, Hyun Eung (Department of Anesthesiology and Pain Medicine, Chonnam National University Hwasun Hospital) ;
  • Choi, Jeong Il (Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School) ;
  • Yoon, Myung Ha (Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School)
  • Received : 2020.10.28
  • Accepted : 2020.12.16
  • Published : 2021.01.01
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Abstract

Background: Supraspinal delivery of neurotensin (NTS), which may contribute to the effect of a systemically administered agonist, has been reported to be either pronociceptive or antinociceptive. Here, we evaluated the effects of systemically administered NTSR1 agonist in a rat model of neuropathic pain and elucidated the underlying supraspinal mechanism. Methods: Neuropathic pain was induced by L5 and L6 spinal nerve ligation in male Sprague-Dawley rats. The effects of intraperitoneally administered NTSR1 agonist PD 149163 was assessed using von Frey filaments. To examine the role of 5-HT neurotransmission, a serotonin (5-HT) receptor antagonist dihydroergocristine was pretreated intrathecally, and spinal microdialysis studies were performed to measure the change in extracellular level of 5-HT in response to PD 149163 administration. To investigate the supraspinal mechanism, NTSR1 antagonist 48692 was microinjected into the rostral ventromedial medulla (RVM) prior to systemic PD 149163. Additionally, the effect of intrathecal DHE on intra-RVM PD 149163 was assessed. Results: Intraperitoneally administered PD 149163 exhibited a dose-dependent attenuation of mechanical allodynia. This effect was partially reversed by intrathecal pretreatment with dihydroergocristine and was accompanied by an increased extracellular level of 5-HT in the spinal cord. The PD 149163-produced antinociception was also blocked by intra-RVM SB 48692. Direct injection of PD 149163 into the RVM mimicked the maximum effect of the same drug delivered intraperitoneally, which was reversed by intrathecal dihydroergocristine. Conclusions: These observations indicate that systemically administered NTSR1 agonist produces antinociception through the NTSR1 in the RVM, activating descending serotonergic projection to release 5-HT into the spinal dorsal horn.

Keywords

Acknowledgement

This study was supported by a grant from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2019R1I1A3A01063969), South Korea.

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