Korean J Pain.  2021 Jan;34(1):58-65. 10.3344/kjp.2021.34.1.58.

Systemically administered neurotensin receptor agonist produces antinociception through activation of spinally projecting serotonergic neurons in the rostral ventromedial medulla

• Li Y
• Kang DH
• Kim WM
• Lee HG
• Kim SH
• You HE
• Choi JI
• Yoon MH

• KMID: 2510312
• DOI: http://doi.org/10.3344/kjp.2021.34.1.58

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.

Keyword

Analgesia; Central Nervous System; Microdialysis; Neuralgia; Neurotensin; Rats; Receptors; Neurotensin; Serotonin; Spinal Cord

Figure

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  Fig. 1 Time-response (A) and dose-response (B) data showing the effects of intraperitoneally administered PD 149163, on the hind paw withdrawal response in spinal nerve-ligated rats. Data are presented as the mechanical withdrawal thresholds in grams or the area under the time course curve (AUC) for the withdrawal threshold. Each line or bar represents the mean ± standard error of mean of 6 rats. i.p.: intraperitoneal, BL: baseline value, i.t.: intrathecal, DHE: dihydroergocristine. *P = 0.048 compared to the vehicle group. §P < 0.001 compared to the vehicle group. †P = 0.032 compared to the PD 149163 300 μg/kg group.

• 

  Fig. 2 Microdialysis measurements of spinal 5-HT following intraperitoneal administration of PD 149163 (300 μg/kg) or vehicle. Data are presented over time as a mean ± standard error of mean percentage of the baseline (n = 5 in each group). BL: baseline value. *P < 0.05 compared to baseline value.

• 

  Fig. 3 Time-response data (A) and quantification by area under the time course curves (AUC) (B) showing the effects of microinjection of SB 48692 or vehicle into the nucleus raphe magnus (NRM) and intraperitoneal administration of PD 149163 or vehicle. Data are presented as the mechanical withdrawal thresholds in grams or the AUC for the withdrawal threshold. Each line or bar represents the mean ± standard error of mean of 5 rats. inj.: injection, i.p.: intraperitoneal, BL: baseline value, DMSO: dimethyl sulfoxide. *P = 0.002 compared to the intraperitoneal PD 149163 group (300 μg/kg).

• 

  Fig. 4 Time-response (A) and dose-response (B) data showing the effects of intra-nucleus raphe magnus (NRM) administration of PD 149163, on the hind paw withdrawal response in spinal nerve-ligated rats. Data are presented as the mechanical withdrawal thresholds in grams or the area under the time course curve (AUC) for the withdrawal threshold. Each line or bar represents the mean ± standard error of mean of 5 rats. BL: baseline value, i.t.: intrathecal, DHE: dihydroergocristine. *P < 0.005 compared to the vehicle group. §P = 0.048 compared to the PD 149163 5 ng group.

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