Yin Mei, Kim Yeo-Ok, Choi Jeong-Il, Jeong Seongtae, Yang Si-Ho, Bae Hong-Beom, Yoon Myung-Ha
Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Korea.
The Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University, Gwangju, Korea.
Korean J Pain. 2020 Oct 1;33(4):318-325. doi: 10.3344/kjp.2020.33.4.318.
Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of anti-cancer drugs. Neurotensin receptors (NTSRs) are widely distributed within the pain circuits in the central nervous system. The purpose of this study was to determine the role of NTSR1 by examining the effects of an NTSR1 agonist in rats with CIPN and investigate the contribution of spinal serotonin receptors to the antinociceptive effect.
Sprague-Dawley rats (weight 150-180 g) were used in this study. CIPN was induced by injecting cisplatin (2 mg/kg) once a day for 4 days. Intrathecal catheters were placed into the subarachnoid space of the CIPN rats. The antiallodynic effects of intrathecally or intraperitoneally administered PD 149163, an NTSR1 agonist, were evaluated. Furthermore, the levels of serotonin in the spinal cord were measured by high-performance liquid chromatography.
Intrathecal or intraperitoneal PD 149163 increased the paw withdrawal threshold in CIPN rats. Intrathecal administration of the NTSR1 antagonist SR 48692 suppressed the antinociceptive effect of PD 149163 given via the intrathecal route, but not the antinociceptive effect of intraperitoneally administered PD 149163. Intrathecal administration of dihydroergocristine, a serotonin receptor antagonist, suppressed the antinociceptive effect of intrathecally administered, but not intraperitoneally administered, PD 149163. Injecting cisplatin diminished the serotonin level in the spinal cord, but intrathecal or intraperitoneal administration of PD 149163 did not affect this reduction.
NTSR1 played a critical role in modulating CIPN-related pain. Therefore, NTSR1 agonists may be useful therapeutic agents to treat CIPN. In addition, spinal serotonin receptors may be indirectly involved in the effect of NTSR1 agonist.
化疗引起的周围神经病变（CIPN）是抗癌药物的一种主要副作用。神经降压素受体（NTSRs）广泛分布于中枢神经系统的疼痛传导通路中。本研究的目的是通过检测NTSR1激动剂对CIPN大鼠的影响来确定NTSR1的作用，并研究脊髓5-羟色胺受体在其镇痛作用中的贡献。
本研究使用体重150 - 180 g的Sprague-Dawley大鼠。通过每天注射一次顺铂（2 mg/kg），连续注射4天来诱导CIPN。将鞘内导管置于CIPN大鼠的蛛网膜下腔。评估鞘内或腹腔内注射NTSR1激动剂PD 149163的抗痛觉过敏作用。此外，通过高效液相色谱法测量脊髓中的5-羟色胺水平。
鞘内或腹腔内注射PD 149163可提高CIPN大鼠的爪部缩足阈值。鞘内注射NTSR1拮抗剂SR 48692可抑制经鞘内途径给予的PD 149163的镇痛作用，但不影响腹腔内注射PD 149163的镇痛作用。鞘内注射5-羟色胺受体拮抗剂双氢麦角隐亭可抑制鞘内注射而非腹腔内注射的PD 149163的镇痛作用。注射顺铂可降低脊髓中的5-羟色胺水平，但鞘内或腹腔内注射PD 149163并不影响这种降低。
NTSR1在调节CIPN相关疼痛中起关键作用。因此，NTSR1激动剂可能是治疗CIPN的有用治疗药物。此外，脊髓5-羟色胺受体可能间接参与NTSR1激动剂的作用。
