Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Eur J Pain. 2012 Apr;16(4):473-84. doi: 10.1016/j.ejpain.2011.07.008.
Chronic neuropathic pain arising from peripheral nerve damage is a severe clinical issue where there is a major unmet medical need. We previously demonstrated that both neurotensin (NT) receptor subtypes 1 (NTS1) and 2 (NTS2) are involved in mediating the naloxone-insensitive antinociceptive effects of neurotensin in different analgesic tests including hotplate, tail-flick, and tonic pain. However, the role of these receptors in neuropathic pain management has been poorly investigated. In the present study, we therefore examined whether intrathecal delivery of NTS1 agonists was effective in reducing neuropathic pain symptoms in rats. Neuropathy was induced by sciatic nerve constriction (CCI model), and the development of mechanical allodynia and thermal hyperalgesia on the ipsi- and contralateral hind paws was examined 3, 7, 14, 21, and 28 days post-surgery. CCI-operated rats exhibited significant increases in thermal and mechanical hypersensitivities over a 28-day testing period. Spinal injection of NT to CCI rats alleviated the behavioral responses to radiant heat and mechanical stimuli, with a maximal reversal of 91% of allodynia at 6 μg/kg. Intrathecal administration of the NTS1-selective agonist, PD149163 (30-90 μg/kg) also produced potent anti-allodynic and anti-hyperalgesic effects in nerve-injured rats. Likewise, heat hyperalgesia and tactile allodynia produced by CCI of the sciatic nerve were fully reversed by the NTS1 agonist, NT69L (5-25 μg/kg). Altogether, these results support the idea that the NTS1 receptor subtype is involved in pain modulation, and the potential use of NTS1 agonists for the treatment of painful neuropathies.
外周神经损伤引起的慢性神经性疼痛是一个严重的临床问题，存在着重大的未满足的医疗需求。我们之前的研究表明，神经降压素（NT）受体亚型 1（NTS1）和 2（NTS2）都参与介导神经降压素在不同镇痛测试中的纳洛酮不敏感的镇痛作用，包括热板、尾巴闪烁和强直性疼痛。然而，这些受体在神经性疼痛管理中的作用还没有得到充分的研究。在本研究中，我们因此研究了鞘内给予 NTS1 激动剂是否能有效减轻大鼠的神经性疼痛症状。通过坐骨神经缩窄（CCI 模型）诱导神经病变，在手术后第 3、7、14、21 和 28 天检测对侧和同侧后爪的机械性痛觉过敏和热痛觉过敏的发展情况。CCI 手术大鼠在 28 天的测试期间表现出明显的热和机械性超敏反应增加。NT 鞘内注射到 CCI 大鼠中减轻了对辐射热和机械刺激的行为反应，在 6μg/kg 时对痛觉过敏的最大逆转率为 91%。鞘内给予 NTS1 选择性激动剂 PD149163（30-90μg/kg）也在神经损伤大鼠中产生了有效的抗痛觉过敏和抗痛觉过敏作用。同样，CCI 坐骨神经引起的热痛觉过敏和触觉痛觉过敏也被 NTS1 激动剂 NT69L（5-25μg/kg）完全逆转。总之，这些结果支持了 NTS1 受体亚型参与疼痛调节的观点，以及 NTS1 激动剂用于治疗疼痛性神经病变的潜在用途。
