Intrathecal administration of NTS1 agonists reverses nociceptive behaviors in a rat model of neuropathic pain
Intrathecal administration of NTS1 agonists reverses nociceptive behaviors in a rat model of neuropathic pain
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DOI：
10.1016/j.ejpain.2011.07.008
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发表时间：
2012-04-01
影响因子：
3.6
通讯作者：
Sarret, P.
中科院分区：
文献类型：
--
作者：
Guillemette, A.;Dansereau, M. A.;Sarret, P.
由周围神经损伤引起的慢性神经性疼痛是一个严重的临床问题，其中有一个主要的未满足的医疗需求。我们之前在不同的镇痛试验中（包括热板、甩尾和强直性疼痛）证明了神经紧张素（NT）受体亚型1 （NTS1）和2 （NTS2）参与介导神经紧张素对纳洛酮不敏感的抗感觉作用。然而，这些受体在神经性疼痛管理中的作用尚未得到充分研究。因此，在本研究中，我们研究了鞘内递送NTS1激动剂是否能有效减轻大鼠的神经性疼痛症状。术后3、7、14、21、28 d观察坐骨神经收缩引起的神经病变，观察单侧和对侧后爪机械性异常痛和热痛觉过敏的发生情况。在28天的测试期间，cci手术大鼠表现出明显的热和机械超敏反应。脊髓注射NT可减轻CCI大鼠对辐射热和机械刺激的行为反应，当剂量为6 μ g/kg时，可最大逆转91%的异常性疼痛。鞘内给予nts1选择性激动剂PD149163 （30-90 μ g/kg）对神经损伤大鼠也产生了有效的抗异动和抗痛感作用。同样，NTS1激动剂NT69L （5-25 μ g/kg）可完全逆转坐骨神经CCI引起的热痛觉过敏和触觉异常痛。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激动剂治疗疼痛性神经病的潜在用途。
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 mu g/kg. Intrathecal administration of the NTS1-selective agonist, PD149163 (30-90 mu g/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 mu g/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.