Physiological, pharmacological, and biochemical mechanisms of pain transmission in the spinal cord

谷氨酸能系统在诱发和维持痛觉异常中的作用我们以前证明了鞘内(I.T.)给予前列腺素E_2和前列腺素F_2α&gt；通过不同的机制通过谷氨酸能系统诱导触觉诱发疼痛(痛觉过敏)。在本研究中，我们研究了N-甲基-D-天冬氨酸受体亚型和谷氨酸转运体在前列腺素E_2和前列腺素F_2α引起的痛觉异常的诱导和维持中的作用。在N-甲基-D-天冬氨酸受体ε-4(NR2D)亚单位敲除[GluRε4(-/-)]小鼠中观察到前列腺素E_2诱导的痛觉过敏，而在ε-1(NR2a)亚单位敲除[Glurε1(-/-)]小鼠中未观察到PGE_2诱导的痛觉过敏。相反，在Glurα1(-/-)小鼠中观察到前列腺素F_2ε&gt；2引起的痛觉异常，而在Glurε4(-/-)小鼠中未观察到。N-甲基-D-天冬氨酸受体ε-2(NR2B)拮抗剂CP-101、606和新生辣椒素治疗可消除前列腺素E_2引起的痛觉异常。CP-101、606和新生辣椒素治疗均不影响α-2诱导的痛觉过敏。另一方面，谷氨酸转运体阻滞剂DL-TboA阻断…对前列腺素E_2和前列腺素F_2α&gt；这些结果表明，由谷氨酸能系统介导的痛敏反应有两条途径，谷氨酸转运体在痛觉过敏的诱导和维持中是必不可少的。伤害素/孤啡肽FQ诱导的疼痛反应的特征在脊髓水平上，伤害素/孤啡肽FQ(Noc/Ofq)在低剂量(Pg范围)时产生前痛和痛觉超敏效应，而在高剂量时(μg范围)产生抗伤害效应。不同剂量的Noc/OFQ对痛觉的调制作用不同，这提出了一个问题：Noc/OFQ是否通过相同的Noc/OFQ受体发挥作用。我们用新型非肽拮抗剂JTC-801研究了Noc/OFQ受体在疼痛反应中的作用。鞘内注射Noc/OFQ引起的痛觉过敏和痛觉过敏可被同时给予JTC-801剂量依赖性地阻断。10pg的NOC/OFQ可增强1%福尔马林所致的第二相痛行为，对1μg的2%福尔马林所致的第一时相和第二相痛均有明显的抑制作用，但JTC-801可剂量依赖地阻断10pg的NOC/OFQ的致痛作用，但不能拮抗1μg的NOC/OFQ的抗伤害效应。JTC-801的这些结果表明，小剂量Noc/OFQ诱导的伤害性反应可能是通过脊髓中的Noc/OFQ受体介导的，而在福尔马林实验中，大剂量Noc/OFQ的抗伤害性反应可能是通过克隆的Noc/OFQ受体以外的另一种受体来介导的。较少

Characterization of the glutamatergic system for induction and maintenance of allodyniaWe previously demonstrated that intrathecal (i.t.) administration of PGE_2 and PGF_<2α> induced touch-evoked pain (allodynia) through the glutamatergic system by different mechanisms. In the present study, we characterized NMDA receptor subtypes and glutamate transporters involved in induction and maintenance of PGE_2- and PGF_<2α>-evoked allodynia. PGE_2-induced allodynia was observed in NMDA receptor ε4 (NR2D) subunit knockout [GluRε4(-/-)] mice, but not in ε1 (NR2A) subunit knockout [GluRε1(-/-)] mice. Conversely, PGF_<2α>-induced allodynia were observed in GluRε1(-/-) mice, but not in GluRε4(-/-) mice. The induction of allodynia by PGE_2 was abolished by the NMDA receptor ε2 (NR2B) antagonist CP-101,606 and neonatal capsaicin treatment. PGF_<2α>-induced allodynia were not affected by CP-101,606 and by neonatal capsaicin treatment. On the other hand, the glutamate transporter blocker DL-TBOA block … More ed both the allodynia induced by PGE_2 and PGF_<2α>. These results demonstrate that there are two pathways for induction of allodynia mediated by the glutamatergic system and suggest that the glutamate transporter is essential for the induction and maintenance of allodynia.Characterization of nociceptin/orphanin FQ-induced pain responsesAt the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pro-nociceptive and allodynic effects at low doses (pg range), while causing anti-nociceptive effects at high doses (μg range). The discrepancy of pain modulation by Noc/OFQ at doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. We examined the involvement of the Noc/OFQ receptor in pain responses with the novel non-peptide antagonist JTC-801. Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ were dose-dependently blocked by simultaneous administration of JTC-801. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, while it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1μg. While the pro-nociceptive effect by 10 pg Noc/OFQ was dose-dependently blocked by JTC-801, the anti-nociceptive effects by 1 μg Noc/OFQ were not antagonized by JTC-801. These results with JTC-801 demonstrate that pro-nociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that the anti-nociceptive effect by a high dose of Noc/OFQ in the formalin test may be mediated through a receptor besides the cloned Noc/OFQ receptor. Less