Hua X Y, Chen P, Marsala M, Yaksh T L
Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818, USA.
Neuroscience. 1999 Mar;89(2):525-34. doi: 10.1016/s0306-4522(98)00488-6.
Substance P is an important neuromediator in spinal synaptic transmission, particularly in processing nociceptive afferent information. The effects of substance P are mediated by activation of the neurokinin 1 receptor. Evidence has suggested that excitatory amino acids such as glutamate, and prostaglandins including prostaglandin E2 are involved in the enhanced spinal excitability and hyperalgesia produced by spinal substance P. In the present study, we have demonstrated that intrathecal injection of substance P (20 nmol) in rats chronically implanted with intrathecal dialysis catheters induced a decrease in thermal paw withdrawal latency (before: 10.4+/-0.3 s; after 7.6+/-0.6 s), which was accompanied by an increase in prostaglandin E2 (362+/-37% of baseline), glutamate (267+/-84%) and taurine (279+/-57%), but not glycine, glutamine, serine or asparagine. Intrathecal injection of artificial cerebrospinal fluid had no effect upon the behavior or release. Substance P-induced thermal hyperalgesia and prostaglandin E2 release were significantly attenuated by a selective neurokinin 1 receptor antagonist RP67580, but not by an enantiomer RP68651. However, substance P-induced release of glutamate and taurine was not reduced by treatment with RP67580. SR140333, another neurokinin 1 receptor antagonist, displayed the same effects as RP67580 (i.e. block of thermal hyperalgesia and prostaglandin E2 release, but not release of amino acids). These results provide direct evidence suggesting that the spinal substance P-induced thermal hyperalgesia is mediated by an increase in spinal prostaglandin E2 via activation of the neurokinin 1 receptor. These findings define an important linkage between small afferents, sensory neurotransmitter release and spinal prostanoids in the cascade of spinally-mediated hyperalgesia. The evoked release of glutamate is apparently not a result of activation of neurokinin 1 receptors. Accordingly, consistent with other pharmacological data, acute spinal glutamate release does not contribute to the hyperalgesia induced by activation of spinal neurokinin 1 receptors.
P物质是脊髓突触传递中的一种重要神经介质，尤其在处理伤害性传入信息方面。P物质的作用是通过神经激肽1受体的激活来介导的。有证据表明，兴奋性氨基酸如谷氨酸，以及前列腺素包括前列腺素E2参与了脊髓P物质所产生的脊髓兴奋性增强和痛觉过敏。在本研究中，我们已证明，在长期植入鞘内透析导管的大鼠中鞘内注射P物质（20 nmol）会导致热足退缩潜伏期缩短（注射前：10.4±0.3秒；注射后7.6±0.6秒），同时伴有前列腺素E2（为基线的362±37%）、谷氨酸（267±84%）和牛磺酸（279±57%）增加，但甘氨酸、谷氨酰胺、丝氨酸或天冬酰胺未增加。鞘内注射人工脑脊液对行为或释放没有影响。P物质诱导的热痛觉过敏和前列腺素E2释放被选择性神经激肽1受体拮抗剂RP67580显著减弱，但对映体RP68651则无此作用。然而，用RP67580处理并未减少P物质诱导的谷氨酸和牛磺酸释放。另一种神经激肽1受体拮抗剂SR140333表现出与RP67580相同的作用（即阻断热痛觉过敏和前列腺素E2释放，但不阻断氨基酸释放）。这些结果提供了直接证据，表明脊髓P物质诱导的热痛觉过敏是通过神经激肽1受体的激活使脊髓前列腺素E2增加来介导的。这些发现确定了在脊髓介导的痛觉过敏级联反应中小传入纤维、感觉神经递质释放和脊髓前列腺素之间的重要联系。诱发的谷氨酸释放显然不是神经激肽1受体激活的结果。因此，与其他药理学数据一致，急性脊髓谷氨酸释放对脊髓神经激肽1受体激活所诱导的痛觉过敏没有作用。
