大鼠感觉神经元特异性受体在CFA炎症性疼痛中的作用机制
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摘要
一氧化氮(nitro oxide, NO)、c-Fos蛋白、内源性阿片肽都表达于神经系统内,参与机体炎性疼痛的病理过程。大鼠感觉神经元特异性受体(rat Sensory neuron-specific receptors 1, rSNSRl)在完全弗氏佐剂(complete Freund's adjuvant, CFA)炎症性疼痛中起镇痛作用。本实验应用rSNSRl受体的激动剂通过蛋白质印迹、免疫组织化学等实验方法,研究rSNSRl受体在CFA慢性炎症痛中的作用机制。
研究发现在CFA炎性痛模型中,鞘内激活rSNSRl,导致脊髓神经元型一氧化氮合酶(neuronal nitric oxide synthesis, nNOS)、c-Fos蛋白表达下调。同时,鞘内注射CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2)减轻了rSNSR1的抗伤害作用。另外,在CFA炎性痛模型中,鞘内激活rSNSR1,背根神经节(Dorsal root ganglion, DRG)及炎症组织内,β-内啡肽(β-endorphin,β-EP)的表达基本不受影响。
以上结果表明在CFA炎性痛模型中,鞘内激活rSNSR1产生的镇痛作用,可能是通过激活内源性阿片、抑制一氧化氮、c-Fos信号通路实现的,但与内源性阿片中的p-EP通路是否相关有待进一步研究。
Nitro oxide (NO)、c-Fos protein and endogenous opioid peptide are present in the nervous system and involved in the pathological process of inflammatory pain. It has been demonstrated that rSNSR1 alleviates CFA-evoked inflammatory pain. The present study was designed to investigate the mechanisms of the analgesia effect of intrathecal activation of rSNSR1 on CFA-evoked inflammatory pain.
This study was conducted by using behavioral、immunohistochemical and Western blot techniques. We found that: intrathecal injection of CTAP, inhibited the analgesia effect of intrathecal activation of rSNSR1 on CFA-evoked inflammatory pain; intrathecal activation of rSNSR1 produced an decrease in the expression of nruronal nitric oxide synthase(nNOS),and c-fos protein in the spinal cord dorsal horn, but P-endorphin is not changed in DRG and inflamed tissue.
This study shows that the mechanisms of the analgesia effect of intrathecal activation of rSNSR1 on CFA-evoked inflammatory pain may be related to endogenous opioid peptide、NO and c-Fos signaling pathways, but if related toβ-EP signaling pathway has to be researched more.
研究发现在CFA炎性痛模型中,鞘内激活rSNSRl,导致脊髓神经元型一氧化氮合酶(neuronal nitric oxide synthesis, nNOS)、c-Fos蛋白表达下调。同时,鞘内注射CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2)减轻了rSNSR1的抗伤害作用。另外,在CFA炎性痛模型中,鞘内激活rSNSR1,背根神经节(Dorsal root ganglion, DRG)及炎症组织内,β-内啡肽(β-endorphin,β-EP)的表达基本不受影响。
以上结果表明在CFA炎性痛模型中,鞘内激活rSNSR1产生的镇痛作用,可能是通过激活内源性阿片、抑制一氧化氮、c-Fos信号通路实现的,但与内源性阿片中的p-EP通路是否相关有待进一步研究。
Nitro oxide (NO)、c-Fos protein and endogenous opioid peptide are present in the nervous system and involved in the pathological process of inflammatory pain. It has been demonstrated that rSNSR1 alleviates CFA-evoked inflammatory pain. The present study was designed to investigate the mechanisms of the analgesia effect of intrathecal activation of rSNSR1 on CFA-evoked inflammatory pain.
This study was conducted by using behavioral、immunohistochemical and Western blot techniques. We found that: intrathecal injection of CTAP, inhibited the analgesia effect of intrathecal activation of rSNSR1 on CFA-evoked inflammatory pain; intrathecal activation of rSNSR1 produced an decrease in the expression of nruronal nitric oxide synthase(nNOS),and c-fos protein in the spinal cord dorsal horn, but P-endorphin is not changed in DRG and inflamed tissue.
This study shows that the mechanisms of the analgesia effect of intrathecal activation of rSNSR1 on CFA-evoked inflammatory pain may be related to endogenous opioid peptide、NO and c-Fos signaling pathways, but if related toβ-EP signaling pathway has to be researched more.
引文
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3. Woolf, C.J. and Q. Ma, Nociceptors--noxious stimulus detectors. Neuron,2007. 55(3):353-64.
4. Haddad, J.J., On the enigma of pain and hyperalgesia:A molecular perspective. Biochem Biophys Res Commun,2007.353(2):217-24.
5. Bendele, A., et al., Animal models of arthritis:relevance to human disease. Toxicol Pathol,1999.27(1):134-42.
6. Hylden, J.L., F. Anton, and R.L. Nahin, Spinal lamina I projection neurons in the rat: collateral innervation of parabrachial area and thalamus. Neuroscience, 1989.28(1):27-37.
7. Dong, X., et al., A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell,2001.106(5):619-32.
8. Zylka, M J., et al., Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family. Proc Natl Acad Sci U S A,2003.100(17): 10043-8.
9. Dong, X., et al., A Diverse Family of GPCRs Expressed in Specific Subsets of Nociceptive Sensory Neurons. Cell,2001.106(5):619-632.
10. Liu, Y., et al., Mechanisms of compartmentalized expression of Mrg class G-protein-coupled sensory receptors. J Neurosci,2008.28(1):125-32.
11. Grazzini, E., et al., Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats. Proc Natl Acad Sci U S A,2004.101(18): 7175-80.
12. Chen, H. and S.R. Ikeda, Modulation of ion channels and synaptic transmission by a human sensory neuron-specific G-protein-coupled receptor, SNSR4/mrgXl, heterologously expressed in cultured rat neurons. J Neurosci,2004.24(21): 5044-53.
13. Guan, Y., et al., Mas-related G-protein-coupled receptors inhibit pathological pain in mice. Proc Natl Acad Sci U S A,2010.107(36):15933-8.
14. Hong, Y, et al., Dual effects of intrathecal BAM22 on nociceptive responses in acute and persistent pain--potential function of a novel receptor. Br J Pharmacol, 2004.141(3):423-30.
15. Heitzer, T., et al., Clopidogrel improves systemic endothelial nitric oxide bioavailability in patients with coronary artery disease:evidence for antioxidant and antiinflammatory effects. Arterioscler Thromb Vasc Biol,2006.26(7): 1648-52.
16. Alessandri-Haber, N., et al., TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. J Neurosci, 2009.29(19):6217-28.
17. Omote, K., et al., Peripheral nitric oxide in carrageenan-induced inflammation. Brain Res,2001.912(2):171-5.
18. MacMicking, J., Q.W. Xie, and C. Nathan, Nitric oxide and macrophage function. Annu Rev Immunol,1997.15:323-50.
19. Lacza, Z., et al., Mitochondria produce reactive nitrogen species via an arginine-independent pathway. Free Radic Res,2006.40(4):369-78.
20. Elfering, S.L., T.M. Sarkela, and C. Giulivi, Biochemistry of mitochondrial nitric-oxide synthase. J Biol Chem,2002.277(41):38079-86.
21. Boissel, J.P., P.M. Schwarz, and U. Forstermann, Neuronal-type NO synthase: transcript diversity and expressional regulation. Nitric Oxide,1998.2(5):337-49.
22. Saini, R., et al., Nitric oxide synthase localization in the rat neutrophils: immunocytochemical, molecular, and biochemical studies. J Leukoc Biol,2006. 79(3):519-28.
23. Korzhevskii, D.E., et al., [Immunocytochemical demonstration of neuronal NO-synthase in rat brain cells]. Morfologiia,2007.132(4):77-80.
24. Kavya, R., et al., Nitric oxide synthase regulation and diversity: implications in Parkinson's disease. Nitric Oxide,2006.15(4):280-94.
25. Guhring, H., et al., Suppressed injury-induced rise in spinal prostaglandin E2 production and reduced early thermal hyperalgesia in iNOS-deficient mice. J Neurosci,2000.20(17):6714-20.
26. Wu, J., et al., Nitric oxide synthase in spinal cord central sensitization following intradermal injection of capsaicin. Pain,2001.94(1):47-58.
27. Wu, J., et al., Fos expression is induced by increased nitric oxide release in rat spinal cord dorsal horn. Neuroscience,2000.96(2):351-7.
28. Chu, Y.C., et al., Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain. Pain,2005.119(1-3):113-23.
29. Mabuchi, T., et al., Attenuation of neuropathic pain by the nociceptin/orphanin FQ antagonist JTC-801 is mediated by inhibition of nitric oxide production. Eur J Neurosci,2003.17(7):1384-92.
30. Lui, P.W. and C.H. Lee, Preemptive effects of intrathecal cyclooxygenase inhibitor or nitric oxide synthase inhibitor on thermal hyper sensitivity following peripheral nerve injury. Life Sci,2004.75(21):2527-38.
31. Guan, Y., et al., Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice. Mol Pain,2007.3:29.
32. Boettger, M.K., et al., Differences in inflammatory pain in nNOS-, iNOS-and eNOS-deficient mice. Eur J Pain,2007.11(7):810-8.
33. De Alba, J., et al., GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain,2006.120(1-2):170-81.
34. LaBuda, C.J., et al., Antinociceptive activity of the selective iNOS inhibitor AR-C 102222 in rodent models of inflammatory, neuropathic and post-operative pain. Eur J Pain,2006.10(6):505-12.
35. Tanabe, M., et al., Pharmacological assessments of nitric oxide synthase isoforms and downstream diversity of NO signaling in the maintenance of thermal and mechanical hypersensitivity after peripheral nerve injury in mice. Neuropharmacology,2009.56(3):702-8.
36. Levy, D., et al., Transient action of the endothelial constitutive nitric oxide synthase (ecNOS) mediates the development of thermal hypersensitivity following peripheral nerve injury. Eur J Neurosci,2000.12(7):2323-32.
37. Tao, F., et al., Differential roles of neuronal and endothelial nitric oxide synthases during carrageenan-induced inflammatory hyperalgesia. Neuroscience,2004. 128(2):421-30.
38. Tao, F., et al., Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase. Neuroscience,2003.120(3):847-54.
39. Kieffer, B.L. and C. Gaveriaux-Ruff, Exploring the opioid system by gene knockout. Prog Neurobiol,2002.66(5):285-306.
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