神经肽FF在外周阿片镇痛调节和脊髓心血管活性方面的研究
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摘要
神经肽FF (NPFF)是具有阿片调节活性的神经肽家族,其包含着两个不同前体(pro-NPFFA和]pro-NPFFB)和两个不同受体(NPFF1和NPFF2)。已有的研究表明,NPFF在痛觉、包括痛觉、心血管活性、阿片耐受和成瘾、体温、胃肠道等方面具有重要的调节作用。为了进一步揭示NPFF系统生物学功能,在此论文中探讨了NPFF及其特异性配体分别在外周阿片镇痛活性调节和脊髓水平心血管活性方面的生物活性及其作用机制。
在痛觉研究方面,利用光热甩尾实验来评价中枢注射NPFF及其相关肽对外周吗啡所引起镇痛活性的影响。实验结果发现,i.c.v.注射NPFF (1,3和10nmol)能剂量依赖地抑制外周注射吗啡(0.12mg,i.p.)所引起的镇痛作用。同样,i.c.v.注射NPFF2和NPFF1受体的高选择性激动剂dNPA和NPVF也都能显著地减弱外周注射吗啡(0.12mg,i.p.)的镇痛活性。此外,NPFF及其相关肽的这种抗阿片镇痛的作用能被预注射NPFF受体的选择性拮抗剂RF9 (10nmol i.c.v.)所拮抗。这一研究表明中枢NPFF1和NPFF2受体的激活都能介导抗外周吗啡镇痛的活性。
在心血管方面,利用大鼠整体血压实验检测了NPFF系统在脊髓水平对麻醉大鼠心血管活性的调节作用。研究表明鞘内注射NPFF能剂量依赖地引起大鼠平均动脉血压(MAP)和心率(HR)的增加,而且NPFF1和NPFF2受体的高选择性激动剂dNPA和NPVF在脊髓水平都产生升血压和升心率作用。NPFF及其相关肽所引起的心血管调节作用能被NPFF受体选择性拮抗剂RF9 (i.t.)所拮抗。进一步研究还发现,预注射α-肾上腺素能受体拮抗剂芬托拉明(1mg/kg i.v.)能显著地减弱NPFF所介导的升压作用,而预注射毒蕈碱能受体以及肾上腺素能受体的拮抗剂能阻遏NPFF的升心率作用。这些结果显示了鞘内注射NPFF及其相关肽所引起的升血压和升心率作用可能是由脊髓中NPFF1和NPFF2受体所共同介导的。并且,毒蕈碱能受体和肾上腺素能受体参与调节了由鞘内注射NPFF所诱导升心率作用,而α-肾上腺素能受体则在由鞘内注射NPFF所诱导升压效应中起了重要的调节作用。
Neuropeptide FF (NPFF) belongs to an opioid-modulating peptide family, including two precursors (pro-NPFFA and pro-NPFFB) and two receptors (NPFF1 and NPFF2). NPFF has been reported to play important roles in the control of pain, cardiovascular activity, opiate tolerance and addiction, body temperature and gastrointestinal function through interactions with the opioid system. In order to further explore the biological function of NPFF system, in the present study, NPFF and its selective ligands were used to investigate the regulatory effects of NPFF system on peripheral analgesia induced by opioids and the spinal cardiovascular activities.
In the mouse tail flick test, the effects of central administration of NPFF and related peptides on analgesia induced by morphine administered at the peripheral level were studied. The result showed that intracerebroventricular (i.c.v.) injection of NPFF (1,3 and 10 nmol) dose-dependently inhibited the analgesia induced by morphine (0.12 mg, i.p.) administered at the peripheral level. Similarly, i.c.v. administration of dNPA and NPVF, two agonists highly selective for NPFF2 and NPFF1 receptors, respectively, decreased the peripheral antinociceptive effect of 0.12 mg morphine in mice. Furthermore, these anti-opioid activities of NPFF and related peptides were blocked by pretreatment with the NPFF receptors selective antagonist RF9 (10 nmol, i.c.v.). These results demonstrate that activation of central NPFF1 and NPFF2 receptors has the similar anti-opioid action on the peripheral analgesic effect of morphine.
In urethane-anesthetized rats, the cardiovascular responses to intrathecal (i.t.) injection of NPFF and related agonists were investigated. It is noteworthy that NPFF elicited increases in mean arterial pressure (MAP) and heart rate (HR) in a dose-dependent manner. Interestingly, NPVF and dNPA, the two highest selective agonists for NPFF1 and NPFF2 receptors, produced significant pressor and tachycardic responses at the spinal cord level. Furthermore, the cardiovascular effects induced by NPFF and related peptides were significantly antagonized by NPFF receptors selective antagonist RF9 (i.t.). Moreover, pretreatment of the rats with a-adrenoceptor antagonist phentolamine (1 mg/kg, i.v.) significantly reduced the pressor effects of NPFF. Nevertheless, pretreatment with muscarinic receptor and adrenoceptor antagonists (i.v.) could block the tachycardic effects induced by NPFF. Collectively, our results suggested that i.t. administration of NPFF and related peptides increased MAP and HR which were possibly mediated by the activation of both NPFF1 and NPFF2 receptors in the rat spinal cord. In addition, our results showed that the muscarinic receptor and adrenoceptor participated in the tachycardic response to i.t. NPFF, whileα-adrenoceptor played an important role in the regulation of pressor effect of NPFF (i.t.).
在痛觉研究方面,利用光热甩尾实验来评价中枢注射NPFF及其相关肽对外周吗啡所引起镇痛活性的影响。实验结果发现,i.c.v.注射NPFF (1,3和10nmol)能剂量依赖地抑制外周注射吗啡(0.12mg,i.p.)所引起的镇痛作用。同样,i.c.v.注射NPFF2和NPFF1受体的高选择性激动剂dNPA和NPVF也都能显著地减弱外周注射吗啡(0.12mg,i.p.)的镇痛活性。此外,NPFF及其相关肽的这种抗阿片镇痛的作用能被预注射NPFF受体的选择性拮抗剂RF9 (10nmol i.c.v.)所拮抗。这一研究表明中枢NPFF1和NPFF2受体的激活都能介导抗外周吗啡镇痛的活性。
在心血管方面,利用大鼠整体血压实验检测了NPFF系统在脊髓水平对麻醉大鼠心血管活性的调节作用。研究表明鞘内注射NPFF能剂量依赖地引起大鼠平均动脉血压(MAP)和心率(HR)的增加,而且NPFF1和NPFF2受体的高选择性激动剂dNPA和NPVF在脊髓水平都产生升血压和升心率作用。NPFF及其相关肽所引起的心血管调节作用能被NPFF受体选择性拮抗剂RF9 (i.t.)所拮抗。进一步研究还发现,预注射α-肾上腺素能受体拮抗剂芬托拉明(1mg/kg i.v.)能显著地减弱NPFF所介导的升压作用,而预注射毒蕈碱能受体以及肾上腺素能受体的拮抗剂能阻遏NPFF的升心率作用。这些结果显示了鞘内注射NPFF及其相关肽所引起的升血压和升心率作用可能是由脊髓中NPFF1和NPFF2受体所共同介导的。并且,毒蕈碱能受体和肾上腺素能受体参与调节了由鞘内注射NPFF所诱导升心率作用,而α-肾上腺素能受体则在由鞘内注射NPFF所诱导升压效应中起了重要的调节作用。
Neuropeptide FF (NPFF) belongs to an opioid-modulating peptide family, including two precursors (pro-NPFFA and pro-NPFFB) and two receptors (NPFF1 and NPFF2). NPFF has been reported to play important roles in the control of pain, cardiovascular activity, opiate tolerance and addiction, body temperature and gastrointestinal function through interactions with the opioid system. In order to further explore the biological function of NPFF system, in the present study, NPFF and its selective ligands were used to investigate the regulatory effects of NPFF system on peripheral analgesia induced by opioids and the spinal cardiovascular activities.
In the mouse tail flick test, the effects of central administration of NPFF and related peptides on analgesia induced by morphine administered at the peripheral level were studied. The result showed that intracerebroventricular (i.c.v.) injection of NPFF (1,3 and 10 nmol) dose-dependently inhibited the analgesia induced by morphine (0.12 mg, i.p.) administered at the peripheral level. Similarly, i.c.v. administration of dNPA and NPVF, two agonists highly selective for NPFF2 and NPFF1 receptors, respectively, decreased the peripheral antinociceptive effect of 0.12 mg morphine in mice. Furthermore, these anti-opioid activities of NPFF and related peptides were blocked by pretreatment with the NPFF receptors selective antagonist RF9 (10 nmol, i.c.v.). These results demonstrate that activation of central NPFF1 and NPFF2 receptors has the similar anti-opioid action on the peripheral analgesic effect of morphine.
In urethane-anesthetized rats, the cardiovascular responses to intrathecal (i.t.) injection of NPFF and related agonists were investigated. It is noteworthy that NPFF elicited increases in mean arterial pressure (MAP) and heart rate (HR) in a dose-dependent manner. Interestingly, NPVF and dNPA, the two highest selective agonists for NPFF1 and NPFF2 receptors, produced significant pressor and tachycardic responses at the spinal cord level. Furthermore, the cardiovascular effects induced by NPFF and related peptides were significantly antagonized by NPFF receptors selective antagonist RF9 (i.t.). Moreover, pretreatment of the rats with a-adrenoceptor antagonist phentolamine (1 mg/kg, i.v.) significantly reduced the pressor effects of NPFF. Nevertheless, pretreatment with muscarinic receptor and adrenoceptor antagonists (i.v.) could block the tachycardic effects induced by NPFF. Collectively, our results suggested that i.t. administration of NPFF and related peptides increased MAP and HR which were possibly mediated by the activation of both NPFF1 and NPFF2 receptors in the rat spinal cord. In addition, our results showed that the muscarinic receptor and adrenoceptor participated in the tachycardic response to i.t. NPFF, whileα-adrenoceptor played an important role in the regulation of pressor effect of NPFF (i.t.).
引文
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