Gouardères C, Sutak M, Zajac J M, Jhamandas K
Institut de Pharmacologie et de Biologie Structurale, C.N.R.S., 205 Route de Narbonne, Toulouse, France.
Eur J Pharmacol. 2000 Oct 20;406(3):391-401. doi: 10.1016/s0014-2999(00)00716-0.
The neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH(2)) and its synthetic analogs bind to specific receptors in the spinal cord to produce antinociceptive effects that are partially attenuated by opioid antagonists, and at sub-effective doses neuropeptide FF receptor agonists augment spinal opioid antinociception. Since adenosine plays an intermediary role in the production of spinal opioid antinociception, this study investigated whether this purine has a similar role in the expression of spinal effects produced by neuropeptide FF receptor agonists. In rats bearing indwelling spinal catheters, injection of adenosine receptor agonists, N6-cyclohexyladenosine (CHA, 1.72 nmol) and N-ethylcarboxiamidoadenosine (NECA, 1.95 nmol), as well as morphine (13.2 nmol) elicited antinociception in the tail-flick and paw-pressure tests. Pretreatment with intrathecal 8-phenyltheophylline (5.9 and 11.7 nmol), an adenosine receptor antagonist, blocked the effect of all three agents without influencing baseline responses. Administration of two synthetic neuropeptide FF (NPFF) analogs, [D-Tyr(1),(NMe)Phe(3)]NPFF (1DMe, 0. 86 nmol) and [D-Tyr(1),D-leu(2),D-Phe(3)]NPFF (3D, 8.6 nmol) produced sustained thermal and mechanical antinociception. Pretreatment with doses of intrathecal 8-phenyltheophylline (5.9, 11. 7 and 23.5 nmol), producing adenosine receptor blockade, significantly inhibited the antinociceptive effects of 1DMe or 3D. Injection of a sub-antinociceptive dose of 1DMe (0.009 nmol) significantly augmented the antinociceptive effect of intrathecal morphine (13.2 nmol) in the tail-flick and paw-pressure tests. Intrathecal 8-phenyltheophylline (11.7 nmol) reduced the effect of this combination. Administration of low dose of 1DMe (0.009 nmol) or 3D (0.009 nmol) very markedly potentiated the antinociceptive actions of the adenosine receptor agonist, N6-cyclohexyladenosine (0. 43, 0.86 and 1.72 nmol) in the tail-flick and paw-pressure tests 50 min after injection. The results suggest that the antinociceptive and morphine modulatory effects resulting from activation of spinal NPFF receptors could be due to an increase in the actions or availability of adenosine.
神经肽FF（苯丙氨酸-亮氨酸-苯丙氨酸-谷氨酰胺-脯氨酸-谷氨酰胺-精氨酸-苯丙氨酸-NH₂）及其合成类似物与脊髓中的特定受体结合，产生镇痛作用，该作用部分被阿片类拮抗剂减弱，且在亚有效剂量下，神经肽FF受体激动剂可增强脊髓阿片类镇痛作用。由于腺苷在脊髓阿片类镇痛作用的产生中起中介作用，本研究调查了这种嘌呤在神经肽FF受体激动剂产生的脊髓效应表达中是否具有类似作用。在留置脊髓导管的大鼠中，注射腺苷受体激动剂N⁶-环己基腺苷（CHA，1.72 nmol）和N-乙基羧酰胺腺苷（NECA，1.95 nmol）以及吗啡（13.2 nmol），在甩尾和爪压试验中引起镇痛作用。鞘内注射腺苷受体拮抗剂8-苯基茶碱（5.9和11.7 nmol）预处理可阻断这三种药物的作用，而不影响基线反应。给予两种合成神经肽FF（NPFF）类似物[D-酪氨酸（1），（N-甲基）苯丙氨酸（3）]NPFF（1DMe，0.86 nmol）和[D-酪氨酸（1），D-亮氨酸（2），D-苯丙氨酸（3）]NPFF（3D，8.6 nmol）可产生持续的热和机械镇痛作用。鞘内注射不同剂量（5.9、11.7和23.5 nmol）的8-苯基茶碱进行腺苷受体阻断预处理，可显著抑制1DMe或3D的镇痛作用。在甩尾和爪压试验中，注射亚镇痛剂量的1DMe（0.009 nmol）可显著增强鞘内吗啡（13.2 nmol）的镇痛作用。鞘内注射8-苯基茶碱（11.7 nmol）可减弱这种联合作用。在注射后50分钟的甩尾和爪压试验中，给予低剂量的1DMe（0.009 nmol）或3D（0.009 nmol）可非常显著地增强腺苷受体激动剂N⁶-环己基腺苷（0.43、0.86和1.72 nmol）的镇痛作用。结果表明，脊髓NPFF受体激活产生的镇痛和吗啡调节作用可能是由于腺苷作用或可用性的增加。
