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Central Administration of Neuropeptide FF and Related Peptides Attenuate Systemic Morphine Analgesia in Mice

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Central Administration of Neuropeptide FF and Related Peptides Attenuate Systemic Morphine Analgesia in Mice Protein & Peptide Letters, 2011, 18, 403-409 403 Central Administration of Neuropeptide FF and Related Peptides Attenuate Systemic Morphine Analgesia in Mice Quan Fang1,#, Tian-nan Jiang1,#, Ning Li1, Zheng-lan Han1 and Rui Wang1,2,* 1Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Medicine, and Institute of Biochemis- try and Molecular Biology, School of Life Sciences, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tian Shui South Road, Lanzhou, 730000, PR China; 2State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic Uni- versity, Hong Kong, China Abstract: Neuropeptide FF (NPFF) belongs to an opioid-modulating peptide family. NPFF has been reported to play im- portant roles in the control of pain and analgesia through interactions with the opioid system. However, very few studies examined the effect of supraspinal NPFF system on analgesia induced by opiates administered at the peripheral level. In the present study, intracerebroventricular (i.c.v.) injection of NPFF (1, 3 and 10 nmol) dose-dependently inhibited sys- temic morphine (0.12 mg, i.p.) analgesia in the mouse tail flick test. Similarly, i.c.v. administration of dNPA and NPVF, two agonists highly selective for NPFF2 and NPFF1 receptors, respectively, decreased analgesia induced by i.p. 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 actions on the antinociceptive effect of systemic morphine. Keywords: Analgesia, neuropeptide FF (NPFF), mice, morphine, receptor, intraperitoneal (i.p.) injection. INTRODUCTION studies. At the cellular level, many pharmacological data suggested that NPFF and related peptides exhibited anti- Neuropeptide FF (NPFF, FLFQPQRFamide) was origi- opioid effects via NPFF and NPFF receptors [14-17]. The nally isolated from bovine brain through its cross-reaction 1 2 biochemical studies recently demonstrated that NPFF recep- with antibodies to the molluscan cardioexcitory peptide 2 tor in the rat spinal cord could exert a molecular anti-opioid FMRF-NH , which possessed the similar C-terminal se- 2 effect [18]. Moreover, at the whole animal level, NPFF ex- quence [1]. Recent reports have shown that NPFF belongs to hibited complex opioid-modulating activities in different a neuropeptide family including two precursors (pro-NPFFA pharmacological studies [13]. Intracerebroventricularly ad- and pro-NPFF ) and two G-protein coupled receptors B ministration of NPFF exhibited opioid-like inhibition of the (NPFF and NPFF ) [2-7]. NPFF and NPFF receptors are 1 2 1 2 mouse colonic bead propulsion time and inhibited small in- about 50 % identical structure [4, 5, 7]. However, several testinal transit [19, 20]. In contrast, the previous reports sug- studies suggested that the pro-NPFF peptides (such as A gested that central administration of NPFF acted as an anti- NPFF and NPA-NPFF) and pro-NPFF peptides (such as B opioid peptide in nociceptive modulation, locomotor activity NPVF) were the preferred ligands for NPFF2 and NPFF1 and feeding behavior [13]. receptors, respectively [7, 8]. In addition, the structure- activities studies and pharmacological assays demonstrated The previous studies indicated that NPFF1 and NPFF2 that NPVF and dNPA (a stable analogue of NPA-NPFF) receptors were distributed very differently in the central were the highest selectivities towards NPFF1 and NPFF2 nervous system [4, 7, 21]. Recently, NPFF related peptides receptors, respectively [7-11] (Table 1). exhibiting different selectivities towards NPFF1 and NPFF2 receptors could evoke different effects on morphine-induced Since the isolation of NPFF in 1985, the biological func- analgesia after i.c.v. co-administration in mice [9, 22]. So, tions suggested for this neuropeptide including pain modula- the results demonstrated that pro- and anti-opioid actions of tion, food intake, gastrointestinal and hormonal modulation, NPFF related peptides were not strictly related to the selec- modulation of opiate tolerance and abstinence and cardio- tivity towards NPFF and NPFF receptors [9, 22]. There- vascular action [12, 13]. Similar to other opioid-modulating 1 2 fore, further in vivo studies are required to define the roles of peptides, the link between the functions of NPFF and opioid NPFF receptor subtypes as it pertains to the modulation of systems has been widely investigated in in vitro and in vivo opioid system. To date, the abilities of NPFF and the related peptides to *Address correspondence to this author at the Institute of Biochemistry and modulate supraspinal opioid system have been largely stud- Molecular Biology, School of Life Science, Lanzhou University, 222 Tian Shui South Road, Lanzhou, 730000, P.R.China; Tel: +86-931-8912567; ied in rodents after central administration [9, 22]. However, Fax: +86-931-8912567; E-mail: [email protected] very few studies examined the modulatory role of supraspi- # nal NPFF system in analgesic effect of opioid injected at Both authors contributed equally to this work peripheral level. In addition, no attention has been directed to 0929-8665/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. 404 Protein & Peptide Letters, 2011, Vol. 18, No. 4 Fang et al. Table 1. Affinities (Ki) of NPFF and Related Agonists on Human NPFF1 and NPFF2 Receptors NPFF1 NPFF2 b a S1/2 Ki (nM) Ki (nM) NPFF, FLFQPQRF-NH2 2.82 ± 0.06 0.21 ± 0.03 13.4 NPVF, VPNLPQRF-NH2 0.59 ± 0.07 23.0 ± 2.1 0.026 dNPA, D.NP(N-Me)AFLFQPQRF-NH2 2.9 ± 0.5 0.027 ± 0.001 107.4 Data are cited from the previous reports [10]. a b Ki value are expressed as mean ± S.E.M.; S1/2 = Ki (NPFF1)/Ki (NPFF2) for the selectivity index the exact activities mediated by NPFF1 and NPFF2 receptors Administration of Drugs towards systemic opioid analgesia. Therefore, in the present study, the effects of NPFF and its highly selective agonists The i.c.v. administration was performed according to an adaptation of procedure by Haley and McCormick [24]. The (i.c.v.) on antinociceptive action induced by systemic mor- injection site was 2.5 mm posterior and 1.0 mm lateral to the phine were investigated in the mouse tail flick test. bregma, and 3 mm from the surface of the skull. Drugs were i.c.v. administered uniformly in a volume of 5 l at a con- MATERIALS AND METHODS stant rate of 10 l / min by using a 25-l microsyringe. Animals Proper injection site was verified in pilot experiments by administration and localization of methylene blue dye. Male Kunming strain mice (20-22 g) were obtained from the Experimental Animal Center of Lanzhou University. All In order to test the effects of NPFF and related peptides animals were cared for and experiments were carried out in on morphine-induced analgesia, the peptides were adminis- accordance with the European Community guidelines for the trated 5 min before the intraperitoneal (i.p.) injection of mor- use of experimental animals (86/609/EEC). All the protocols phine. Moreover, to further investigate whether or not the in this study were approved by the Ethics Committee of anti-opioid activities of NPFF and related peptides could be Lanzhou University, China. antagonized by RF9, the agonists were i.c.v. injected alone or co-injected with RF9 (i.c.v.) 5 min before the i.p. admini- Chemicals stration of morphine. NPFF, NPVF, dNPA and RF9 were synthesized on a Nociceptive Test solid support following the recent report [23]. Peptides were prepared by manual solid-phase synthesis using standard N- Experiments were performed, as described earlier [25, fluorenylmethoxycarbonyl (Fmoc) chemistry. Fmoc- 26]. The nociceptive response was assessed by the radiant protected amino acids (GL Biochem (Shanghai) Ltd.) were heat tail-flick test. Every mouse was used only once. Briefly, coupled to a Rink Amide MBHA resin (Tianjin Nankai He- the animals were gently restrained by hand, and a light beam cheng Science & Technology Co.,Ltd ,China). The following was focused onto the tail. At the beginning of the study, the schedule was employed: (1) DMF wash (3); (2) 20% lamp intensity was adjusted to elicit a response in control piperidine/DMF (3, 4min); (3) DMF wash (3); (4) N- animals within 3 - 5 sec. A cut-off time was set at 10 sec to Fmoc-Amino Acid (2.5eq.)/HBTU (2.5eq.)/HOBt minimize tissue damage. Tail-flick time was determined be- (2.5eq.)/DIPEA (5eq.) in DMF (1), 1 h; (5) DMF wash fore injection and then at 10, 20, 30, 45, 60, 75 and 90 min (3); (6) Kaiser Test. RF9 was obtained after acylation of the after i.c.v. injection. N-terminus with 1-adamantanecarboxylic acid (3eq.) /HBTU (3eq.)/HOBt (3eq.)/DIPEA (6eq.) in DMF (1), 1 h. The Statistical Analysis protected peptide-resin was treated with reagent K Data are expressed as the percent maximum possible (TFA/H O/phenol/ethanedithiol/thioanisole, 82.5:5:5:2.5:5) 2 effect (% MPE) calculated as: % MPE = 100 [(post-drug for 2 h at room temperature. Gel filtration (Sephadex G-10) response – baseline response)/(cut-off response – baseline was performed to desalt the crude peptides. The desalted response)]. The raw data from each animal were converted to peptide was purified by preparative reversed-phase HPLC area under the curve (AUC). We calculated the AUC data using a Waters Delta 600 system coupled to a UV detector. over the period 0 to 60 min. Data were statistically compared Fractions containing the purified peptides were pooled and by means of one-way ANOVA followed by the Dunnett’s or lyophilized.
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