Neuropeptide FF receptors antagonist, RF9, attenuates opioid-evoked hypothermia in mice
Introduction
Opioid receptors are currently classified as classical (MOP, DOP and KOP receptors) and nonclassical (NOP receptor) [40]. Opioid receptors were involved in the physiological control of numerous functions of the central nervous system, including thermoregulation. It has long been recognized that opioid such as morphine could produce a range of effects on body temperature in a number of species including man [1], [37], [41]. The effect on body temperature of morphine, which acted on the classical opioid receptors, were biphasic in mice, with low doses producing hyperthermia and higher doses resulting in hypothermia [3], [12], [32], [44]. The hypothermia induced by morphine could be antagonized by the opioid receptor antagonists naloxone (classical opioid receptors antagonist), naloxonazine (MOP receptor antagonist), BNTX (DOP receptor antagonist) and DIPPA (KOP receptor antagonist), which provided further evidence for the involvement of classical opioid receptors [3], [33]. N-nitro-l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, enhanced the hypothermic effects of morphine in mice [38]. In addition, NOP receptor is the fourth member of the opioid receptor family [20]. Nociceptin/orphanin FQ (N/OFQ) isolated from the mammal brain, a 17-amino-acid peptide, was an endogenous ligand of the NOP receptor [19], [29]. N/OFQ decreased body temperature in rats, which was reduced by NOP receptor antisense oligonucleotides treatment in rats [5], [14], [28], [39], [42].
Neuropeptide FF (NPFF, FLFQPQRF-NH2) belongs to a family of amidated neuropeptides related to the molluscan cardioexcitatory neuropeptide FMRFamide (FMRFa) [25]. NPFF immunoreactivity was localized in different CNS sites involved in temperature regulation [2], [7]. In thermoregulatory study, injection into the third ventricle of NPFF or 1DMe (a stable NPFF analog) elicited a marked decrease in basal rectal temperature [6], [8], [10], [11], [27]. L-NAME markedly potentiated hypothermia induced by 1DMe injected in the mouse brain [45]. The previous studies indicated that NPFF might act as a modulator of endogenous opioid functions [22], [23], [24], [34], [35], [43]. At the cellular level, NPFF receptors induced anti-opioid actions [34]. In vivo, the studies of NPFF were mostly focused on the pro- and anti-opioid effects on morphine antinociception or morphine tolerance and dependence [16], [17], [18], [26]. However, the possible interactions between NPFF and opioid agonists in the mediation of hypothermic effects are not very clear and need more investigations.
Both opioid and NPFF systems were involved in thermoregulation of the rodents. NO participated, in the same manner, in hypothermia evoked by NPFF and morphine [38], [45]. Therefore, these data suggested a link between opioid and NPFF systems in body temperature regulation. In the present study, we used the endpoint of hypothermia to investigate opioid and NPFF systems interactions in conscious mice.
Section snippets
Animals
Male Kunming strain mice were obtained from the Experimental Animal Center of Lanzhou University. All animals were cared for and experiments were carried out in accordance with the European Community guidelines for the use of experimental animals (86/609/EEC). All the protocols in this study were approved by the Ethics Committee of Lanzhou University, China.
Chemicals
NPFF, RF9, N/OFQ and [Nphe1]NC(1-13)NH2 were synthesized on a solid-phase support following the previous report [9]. Peptides were prepared
Morphine–NPFF interaction
As shown in Fig. 1, Fig. 2, central injection of morphine (5 nmol) evoked the decrease in body temperature (AUC: −108.2 ± 7.8; P < 0.001, vs. saline), which was blocked by co-injection of naloxone (10 nmol) (P < 0.01, vs. 5 nmol morphine group) (Fig. 2A). At a dose of 45 nmol, NPFF produced significant hypothermia following injection into the third ventricle (AUC: −87.9 ± 16.1; P < 0.01, vs. saline) (Fig. 1, Fig. 2). The hypothermic effects of NPFF (45 nmol) were fully prevented by co-injection of RF9 (30
Discussion
The major finding of the present study was that the NPFF receptors antagonist RF9 attenuated the hypothermia caused by two different opioid agonists, morphine and N/OFQ. In contrast, the hypothermia evoked by the central administration of NPFF was not affected by opioid antagonists.
The previous studies indicated that NPFF might act as a modulator of opioid functions [22], [23], [24], [34], [35], [43]. In rodents, NPFF receptors agonists exhibited either anti-opioid activities or potentiate
Acknowledgements
This study was supported by the grants from the National Natural Science Foundation of China (Nos. 20525206, 20772052 and 20621091), the Specialized Research Fund for the Doctoral Program in Higher Education Institutions (No. 20060730017), and the Chang Jiang Program of the Ministry of Education of China.
References (45)
- et al.
Autoradiographic distribution of receptors to FLFQPQRFamide, a morphine-modulating peptide, in rat central nervous system
Neuroscience
(1992) - et al.
Possible mechanism of hypothermia induced by intracerebroventricular injection of orphanin FQ/nociceptin
Brain Res
(2001) - et al.
Hypothermic effects of neuropeptide FF analogues in mice
Pharmacol Biochem Behav
(1997) - et al.
In vivo inhibition of neuropeptide FF agonism by BIBP3226, an NPY Y1 receptor antagonist
Peptides
(2006) - et al.
In vitro and in vivo studies of dansylated compounds, the putative agonists and antagonists on neuropeptide FF receptors
Peptides
(2006) - et al.
Inhibition of neuropeptide FF (NPFF)-induced hypothermia and anti-morphine analgesia by RF9, a new selective NPFF receptors antagonist
Regul Pept
(2008) - et al.
Cholera and pertussis toxins inhibit differently hypothermic and anti-opioid effects of neuropeptide FF
Regul Pept
(2001) - et al.
Influence of the selective ORL1 receptor agonist, Ro64-6198, on rodent neurological function
Neuropharmacology
(2001) - et al.
IgG from neuropeptide FF antiserum reverses morphine tolerance in the rat
Neurosci Lett
(1991) - et al.
Analog of neuropeptide FF attenuates morphine tolerance
Neurosci Lett
(1992)
Subcutaneous injection of an analog of neuropeptide FF precipitates morphine abstinence syndrome
Life Sci
Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor
Eur J Pharmacol
Functional antagonism of mu-, delta- and kappa-opioid antinociception by orphanin FQ
Neurosci Lett
A mammalian neuropeptide with multiple functions
Prog Neurobiol
Neuropeptide FF and modulation of pain
Brain Res
Dissociation of pharmacological proand anti-opioid effects by neuropeptide FF analogs
Eur J Pharmacol
Comparison of pharmacological activities of neuropeptide FF1 and neuropeptide FF2 receptor agonists
Eur J Pharmacol
NOP receptor antagonist, JTC-801, blocks cannabinoid-evoked hypothermia in rats
Neuropeptides
Cholecystokinin and morphine-induced hypothermia
Eur Neuropsychopharmacol
Neuropeptide FF receptors 1 and 2 exert an anti-opioid activity in acutely dissociated rat dorsal raphe and periventricular hypothalamic neurones
Neurosci Lett
Neuropeptide FF, pain and analgesia
Eur J Pharmacol
Opposing interplay between Neuropeptide FF and nitric oxide in antinociception and hypothermia
Peptides
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