Blockade of the nociceptin/orphanin FQ/NOP receptor system in the rat ventrolateral periaqueductal gray potentiates DAMGO analgesia

doi:10.1016/j.peptides.2007.05.013

Peptides

Volume 28, Issue 7, July 2007, Pages 1441-1446

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Abstract

Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are involved in various biological functions including pain. High density of NOP receptor has been found in the ventrolateral periaqueductal gray (vlPAG), the main output pathway involved in descending pain-control system. The aim of our work was to evaluate the involvement of the N/OFQ/NOP system in the modulation of MOP analgesia in the rat vlPAG using UFP-101, a selective NOP antagonist. N/OFQ significantly blocked DAMGO (a selective MOP agonist) analgesia, while UFP-101 enhanced the effect of the opioid given at a subanalgesic dose. These results confirm our hypothesis of an antiopioid role for N/OFQ in the vlPAG.

Introduction

Nociceptin/orphanin FQ (N/OFQ), a heptadecapeptide derived from ppN/OFQ, is the endogenous ligand of the NOP receptor similar in sequence to the MOP, DOP and KOP receptors [22], [25], [34]. Despite this homology, the NOP receptor shows low affinity for opioid agonists and antagonists [12].

In analogy with opioid receptors, NOP is widely distributed through the CNS in those regions involved in pain transmission processing [28]. Pharmacological studies, examining the N/OFQ effect on nociception, have generated conflicting results depending on the dose and the site of administration [28]. When supraspinally administered, the peptide may produce hyperalgesia, allodynia, and, in some circumstances, naloxone-reversible analgesia [15]. There is no doubt, instead, that N/OFQ interferes with the supraspinal analgesia induced by opioids [26]. Intracerebroventricular (i.c.v.) injection of N/OFQ, indeed, reverses the tail-flick inhibition induced by morphine [14], selective opioid receptor agonists [27], [37] and opioid-mediated stress- and electroacupuncture-induced analgesia [26], [38].

However, the real site or sites of action for this physiological antagonism are not known. In vitro and in vivo experiments suggest that a likely area of this action could be the midbrain periaqueductal gray (PAG) matter, divided, at its rostrocaudal axis, into dorsomedial, dorsolateral, lateral and ventrolateral columns [3]: the ventrolateral columns are those proposed as integrating the behavioral nociceptive response [32]. PAG activation inhibits, through the projection to the rostral ventral medulla (RVM), the neuron activity of the spinal dorsal horn and the behavioral response to pain stimulation [24], [2].

Electrophysiological and anatomical studies have demonstrated that opioid receptors exist on some PAG neurons projecting into the RVM [41], and it is well known that local administration of opioid peptides in this region induces pain relief [19], [23]. In particular, opioid analgesia in the PAG appears to be especially dependent on the MOP receptor, given the effectiveness of morphine and DAMGO [36], [4] microinjections in this area, blocked by the MOP antagonist naloxonazine [4].

Immunohistochemical studies have shown a high density of NOP receptors, localized with opioid receptors, within the PAG [1] where a high concentration of ppN/OFQ mRNA has also been found [18]. Microinjection of N/OFQ in the vlPAG decreases the withdrawal latency to heat and loading [6], in addition the peptide in the PAG can increase rat pain sensitivity and antagonize acupuncture analgesia [42].

The biological activities of N/OFQ, including pain modulation, can be better elucidated blocking N/OFQ signaling. Recently, Calo et al. [7] synthesized a peptidergic NOP receptor antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH₂ (UFP-101) exhibiting high affinity (pK_i 10.2) and selectivity (∼3000-fold over classical opioid receptors) to the human recombinant NOP receptor expressed in CHO cells [8].

The aim of our work was to clarify the effect of N/OFQ on the descending system of pain modulation and to determine if the vlPAG could be the site of N/OFQ functional antagonism toward MOP analgesia in the rat. To achieve this objective and get new information on this relationship, we evaluated the effect of vlPAG N/OFQ on the MOP selective agonist DAMGO; we also assessed N/OFQ signaling interruption, by examining the effect of vlPAG UFP-101 on a subanalgesic dose of the opioid peptide.

Section snippets

Animals

Male Sprague–Dawley rats (Morini, S. Polo d’Enza, RE, Italy), weighing 180–200 g, were used. The animals were kept at a constant room temperature (25 ± 1 °C) under a 12:12 h light and dark cycle, with free access to food and water. Each rat was used for only one experiment. All tests were performed between 09:00 and 14:00. Experimental procedures were approved by the local ethical committee, Institutional Animal Care and Use Committee (IACUC) and conducted in accordance with International Guidelines

Effect of i.vlPAG UFP-101 on N/OFQ hyperalgesia

Intra vlPAG injection of N/OFQ, at the same dose previously [37] used for i.c.v. experiments, 10 nmol/rat, decreased the nociceptive latency following thermal stimulation (tail-flick), causing a hyperalgesic effect (Fig. 1). Compared with the group of rats receiving a microinjection of saline, N/OFQ reduced TFLs with the maximal effect after 10 min when the mean of the baseline TFL decreased from 3.5 ± 0.4 s to 2.06 ± 0.3 s. Moreover, the percentage changes from basal level of TFL (MAUC in 60 min of

Discussion

In our study we have shown that i.vlPAG N/OFQ significantly decreased tail withdrawal latency to thermal stimulation and that the N/OFQ peptidic antagonist UFP-101 reversed this effect, demonstrating the involvement of the NOP receptor. Moreover, these results show how a microinjection of N/OFQ into the vlPAG blocked analgesia mediated by MOP receptor stimulation, while UFP-101 enhanced the effect of the MOP agonist given at a very weak analgesic dose, strongly suggesting that N/OFQ can act as

References (44)

M.M. Behbehani
Functional characteristics of the midbrain periaqueductal gray
Prog Neurobiol
(1995)
R.J. Bodnar et al.
Role of mu 1-opiate receptors in supraspinal opiate analgesia: a microinjection study
Brain Res
(1988)
B. Bytner et al.
Nociceptin/orphanin FQ into the rat periaqueductal gray decreases the withdrawal latency to heat and loading, an effect reversed by (Nphe(1))nociceptin(1–13)NH(2)
Brain Res
(2001)
X. Chen et al.
Nociceptin/orphanin FQ blocks the antinociception induced by mu, kappa and delta opioid agonists on the cold water tail-flick test
Eur J of Pharmacol
(2007)
L. Chiou et al.
[Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ is a competitive antagonist of NOP receptor in the periaqueductal gray
Eur J Pharmacol
(2005)
D. Economidou et al.
Effect of novel NOP receptor ligands on food intake in rats
Peptides
(2006)
J.E. Grisel et al.
Effects of supraspinal orphanin FQ/nociceptin
Peptides
(2000)
M.M. Heinricher
Orphanin FQ/nociceptin: from neural circuitry to behaviour
Life Sci.
(2003)
T. Houtani et al.
Structure and regional distribution of nociceptin/orphanin FQ precursor
Biochem Biophys Res Commun
(1996)
T.S. Jensen et al.
Comparison of the antinociceptive action of mu and delta opioid receptor ligands in the periaqueductal gray matter, medial and paramedial ventral medulla in the rat as studied by the microinjection technique
Brain Res
(1986)

P. Mason

Central mechanism of pain modulation

Curr Opin Neurobiol

(1999)

J.S. Mogil et al.

Orphanin FQ is a functional anti-opioid peptide

Neuroscience

(1996)

J.S. Mogil et al.

Functional antagonism of μ-, δ- and κ-opioid antinociception by orphanin FQ

Neurosci Lett

(1996)

C. Nazzaro et al.

UFP-101 antagonizes the spinal antinociceptive effects of nociceptin/orphanin FQ: behavioral and electrophysiological studies in mice

Peptides

(2007)

F. Odeh et al.

Heterogeneous synaptic inputs from the ventrolateral periaqueductal gray matter to neurons responding to somatosensory stimuli in the rostral ventromedial medulla of rats

Brain Res

(2003)

G.C. Rossi et al.

Mu and delta opioid synergy between the periaqueductal gray and the rostroventral medulla

Brain Res

(1994)

G.M. Scoto et al.

Effect of supraspinal nocistatin on nociceptin/orphanin FQ antagonism of selective opioid analgesia

Neurosci Lett

(2005)

G. Vitale et al.

Anxiolytic-like effects of nociceptin/orphanin FQ in the elevated plus maze and in the conditioned defensive burying test in rats

Peptides

(2006)

H. Wang et al.

μ- and δ-Opioid receptor mRNAs are expressed in periaqueductal gray neurons projecting to the rostral ventromedial medulla

Neuroscience

(2002)

H. Wang et al.

Effect of orphanin FQ on acupuncture analgesia and noxious stimulation in the periaqueductal gray

Sheng Li Xue Bao

(1998)

Z.L. Yang et al.

Effects of microinjection of OFQ into PAG on spinal dorsal horn WDR neurons in rats

Brain Res

(2001)

L. Yuan et al.

Accelerated release and production of orphanin FQ in brain of chronic morphine tolerant rats

Brain Res

(1999)

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Blockade of the nociceptin/orphanin FQ/NOP receptor system in the rat ventrolateral periaqueductal gray potentiates DAMGO analgesia

Abstract

Introduction

Section snippets

Animals

Effect of i.vlPAG UFP-101 on N/OFQ hyperalgesia

Discussion

Prog Neurobiol

Brain Res

Brain Res

Eur J of Pharmacol

Eur J Pharmacol

Peptides

Peptides

Life Sci.

Biochem Biophys Res Commun

Brain Res

Curr Opin Neurobiol

Neuroscience

Neurosci Lett

Peptides

Brain Res

Brain Res

Neurosci Lett

Peptides

Neuroscience

Sheng Li Xue Bao

Brain Res

Brain Res