Nociceptin and the ORL‐1 ligand [Phe1ψ (CH2‐NH)Gly2]nociceptin(1‐13)NH2 exert anti‐opioid effects in the Freund's adjuvant‐induced arthritic rat model of chronic pain

Bertorelli, Rosalia; Corradini, Laura; Rafiq, Kamran; Tupper, Joanna; Calò, Girolamo; Ongini, Ennio

doi:10.1038/sj.bjp.0702884

Cited by 57 publications

(41 citation statements)

References 39 publications

(70 reference statements)

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“…In previous studies (34,35), NC(1-17)NH 2 displayed a higher potency than NC, probably due to a greater metabolic stability. Such a benefit was not observed in the ibotenate model, suggesting that NC degradation following systemic injection in neonatal mice is not a fully mature phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…Such a benefit was not observed in the ibotenate model, suggesting that NC degradation following systemic injection in neonatal mice is not a fully mature phenomenon. In different experimental paradigms, [F/G]NC(1-13)NH 2 has been shown to behave as an antagonist, an agonist, or a partial antagonist of the ORL1 receptor (35,37,38 (37,39).…”

Section: Discussionmentioning

confidence: 99%

“…[Phe 1 ψ(CH 2 -NH)Gly 2 ]NC(1-13)NH 2 ([F/G]NC(1-13)NH 2 ) was the first available compound found to be a specific ORL1-receptor antagonist (37). However, more recent studies revealed that this compound can behave as an antagonist, an agonist, or a partial antagonist of the ORL1 receptor, depending on the experimental model used (35,37,38). [Nphe 1 ]NC(1-13)NH 2 is a recently described selective NC receptor antagonist that lacks any residual agonist activity (39,40).…”

Section: Animals and Injectionsmentioning

confidence: 99%

“…NC(1-17)NH 2 is a selective ORL1-receptor agonist and has demonstrated higher potency than NC in some assays (34,35). [desPhe 1 ]NC(1-17)NH 2 , which lacks the NH 2 -terminal Phe residue, has been shown to be inactive at the ORL1 receptor both in vivo and in vitro (36).…”

Section: Animals and Injectionsmentioning

confidence: 99%

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Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Laudenbach¹,

Calò²,

Guerrini³

et al. 2001

J. Clin. Invest.

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IntroductionPeriventricular leukomalacia (PVL) is a hemispheric white-matter lesion that is often cystic and occurs most frequently in infants born before 32 weeks of gestation (1). PVL is the major cause of cerebral palsy among premature infants (2). Based on epidemiological and experimental studies, the pathophysiology of PVL appears to be multifactorial. It potentially involves the combined toxicity of hypoxic-ischemic insults, excess free radicals, maternal-fetal infection with increased cytokine production, and growth factor deficiency (1,(3)(4)(5)(6)(7)(8). Excess release of glutamate and the subsequent overactivation of the excitotoxic cascade could represent a common molecular pathway for several of these risk factors (6, 9).Findings from several experimental studies support this hypothesis. Newborn mice injected intracerebrally with ibotenate, a glutamate analog acting mainly on N-methyl-D-aspartate (NMDA) receptors, develop periventricular cystic white-matter lesions mimicking several aspects of human PVL (10). In this well characterized murine model, several drugs that interfere with the excitotoxic cascade have been shown to be neuroprotective (7,(11)(12)(13)(14) while proinflammatory cytokines (15) and iron (16) exacerbated ibotenateinduced white-matter lesions. In order to further understand the pathophysiology of the ibotenateinduced cystic lesions, we targeted the NMDA receptors thought to be present on white-matter glial cells. Newborn mice were injected intracerebrally with sense, antisense, or missense oligonucleotides specific for the NMDA R1 receptor subunit (P. Gressens, unpublished work). The sequences of the oligonucleotides were identical to those previously used by Wahlestedt et al. in an in vitro assay (17). In newborn mice, pretreatment with antisense oligonucleotides was neuroprotective while control sense oligonucleotides had no effect on the ibotenate-induced lesion. Unexpectedly, missense oligonucleotides, which were used as another control, induced a threefold reduction in the severity of the excitotoxic whitematter lesions. A search of databases with Basic Local Alignment Search Tool (BLAST) revealed that 12 successive nucleotides of the so-called "NMDA R1 missense oligonucleotide" were actually complementary to a triplicated motif of the murine nociceptin (NC) mRNA, suggesting that the blockade of NC production is neuroprotective in the ibotenate model. Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white-matter lesions, mimicking brain lesions that occur in human preterm infants. Nociceptin (NC), also called orphanin FQ, is the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor and does not bind classical high-affinity opioid receptors. In the present study, administration of NC exacerbated ibotenate-induced white-matter lesions while coadministration of ibotenate with either of two NC antagonists reduced excitotoxic white-matter lesions by up to 64%. Neither ibotenate plus endomorphin I (a selective µ receptor agonist), nor ibot...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Animals and Injectionsmentioning

confidence: 99%

Section: Animals and Injectionsmentioning

confidence: 99%

See 2 more Smart Citations

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Laudenbach¹,

Calò²,

Guerrini³

et al. 2001

J. Clin. Invest.

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“…OFQ has been reported to produce pronociceptive or antinociceptive effects, depending on the route of administration (Meunier et al, 1995;Reinscheid et al, 1995;Erb et al, 1997;Caló et al, 2000). Intracerebroventricular administration of OFQ has been reported to produce (1) hyperalgesia (Meunier et al, 1995;Reinscheid et al, 1995;Wang et al, 1999), (2) hyperalgesia followed by analgesia (Rossi et al, 1996), and (3) reversal of opioidinduced analgesia Mogil et al, 1996;Heinricher et al, 1997;Bertorelli et al, 1999). However, a consensus has emerged that intrathecal application of OFQ into the spinal cord primarily produces analgesia (Xu et al, 1996;King et al, 1997;Hao and Ogawa, 1998;Wang et al, 1999;) (for review, see Mogil and Pasternak, 2001;Meunier, 2003).…”

Section: Introductionmentioning

confidence: 99%

Activation of Opioid Receptor Like-1 Receptor in the Spinal Cord Produces Sex-Specific Antinociception in the Rat: Estrogen Attenuates Antinociception in the Female, whereas Testosterone Is Required for the Expression of Antinociception in the Male

Claiborne¹,

Nag²,

Mokha³

2006

J. Neurosci.

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Sex-related differences in the perception and modulation of pain have been reported. The present study is the first to investigate systematically whether activation of opioid receptor-like 1 receptor (ORL 1 ) by orphanin FQ (OFQ) produces sex-specific modulation of spinal nociception and whether estrogen or testosterone contributes to these differences using the rat as an experimental animal. Two behavioral models, the NMDA and heat-induced nociceptive tests, were used to examine sex-specific modulation of spinal nociception. Intrathecal microinjection of OFQ in male, ovariectomized (OVX), and diestrous rats produced a significant antinociceptive effect on both tests. However, OFQ failed to produce antinociception in proestrous rats, the phase of the estrous cycle with the highest levels of circulating estradiol, and produced a dose-dependent effect in OVX females treated with 1 ng to 100 g of estradiol. The antinociceptive effects of OFQ were dose dependent in male and OVX animals and were reversibly antagonized by UFP-101 ([Nphe 1 ,Arg ,Lys 15]N/ OFQ(1-13)-NH 2 ), an ORL 1 receptor-selective antagonist. Interestingly, OFQ was ineffective in gonadectomized (GDX) males, whereas testosterone replacement restored the antinociceptive effect of OFQ in GDX males. We conclude that OFQ produces sex-specific modulation of spinal nociception; estrogen attenuates antinociception in the female in parallel with normal cycling of estrogen levels, and testosterone is required for the expression of antinociception in the male; thus, the sensitivity of the male to the antinociceptive effects of OFQ is not simply attributable to the intrinsically low estrogen levels in these animals.

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Imaging studies in Freund's complete adjuvant model of regional polyarthritis, a model suitable for the study of pain mechanisms, in the rat

Almarestani¹,

Fitzcharles²,

Bennett³

et al. 2011

Arthritis & Rheumatism

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Objective. In view of the extensive distribution in the spinal cord of primary afferent nociceptive nerve fibers from the rat hind paw, a model of regional inflammation would be useful in the study of arthritis pain. However, the subcutaneous intraplantar injection of a single low dose of Freund's complete adjuvant (CFA) has been used mostly as an inflammation model. We undertook this study to characterize this model by means of conventional radiography, microfocal computed tomography, and bone densitometry and by examining changes in pain-related behavior.Methods. Male rats were injected unilaterally with CFA or saline subcutaneously in the hind paw and killed 7, 15, and 30 days after injection. Pain-related behavior was studied using the Hargreaves, von Frey, and acetone tests.Results. CFA-injected animals developed soft tissue inflammation and polyarthritis restricted to the joints of the injected hind paw. No signs of joint involvement were observed 7 days after CFA injection. On day 15 after CFA injection, there was widening of joint space indicative of joint effusion. By day 30 after CFA injection, there was evidence of joint damage with joint space narrowing, erosions, osteophyte formation, and joint deformity. There were no changes contralaterally or in saline-injected rats. Mechanical hyperalgesia and cold allodynia were present in the affected hind paw from day 1 through day 30.Conclusion. Signs of arthritis were strictly unilateral and started only 2 weeks after injection. Since the affected area has a broad representation in the spinal cord, this model has advantages over monarthritis models for the study of plastic changes in the dorsal horn of the spinal cord.

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Nociceptin and the ORL‐1 ligand [Phe¹ψ (CH₂‐NH)Gly²]nociceptin(1‐13)NH₂ exert anti‐opioid effects in the Freund's adjuvant‐induced arthritic rat model of chronic pain

Cited by 57 publications

References 39 publications

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Activation of Opioid Receptor Like-1 Receptor in the Spinal Cord Produces Sex-Specific Antinociception in the Rat: Estrogen Attenuates Antinociception in the Female, whereas Testosterone Is Required for the Expression of Antinociception in the Male

Imaging studies in Freund's complete adjuvant model of regional polyarthritis, a model suitable for the study of pain mechanisms, in the rat

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