Spinal analgesic activity of orphanin FQ/nociceptin and its fragments

doi:10.1016/S0304-3940(97)13414-0

Neuroscience Letters

Volume 223, Issue 2, 21 February 1997, Pages 113-116

https://doi.org/10.1016/S0304-3940(97)13414-0 Get rights and content

Abstract

Previous work reveals that orphanin FQ/nociceptin (OFQ/N) administered supraspinally produces an initial hyperalgesic response followed by analgesia. Spinally, OFQ/N elicits a rapidly appearing, naltrexone-reversible, dose-dependent analgesia in the tailflick assay without any indication of hyperalgesia. Two OFQ/N fragments, OFQ/N (1–7) and OFQ/N (1–11), are active, but far weaker. Blockade of sigma receptors with haloperidol enhances the analgesic potency of spinal OFQ/N, OFQ/N (1–7) and OFQ/N (1–11), but not as dramatically as supraspinal OFQ. Antisense probes targeting the second and third coding exons, but not the first exon, of the cloned mouse OFQ/N receptor (KOR-3) partially block OFQ/N analgesia.

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Acknowledgements

We thank Drs. J. Posner and R. Rapaka for their assistance with these studies. This work was supported, in part, by the National Institute on Drug Abuse by a research grant (DA07242) and a Research Scientist Award (DA00220) to G.W.P. and a Research Scientist Development Award (DA00310) to G.C.R.

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Cited by (126)

Central N/OFQ-NOP Receptor System in Pain Modulation
2016, Advances in Pharmacology
Citation Excerpt :
Since the NOP receptor is present at central pain-processing pathways (Anton et al., 1996; Mollereau & Mouledous, 2000; Neal et al., 1999a), several groups of researchers have investigated the function of spinal N/OFQ-NOP receptor system in pain modulation. In rodents, several lines of evidence demonstrate that intrathecal administration of N/OFQ at nanomole doses produced antinociceptive effects in the rodent tail flick test (King, Rossi, Chang, Williams, & Pasternak, 1997; Xu, Hao, & Wiesenfeld-Hallin, 1996). Intrathecal N/OFQ also had antinociceptive effects in the formalin-induced pain behaviors (Erb et al., 1997; Yamamoto, Nozaki-Taguchi, & Kimura, 1997a) and potentiated morphine-induced antinociception (Tian et al., 1997).
Two decades have passed since the peptide, nociceptin/orphanin FQ (N/OFQ), and its cognate (NOP) receptor were discovered. Although NOP receptor activation causes a similar pattern of intracellular actions as mu-opioid (MOP) receptors, NOP receptor-mediated pain modulation in rodents are more complicated than MOP receptor activation. This review highlights the functional evidence of spinal, supraspinal, and systemic actions of NOP receptor agonists for regulating pain. In rodents, effects of the N/OFQ-NOP receptor system in spinal and supraspinal sites for modulating pain are bidirectional depending on the doses, assays, and pain modalities. The net effect of systemically administered NOP receptor agonists may depend on relative contribution of spinal and supraspinal actions of the N/OFQ-NOP receptor signaling in rodents under different pain states. In stark contrast, NOP receptor agonists produce only antinociception and antihypersensitivity in spinal and supraspinal regions of nonhuman primates regardless of doses and assays. More importantly, NOP receptor agonists and a few bifunctional NOP/MOP receptor agonists do not exhibit reinforcing effects (abuse liability), respiratory depression, itch pruritus, nor do they delay the gastrointestinal transit function (constipation) in nonhuman primates. Depending upon their intrinsic efficacies for activating NOP and MOP receptors, bifunctional NOP/MOP receptor agonists warrant additional investigation in primates regarding their side effect profiles. Nevertheless, NOP receptor-related agonists display a much wider therapeutic window as compared to that of MOP receptor agonists in primates. Both selective NOP receptor agonists and bifunctional NOP/MOP receptor agonists hold great potential as effective and safe analgesics without typical opioid-associated side effects in humans.
Sex differences in the Nociceptin/Orphanin FQ system in rat spinal cord following chronic morphine treatment
2012, Neuropharmacology
Nociceptin/Orphanin FQ (N/OFQ) appears to contribute to the development of morphine tolerance, as blockade of its actions will block or reverse the process. To better understand the contribution of N/OFQ to the development of morphine tolerance, this study examined the effect of chronic morphine treatment on levels of N/OFQ and levels and activity of the N/OFQ peptide (NOP) receptor in spinal cord (SC) from male and female rats. Both male and female Wistar rats showed less responsiveness to morphine after subcutaneous injection of escalating doses of morphine (10, 20, 40, 60 and 80 mg/kg, respectively) twice daily for five consecutive days. Male rats were more tolerant to the antinociceptive actions of morphine than females. The N/OFQ content of SC extracts was higher in females than in males, regardless of treatment; following chronic morphine treatment the difference in N/OFQ levels between males and females was more pronounced. N/OFQ content in cerebrospinal fluid (CSF) was reduced 40% in male and 16% in female rats with chronic morphine exposure, but increased in periaqueductal grey of both sexes. Chronic morphine treatment increased NOP receptor levels 173% in males and 137% in females, while decreasing affinity in both. Chronic morphine increased the efficacy of N/OFQ-stimulated [³⁵S]GTPγS binding to SC membranes from male rats, consistent with increased receptor levels. Taken together, these findings demonstrate sex differences in N/OFQ–NOP receptor expression and NOP receptor activity following chronic morphine treatment. They also suggest interplay between endogenous N/OFQ and chronic morphine treatment that results in nociceptive modulation.
Quantitative study of [Tyr <sup>10</sup>]nociceptin/orphanin FQ (1-11) at NOP receptors in rat periaqueductal gray and expressed NOP receptors in HEK293 cells
2012, Life Sciences
The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor was reported to be functionally heterogeneous. We investigated if [Tyr¹⁰]N/OFQ(1-11), a peptide ligand reported to selectively bind to the high affinity site of ¹²⁵I-[Tyr¹⁴]N/OFQ in rodent brains, can be a tool for revealing the NOP receptor heterogeneity. We have previously founded an NOP receptor subset insensitive to Ro 64-6198 and (+)-5a Compound, two non-peptide NOP agonists, in rat ventrolateral periaqueductal gray (vlPAG) neurons. Here, we examined if [Tyr¹⁰]N/OFQ(1-11) differentiated (+)-5a Compound-sensitive and -insensitive vlPAG neurons. Certain mu-opioid (MOP) receptor ligands highly competing with [Tyr¹⁰]N/OFQ(1-11) in binding studies also showed high affinity at expressed heteromeric NOP–MOP receptors. We also examined if [Tyr¹⁰]N/OFQ(1-11) distinguished heteromeric NOP–MOP receptors from homomeric NOP receptors.
The NOP receptor activity was evaluated by G-protein coupled inwardly rectifying potassium (GIRK) currents in rat vlPAG slices, and by inhibition of cAMP accumulation in HEK293 cells expressing NOP receptors or co-expressing NOP and MOP receptors.
In vlPAG neurons, [Tyr¹⁰]N/OFQ(1-11), like N/OFQ, induced GIRK currents through NOP receptors. It was less potent (EC₅₀: 8.98 μM) but equi-efficacious as N/OFQ. [Tyr¹⁰]N/OFQ(1-11) displayed different pharmacological profiles as (+)-5a Compound, and was effective in both (+)-5a Compound-sensitive and -insensitive neurons. In NOP-expressing HEK293 cells and NOP- and MOP-co-expressing cells, [Tyr¹⁰]N/OFQ(1-11) displayed similar concentration–response curves in decreasing cAMP accumulation.
[Tyr¹⁰]N/OFQ(1-11) is an NOP full agonist and less potent than N/OFQ. However, it can neither reveal the functional heterogeneity of NOP receptors in vlPAG neurons nor differentiate heteromeric NOP–MOP and homomeric NOP receptors.
Antinociceptive effects of spinally administered nociceptin/orphanin FQ and its N-terminal fragments on capsaicin-induced nociception
2011, Peptides
Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for the N/OFQ peptide (NOP) receptors, has been shown to be metabolized into some fragments. We examined to determine whether intrathecal (i.t.) N/OFQ (1–13), (1–11) and (1–7) have antinociceptive activity in the pain-related behavior after intraplantar injection of capsaicin. The i.t. administration of N/OFQ (0.3–1.2 nmol) produced an appreciable and dose-dependent inhibition of capsaicin-induced paw-licking/biting response. The N-terminal fragments of N/OFQ, (1–13) and (1–11), were antinociceptive with a potency lower than N/OFQ. Calculated ID₅₀ values (nmol, i.t.) were 0.83 for N/OFQ, 2.5 for N/OFQ (1–13) and 4.75 for N/OFQ (1–11), respectively. The time-course effect revealed that the antinociceptive effects of these N-terminal fragments lasted longer than those of N/OFQ. Removal of amino acids down to N/OFQ (1–7) led to be less potent than N/OFQ and its fragments, (1–13) and (1–11). Antinociception induced by N/OFQ or N/OFQ (1–13) was reversed significantly by i.t. co-injection of [Nphe¹]N/OFQ (1–13)NH₂, a peptidergic antagonist for NOP receptors, whereas i.t. injection of the antagonist did not interfere with the action of N/OFQ (1–11) and (1–7). Pretreatment with the opioid receptor antagonist naloxone hydrochloride did not affect the antinociception induced by N/OFQ and its N-terminal fragments. These results suggest that N-terminal fragments of N/OFQ are active metabolites and may modulate the antinociceptive effect of N/OFQ in the spinal cord. The results also indicate that N/OFQ (1–13) still possess antinociceptive activity through NOP receptors.
Involvement of NMDA receptor in nociceptive effects elicited by intrathecal [Tyr<sup>6</sup>] γ2-MSH(6-12), and the interaction with nociceptin/orphanin FQ in pain modulation in mice
2009, Brain Research
Citation Excerpt :
The mRNA for NOP receptor was also found in the dorsal spinal cord (Bunzow et al., 1994; Wick et al., 1995), suggesting an important role for N/OFQ–NOP receptor system in the modulation of nociceptive signals at spinal level. N/OFQ was reported to induce behavioral responses (Sakurada et al., 1999b), allodynia and thermal hyperalgesia in conscious mice (Hara et al., 1997; Sakurada et al., 1999a), facilitate the flexor reflex (Xu et al., 1996) at low doses, and produce analgesia (King et al., 1997; Nazzaro et al., 2007; Xu et al., 1996), anti-hyperalgesic and anti-allodynic effects (Hao et al., 1998) at high doses. In the present study, we have observed that intrathecal [Tyr6] γ2-MSH(6-12) elicited hyperalgesia as assayed by tail withdrawal test and nociceptive behavioral responses including biting, licking and scratching in mice.
The mas-related genes (Mrgs, also known as sensory neuron-specific receptors, SNSRs) are specifically expressed in small diameter sensory neurons in the trigeminal and dorsal root ganglia, suggesting an important role of the receptors in pain transmission. The present study aimed to investigate the underlying mechanism of the nociceptive effects after activation of MrgC, and the interaction between MrgC and N/OFQ–NOP receptor system in modulation of nociception in mice. Intrathecal (i.t.) administration of [Tyr⁶] γ2-MSH(6-12), the most potent agonist for MrgC receptor, produced a significant hyperalgesic response as assayed by tail withdrawal test and a series of characteristic nociceptive responses, including biting, licking and scratching, in a dose-dependent manner (0.01–10 pmol and 0.01–10 nmol, respectively) in mice. These pronociceptive effects induced by [Tyr⁶] γ2-MSH(6-12) were inhibited dose-dependently by co-injection of competitive NMDA receptor antagonist D-APV, non-competitive NMDA receptor antagonist MK-801, and nitric oxide (NO) synthase inhibitor L-NAME. However, the tachykinin NK₁ receptor antagonist L-703,606, and tachykinin NK₂ receptor antagonist MEN-10,376, had no influence on pronociceptive effects elicited by [Tyr⁶] γ2-MSH(6-12). In other groups, [Tyr⁶] γ2-MSH(6-12)-induced nociceptive responses were bidirectionally regulated by the co-injection of N/OFQ. N/OFQ inhibited nociceptive responses at high doses (0.01–1 nmol), but potentiated the behaviors at low doses (1 fmol–3 pmol). Furthermore, both hyperalgesia and nociceptive responses were enhanced after the co-administration with NOP receptor antagonist [Nphe¹]N/OFQ(1-13)-NH₂. These results suggest that intrathecal [Tyr⁶] γ2-MSH(6-12)-induced pronociceptive effects may be mediated through NMDA receptor–NO system in the spinal cord, and demonstrate the interaction between MrgC and N/OFQ–NOP receptor system in pain transmission.
Nociceptin produces antinociception after spinal administration in amphibians
2009, Pharmacology Biochemistry and Behavior
Nociceptin, also known as orphanin FQ, is a opioid-like neuropeptide that mediates its effects at the nociceptin receptor, a member of the G protein-coupled receptor superfamily. In mammals, nociceptin produces analgesia after spinal administration, however the role of nociceptin and nociceptin receptors in the modulation of noxious stimuli in non-mammalian species has not been examined. In an amphibian pain model using the acetic acid test with Rana pipiens, nociceptin and nociceptin_1–13 amide produced dose-dependent antinociception (1–100 nmol), blocked by the nociceptin antagonist, [Nphe¹]-nociceptin_1–13 amide (30 nmol), but not the opioid antagonist, naltrexone (100 nmol/g, s.c.). Conversely, the antinociceptive effects of mu, delta, and kappa opioid receptor agonists were not blocked by the nociceptin antagonist. Nociceptin and nociceptin_1–13 amide were the least potent of the opioid agonists tested. These studies demonstrate that spinal nociceptin receptors and not opioid receptors mediate the antinociceptive effect of nociceptin. Considered with previous findings, these behavioral data supports a role for nociceptin inhibition of spinal nociception in amphibians and perhaps all vertebrates.

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Spinal analgesic activity of orphanin FQ/nociceptin and its fragments

Abstract

Section snippets

Acknowledgements

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