Nocistatin reverses nociceptin inhibition of glutamate release from rat brain slices

doi:10.1016/S0014-2999(98)00545-7

European Journal of Pharmacology

Volume 356, Issues 2–3, 4 September 1998, Pages R1-R3

https://doi.org/10.1016/S0014-2999(98)00545-7 Get rights and content

Abstract

We have examined the effects of the recently described heptadecapeptide nocistatin on K⁺-evoked glutamate release from rat cerebrocortical slices in vitro. In vivo, nocistatin reverses the action of nociceptin. Nocistatin (100 nM, n=7) did not inhibit K⁺-evoked glutamate release alone. Nociceptin (100 nM) inhibited glutamate release by 51.7±8.3% (P<0.05, n=6) and this was fully reversed by nocistatin (100 nM). Nocistatin also appears to be an antagonist of nociceptin action in vitro.

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Acknowledgements

We would like to thank The Wellcome Trust for financial support.

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Cited by (51)

Decreased Nociceptin Receptors Are Related to Resilience and Recovery in College Women Who Have Experienced Sexual Violence: Therapeutic Implications for Posttraumatic Stress Disorder
2019, Biological Psychiatry
Citation Excerpt :
It also disrupts the retrieval and reconsolidation of previously consolidated traumatic memories (52). N/OFQ inhibits K+ stimulated glutamate release by ∼38% in rodent cerebellum and midbrain slices—the exact same regions in which we observed clinical correlations between NOP and intrusive symptoms (53). The mechanism by which N/OFQ disrupts trauma-related memory consolidation involves its ability to inhibit glutamate release and interrupt N-methyl-D-aspartic acid–mediated long-term potentiation (43,54).
Posttraumatic stress disorder (PTSD) is a stress disorder that develops in only some individuals following a traumatic event. Data suggest that a substantial fraction of women recover after sexual violence. Thus, the investigation of stress and antistress neuropeptides in this sample has the potential to inform the neurochemistry of resilience following trauma. Nociceptin is an antistress neuropeptide in the brain that promotes resilience in animal models of PTSD.
[¹¹C]NOP-1A positron emission tomography was used to measure the in vivo binding to nociceptin receptors in 18 college women who had experienced sexual violence irrespective of whether they met DSM-5 diagnostic criteria for PTSD. [¹¹C]NOP-1A data from 18 healthy control subjects were also included to provide a contrast with the sexual violence group. [¹¹C]NOP-1A total distribution volume (V_T) in the regions of interest were measured with kinetic analysis using the arterial input function. The relationships between regional V_T and Clinician-Administered PTSD Scale for DSM-5 total symptom and subscale severity were examined using correlational analyses.
No differences in [¹¹C]NOP-1A V_T were noted between the sexual violence and control groups. V_T in the midbrain and cerebellum were positively correlated with PTSD total symptom severity in the past month before positron emission tomography. Intrusion/re-experiencing and avoidance subscale symptoms drove this relationship. Stratification of subjects by a DSM-5 PTSD diagnosis and contrasting their V_T with that in control subjects showed no group differences.
Decreased midbrain and cerebellum nociceptin receptors are associated with less severe PTSD symptoms. Medications that target nociceptin should be explored to prevent and treat PTSD.
Central N/OFQ-NOP Receptor System in Pain Modulation
2016, Advances in Pharmacology
Citation Excerpt :
These cellular events following NOP receptor activation reduce synaptic transmission, by either reducing neurotransmitter release via presynaptically located NOP receptors or inhibiting neuronal excitability via postsynaptically located NOP receptors (Connor, Vaughan, Chieng, & Christie, 1996; Connor, Yeo, & Henderson, 1996; Knoflach, Reinscheid, Civelli, & Kemp, 1996). Indeed, NOP receptor activation has been shown to inhibit the release of a variety of neurotransmitters (e.g., glutamate, gamma aminobutyric acid (GABA), substance P, and noradrenaline) in the CNS (Nicol et al., 1998; Nicol, Lambert, Rowbotham, Smart, & McKnight, 1996; Schlicker & Morari, 2000). Although NOP receptor activation induces a similar pattern of intracellular events as MOP, DOP, and KOP receptors, NOP receptor-mediated effects on pain modulation are more complicated than MOP receptor activation.
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.
Effects of intraplantar Nocistatin and (±)-J 113397 injections on nociceptive behavior in a rat model of inflammation
2012, Pharmacology Biochemistry and Behavior
Citation Excerpt :
The spinal injection of NST diminished the flinching behavior in phase 1, but not phase 2, of the formalin test in rats (Yamamoto and Sakashita, 1999), while supraspinal injection of the peptide has an antihyperalgesic effect on the inflammatory hyperalgesia induced by carrageenan/kaolin (Nakagawa et al., 1999) and reversed the nociceptive effect of N/OFQ and its antagonistic effect against analgesia caused by the selective opioid agonists (Scoto et al., 2005). NST, however, does not displace [3H]N/OFQ-binding (Nicol et al., 1998) or attenuate N/OFQ inhibition of forskolin-induced cAMP accumulation in cells transfected with the NOP receptor (Okuda-Ashitaka et al., 1998) and neither mimics nor blocks NOP receptor-mediated Ca2+ current inhibition (Connor et al, 1999). However NST either failed to affect the N/OFQ-induced actions or even behaves as an agonist (Ishihara et al., 2002; Xu et al., 1999; Zádori et al., 2008).
Nocistatin (NST) and Nociceptin/Orphanin FQ (N/OFQ) are derived from the same precursor protein, pre-proN/OFQ, and exert opposite effects on the modulation of pain signals. However, the role of the peripheral N/OFQ and the NOP receptor, which is located at the endings of sensory nerves, in inflammatory pain was not ascertained. NST administered intrathecally (i.t.) prevented the nociceptive effects induced by i.t. N/OFQ and PGE₂. Moreover an up regulation of N/OFQ was shown in the rat in response to peripheral inflammation. Here, we investigated the effects of intraplantar (i.pl.) administration of functional N/OFQ and NOP receptor antagonists in a rat model of inflammatory pain. Our findings showed that i.pl. injection of (±)-J 113397, a selective antagonist of the NOP receptor, and NST, the functional N/OFQ antagonist, prior to carrageenan significantly reduced the paw allodynic and thermal hyperalgesic threshold induced by the inflammatory agent. The resulting antiallodynic and antihyperalgesic effects by co-administering NST and (±)-J 113397 prior to carrageenan were markedly enhanced, and the basal latencies were restored. Thus, it is likely that the peripheral N/OFQ/NOP receptor system contributes to the abnormal pain sensitivity in an inflammatory state.
Nocistatin excites rostral agranular insular cortex-periaqueductal gray projection neurons by enhancing transient receptor potential cation conductance via G<inf>αq/11</inf>-PLC-protein kinase C pathway
2010, Neuroscience
Citation Excerpt :
Therefore, N/OFQ hyperpolarization of RAIC–PAG pyramidal neurons plays a specific role in mediating N/OFQ-induced supraspinal hyperalgesia in vivo. Except antagonizing N/OFQ-induced supraspinal hyperalgesia, NST also reverses N/OFQ inhibition of glutamate release from brain slices, N/OFQ-induced anxiolytic-like effect, hyperphagia and impairment of learning and memory (Nicol et al., 1998; Hiramatsu and Inoue, 1999; Gavioli et al., 2002). NST fails to compete with nociceptin for [3H] N/OFQ binding and block N/OFQ inhibition of adenylate cyclase in mammalian cells expressing NOP receptors (Okuda-Ashitaka and Ito, 2000).
Rostral agranular insular cortex (RAIC) projects to periaqueductal gray (PAG) and inhibits spinal nociceptive transmission by activating PAG-rostral ventromedial medulla (RVM) descending antinociceptive circuitry. Despite being generated from the same precursor prepronociceptin, nocistatin (NST) and nociceptin/orphanin FQ (N/OFQ) produce supraspinal analgesic and hyperalgesic effects, respectively. Prepronociceptin is highly expressed in the RAIC. In the present study, we hypothesized that NST and N/OFQ modulate spinal pain transmission by regulating the activity of RAIC neurons projecting to ventrolateral PAG (RAIC–PAG). This hypothesis was tested by investigating electrophysiological effects of N/OFQ and NST on RAIC–PAG projection neurons in brain slice. Retrogradely labeled RAIC–PAG projection neurons are layer V pyramidal cells and express mRNA of vesicular glutamate transporter subtype 1, a marker for glutamatergic neurons. N/OFQ hyperpolarized 25% of RAIC–PAG pyramidal neurons by enhancing inwardly rectifying potassium conductance via pertussis toxin-sensitive G_αi/o. In contrast, NST depolarized 33% of RAIC–PAG glutamatergic neurons by causing the opening of canonical transient receptor potential (TRPC) cation channels through G_αq/11-phospholipase C-protein kinase C pathway. There were two separate populations of RAIC–PAG pyramidal neurons, one responding to NST and the other one to N/OFQ. Our results suggest that G_αq/11-coupled NST receptor mediates NST excitation of RAIC–PAG glutamatergic neurons, which is expected to cause the supraspinal analgesia by enhancing the activity of RAIC–PAG–RVM antinociceptive pathway. Opposite effects of NST and N/OFQ on supraspinal pain regulation are likely to result from their opposing effects on RAIC–PAG pyramidal neurons.
Nocistatin and nociceptin exert opposite effects on the excitability of central amygdala nucleus-periaqueductal gray projection neurons
2009, Molecular and Cellular Neuroscience
Central amygdala nucleus (CeA)-periaqueductal gray (PAG) pathway is the component of descending antinociceptive circuitry. Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) produce supraspinal pronociceptive and antinociceptive effects, respectively. We hypothesized that opposite effects of N/OFQ and NST on supraspinal pain modulation result from their opposing effects on the excitability of CeA-PAG projection neurons. This hypothesis was tested by investigating electrophysiological effects of N/OFQ and NST on medial CeA neurons that project to PAG (CeA_M-PAG). N/OFQ hyperpolarized CeA_M-PAG projection neurons by enhancing inwardly rectifying potassium conductance. In contrast, NST depolarized CeA_M-PAG neurons by causing the opening of TRPC cation channels via G_αq/11-PLC-PKC pathway. CeA_M-PAG neurons hyperpolarized by N/OFQ express CRF or neurotensin mRNA. NST-responsive CeA_M-PAG neurons contain CRF or substance P mRNA. Our study provides the evidence that the molecular and cellular basis for opposite effects of N/OFQ and NST on supraspinal pain regulation is their opposing effects on the excitability of peptidergic CeA_M-PAG neurons.
GABA<inf>A</inf> signalling is involved in N/OFQ anxiolytic-like effects but not in nocistatin anxiogenic-like action as evaluated in the mouse elevated plus maze
2008, Peptides
Nociceptin/orphanin FQ (N/OFQ) and nocistatin are two neuropeptides originated from the same precursor prepronociceptin/orphanin FQ (ppN/OFQ). N/OFQ is the endogenous ligand of the NOP receptor, while the target of action of nocistatin is still unknown. N/OFQ modulates various biological functions, including anxiety. Conversely, nocistatin either behaves as a functional N/OFQ antagonist or evokes per se effects opposite to those of N/OFQ. Here we investigated the interaction between the anxiolytic-like effects of N/OFQ and the anxiogenic-like action of nocistatin with those evoked by GABA_A receptor ligands in the mouse elevated plus maze. The anxiogenic-like effects of the GABA_A receptor antagonist pentylenetetrazol (20 mg/kg; intraperitoneal, i.p.) were abolished by the co-treatment with N/OFQ (10 pmol; intracerebroventricular, i.c.v.) while potentiated by the administration of nocistatin (0.01 pmol; i.c.v.). The anxiolytic-like effects of the benzodiazepine receptor agonist diazepam (0.75 mg/kg, i.p.) were reversed by nocistatin (0.1 pmol; i.c.v.), whereas signs of sedation were observed when mice were co-treated with diazepam and N/OFQ (3 pmol). Interesting enough, the i.p. treatment with flumazenil (1 mg/kg) blocked the anxiolytic-like effects of N/OFQ (10 pmol; i.c.v.), but not the anxiogenic effect elicited by nocistatin. Collectively, our findings suggest that the effects on anxiety elicited by pentylenetetrazol and diazepam can be counteracted or potentiated in the presence of N/OFQ and nocistatin. In addition, the effects on anxiety of N/OFQ, but not nocistatin, appear to be dependent on the benzodiazepine site of the GABA_A receptor.

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Abstract

Section snippets

Acknowledgements

TIPS

Eur. J. Pharmacol.

Depression of glutamatergic transmission by nociceptin in the neonatal hemisected spinal cord preparation in vitro

Br. J. Pharmacol.

Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor

Nature

Rapid communication
Nocistatin reverses nociceptin inhibition of glutamate release from rat brain slices

Isolation and structure of the endogenous agonist of opioid receptor-like ORL₁ receptor