Injection of orphanin FQ/nociceptin into the periaqueductal gray suppresses the forebrain-elicited vocalization in the guinea pig

doi:10.1016/S0304-3940(98)00956-2

Neuroscience Letters

Volume 260, Issue 2, 29 January 1999, Pages 113-116

https://doi.org/10.1016/S0304-3940(98)00956-2 Get rights and content

Abstract

Electrical stimulation of the caudoventral part of the anterior cingulate cortex (AC) evokes a species-specific vocalization in the guinea pig. After injections of glutamate receptor antagonists into the periaqueductal gray (PAG) regions where the AC projected, the forebrain-elicited vocalization (FEV) was suppressed completely. This result indicated that the FEV was induced at least partly by glutamatergic activation of PAG neurons. Injection of orphanin FQ/nociceptin (OFQ/N) into the PAG profoundly suppressed the FEV. This inhibitory effect of OFQ/N was not antagonized by naloxone, an opioid receptor antagonist. Since OFQ/N was reported to modify the glutamatergic transmission, the present results suggest that OFQ/N exerts influences upon the vocalization by regulating the glutamatergic inputs into the PAG.

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Acknowledgements

The authors appreciate the Narishige Neuroscience Research Foundation and Grant D from the Kansai Medical University.

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Cited by (17)

Responses of guinea pigs to brain stimulation during isolation: Examining the transition from "protest" to depressive-like behavior
2013, Neurology Psychiatry and Brain Research
Citation Excerpt :
The PAG, in turn, is broadly involved in emotional and pain-related processing,26–28 has been implicated in anxiety as well as panic,29–31 and mediates the control of emotionally driven motor responses,32,33 including guinea pig separation vocalizations.33,34 Earlier studies of brain stimulation in guinea pigs utilized acute stimulation protocols, often with anesthetized animals.11,13,35,36 To date, the effect of repeated stimulation of vocalization-producing brain regions in guinea pigs has not been examined.
It has been known for over 60 years that social isolation of children and the young of some non-human primate species elicits agitated vocalizing and other active behavior, which eventually segues into a second, passive stage of depressive-like responding. How this transition occurs remains obscure. A leading hypothesis proposes that continued activation of the neural substrates underlying the vocalization response drives the onset of the passive stage. Guinea pigs also exhibit a 2-stage, active/passive response during isolation, and much of the identification of neural structures underlying the separation vocalization was based on studies of electrical brain stimulation in guinea pigs. We, therefore, asked whether repeated electrical stimulation of brain sites subserving the isolation vocalization would increase later depressive-like responding in guinea pigs. In Experiments 1 and 2, female guinea pigs with stimulating electrodes placed in the bed nucleus of the stria terminalis (BNST) and periaqueductal gray, respectively, were tested over 10 daily, 30-min trials. Stimulation of either site produced elevated levels of vocalizing, which diminished over repeated isolation trials. However, there was no increase in depressive-like responding either before or after subsequent trials, or during probe trials in which no stimulation was administered. In Experiment 3, stimulation of the BNST increased vocalizing during the first 30-min of the 3-h isolation period, but produced no increase in depressive-like behavior during the remainder of the trial. In sum, continued activation of brain sites underlying isolation vocalizations was not sufficient, in and of itself, to induce later depressive-like responding.
Role of homocysteic acid in the guinea pig (Cavia porcellus) anterior cingulate cortex in tonic immobility and the influence of NMDA receptors on the dorsal PAG
2010, Behavioural Brain Research
Citation Excerpt :
These data suggest that the dPAG may be involved in the modulation of the behavioural responses triggered by the ACC. Vocalisation responses, for example, elicited by electrical stimulation of the ACC, may be abolished by administration of an NMDA antagonist into the PAG [31]. Since the dPAG is activated by ACC stimulation, it is reasonable to hypothesise that it contributes to diminishing the TI response by recruiting the more caudal substrates in the medullary region, such as the nucleus raphe magnus (NRM), for instance.
Tonic immobility (TI) is an innate defensive behaviour elicited by physical restriction and postural inversion, and is characterised by a profound and temporary state of akinesis. Our previous studies demonstrated that glutamatergic stimulation of the dorsomedial/dorsolateral portion of periaqueductal gray matter (dPAG) decreases the duration of TI in guinea pigs (Cavia porcellus). Furthermore, evidence suggests that the anterior cingulate cortex (ACC) constitutes an important source of glutamate for the dPAG. Hence, in the current study, we investigated the effects of microinjection of the excitatory amino acid (EAA) agonist dl-homocysteic acid (DLH) and the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 into the ACC on the duration of TI in guinea pigs. We also assessed the effect of the NMDA receptor antagonist (MK-801) into the dorsal periaqueductal gray matter (dPAG) prior to DLH microinjection into the ACC on the TI duration in the guinea pig. Our results demonstrated that DLH microinjections into the ACC decreased the duration of TI. This effect was blocked by previous MK-801 microinjections into the ACC or into the dPAG. The MK-801 microinjections alone did not influence TI duration. These results provide the new insight that EAAs in the ACC can decrease the duration of TI. The mechanism seems to be dependent on the NMDA receptors present in the ACC and in the dPAG.
Effects of nociceptin/orphanin FQ receptor (NOP) agonist, Ro64-6198, on reactivity to acute pain in mice: Comparison to morphine
2008, European Journal of Pharmacology
The aim of the present study was to clarify the role of nociceptin system in pain modulation. The effects of the synthetic nociceptin (NOP) receptor agonist, Ro64-6198 ((1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one), on reactivity to acute noxious stimuli were assessed in C57BL/6N (B6) mice in tail-flick, hot-plate and shock threshold tests. The mu receptor agonist, morphine, was used in each study for comparison. In the tail-flick test, morphine (4 and 8 mg/kg, i.p.) produced analgesia, while Ro64-6198 (0.3, 1 and 3 mg/kg, i.p.) increased pain sensitivity. The effects of Ro64-6198 were seen in naïve but not in mice previously habituated to testing conditions, indicating that increased pain sensitivity may be due to inhibition of stress-induced analgesia. In the hot-plate and the shock threshold tests, Ro64-6198 produced analgesia in B6 mice, like morphine. These effects were reproduced in wild-type but not in NOP receptor knockout mice. Finally, when injected conjointly at subthreshold doses, Ro64-6198 (1 mg/kg) and morphine (1 mg/kg) acted in additive manner to reduce pain sensitivity in the hot-plate test. Together these results show that systemic activation of NOP receptors produced bidirectional changes in pain sensitivity depending on the experimental conditions. They also suggest that central NOP and mu receptors may inhibit reactivity to acute noxious stimuli via independent neural mechanisms.
Nociceptin/orphanin FQ: Pain, stress and neural circuits
2005, Life Sciences
First isolated some 10 years ago as the endogenous ligand for the “orphan opioid receptor” (ORL-1, now designated NOP), nociceptin/orphanin FQ (N/OFQ) has proved to be a potent inhibitory neuropeptide found across the neuraxis. Because of the homologies between opioids and N/OFQ, functional studies of this peptide have focused most heavily on pain and analgesia. This behavioral literature has been marked by a lack of consistency across laboratories, but much of the data can be explained by considering the potent inhibitory actions of N/OFQ in well-defined modulatory circuits. Presently, the most closely studied such circuit is the rostral ventromedial medulla (RVM), where administration of N/OFQ can block opioid analgesia (by inhibiting opioid-activated pain-inhibiting neurons), but under other conditions produces apparent hypoalgesia (by inhibiting pain-facilitating neurons). The net behavioral effect of N/OFQ in the RVM thus depends on whether experimental conditions are such that the pain-facilitating or pain-inhibiting neurons are active at the time the peptide is given.
An important recent finding is that N/OFQ antagonists have antinociceptive properties when given supraspinally. Although the likelihood of interactions between stress and analgesia systems must be considered in interpreting these data, they suggest that N/OFQ antagonists have potential as clinically useful analgesic drugs.
Impact of environmental housing conditions on the emotional responses of mice deficient for nociceptin/orphanin FQ peptide precursor gene
2003, Behavioural Brain Research
Nociceptin/orphanin FQ (N/OFQ) is a newly discovered neuropeptide that has been implicated in the neurobiological regulation of the behavioral responses to stress and fear. To investigate the role of this peptide in the expression of stress/anxiety-related behaviors in mice, a gene targeting approach to disrupt N/OFQ in the pre-proN/OFQ gene was used. The impact of environmental housing conditions (single and social housing) was assessed on N/OFQ-knockout male and female mice in different experimental paradigms known to trigger distinctive types of stress and anxiety states. Neurological examination of homozygous mutant adult animals indicated that basic neurological functions (vision, audition, olfaction, tactile and pain sensitivity, motor performances) were normal. When housed individually, N/OFQ-knockout animals displayed responses similar to control animals in behavioral tests of emotional reactivity (behavioral despair, locomotor activity, light–dark preference, and acoustic startle tests). In contrast, increased emotional responses were detected when individually housed mice were crowded together (five per cage) under conditions of competitive access to food, water, space, and social contacts. Under those conditions, male mice deficient for N/OFQ developed greater home–cage aggression and increased fear/anxiety-like behaviors in the light–dark and acoustic startle tests, when compared to their wild-type littermates. Group-housed female mutants also showed higher level of anxiety in the acoustic startle test, but needed additional restrain stress to express detectable levels of anxiety in the light–dark test. These data indicate a clear environment-induced rise in fear reactions of N/OFQ-knockout mice. They further suggest that N/OFQ system is essential for development of adequate coping strategies to acute and chronic stress.
Mother's voice "buffers" separation-induced receptor changes in the prefrontal cortex of Octodon degus
2003, Neuroscience
Although the potential vulnerability of the postnatally developing brain toward adverse environmental influences is generally recognized, relatively little is known about the basic mechanisms involved. The plasticity and adaptability of the postnatally developing brain in response to adverse emotional experiences was analyzed in the South American Octodon degus. Our study revealed that repeated brief separation from the parents and exposure to an unfamiliar environment induces an up-regulation of dopamine (D1) and 5-hydroxytrytamine (5HT1_A)-receptor density in the precentral medial, anterior cingulate, prelimbic and infralimbic cortices in female pups. No significant changes of gamma aminobutyric acid (GABA_A) receptor density were found in deprived animals of both genders.
The acoustic presence of the mother during parental separation suppressed the D1-receptor up-regulation as well as the 5-HT1_A-receptor up-regulation, again only in the female pups. These results demonstrate that that early adverse emotional experience alters aminergic function within the prefrontal cortex in the female but not the male brain. The mother’s voice, a powerful emotional signal, can protect the developing cortex from separation-induced receptor changes.

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Injection of orphanin FQ/nociceptin into the periaqueductal gray suppresses the forebrain-elicited vocalization in the guinea pig

Abstract

Section snippets

Acknowledgements

Pharmacol. Biochem. Behav.

Biochem. Biophys. Res. Commun.

Behav. Brain Res.

FEBS Lett.

Mol. Brain Res.

Immunohistochemical localization of ORL-1 in the central nervous system of the rat

J. Comp. Neurol.

The functional characteristics of the midbrain periaqueductal gray

Prog. Neurobiol.

Guinea-pig vocalization: their structure, causation and function

Z. Tierpsychol.