Antagonism of orexin type 1 receptors in the locus coeruleus attenuates signs of naloxone-precipitated morphine withdrawal in rats

Azizi, Hossein; Mirnajafi‐Zadeh, Javad; Rohampour, Kambiz; Semnanian, Saeed

doi:10.1016/j.neulet.2010.07.050

Cited by 46 publications

(21 citation statements)

References 41 publications

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“…Our results indicate that the blockade of OX1R significantly decreased several of the somatic signs of naloxone-precipitated morphine withdrawal as well as the global score, suggesting that activation of OX1R pathways might positively modulate the somatic expression of opiate withdrawal. These data are in agreement with previous results showing that administration of SB334867 directly into LC to rats attenuates signs of morphine withdrawal [16]. In addition, mice lacking the pre-propeptide encoding for orexins or pretreated with SB334867 display markedly reduced symptoms of opiate withdrawal [14], [15].…”

Section: Discussionsupporting

confidence: 93%

Hypothalamic Orexin-A Neurons Are Involved in the Response of the Brain Stress System to Morphine Withdrawal

et al. 2012

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Both the hypothalamus-pituitary-adrenal (HPA) axis and the extrahypothalamic brain stress system are key elements of the neural circuitry that regulates the negative states during abstinence from chronic drug exposure. Orexins have recently been hypothesized to modulate the extended amygdala and to contribute to the negative emotional state associated with dependence. This study examined the impact of chronic morphine and withdrawal on the lateral hypothalamic (LH) orexin A (OXA) gene expression and activity as well as OXA involvement in the brain stress response to morphine abstinence. Male Wistar rats received chronic morphine followed by naloxone to precipitate withdrawal. The selective OX1R antagonist SB334867 was used to examine whether orexins' activity is related to somatic symptoms of opiate withdrawal and alterations in HPA axis and extended amygdala in rats dependent on morphine. OXA mRNA was induced in the hypothalamus during morphine withdrawal, which was accompanied by activation of OXA neurons in the LH. Importantly, SB334867 attenuated the somatic symptoms of withdrawal, and reduced morphine withdrawal-induced c-Fos expression in the nucleus accumbens (NAc) shell, bed nucleus of stria terminalis, central amygdala and hypothalamic paraventricular nucleus, but did not modify the HPA axis activity. These results highlight a critical role of OXA signalling, via OX1R, in activation of brain stress system to morphine withdrawal and suggest that all orexinergic subpopulations in the lateral hypothalamic area contribute in this response.

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Section: Discussionsupporting

confidence: 93%

Hypothalamic Orexin-A Neurons Are Involved in the Response of the Brain Stress System to Morphine Withdrawal

et al. 2012

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“…One possible explanation of a lack of SB334867effect may be that the doses used were not behaviorally relevant. This interpretation is unlikely, however, because it has been shown by others that SB334867 at doses even lower than the ones tested in the present study attenuated physical symptoms of morphine withdrawal as well as cocaine seeking-behavior when injected in the locus coeruleus and in the ventral tegmental area, respectively (Azizi et al, 2010;James et al, 2011). Another more acceptable hypothesis is that the effect of a peripheral administration (i.e., not site specific) of SB334867 may be attributable to its action in brain regions other than the PVT.…”

Section: Discussioncontrasting

confidence: 60%

Orexin-A/Hypocretin-1 Mediates Cocaine-Seeking Behavior in the Posterior Paraventricular Nucleus of the Thalamus via Orexin/Hypocretin Receptor-2

Matzeu

Kerr

Weiss

et al. 2016

J Pharmacol Exp Ther

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Orexin/hypocretin (Orx/Hcrt) projections from the lateral hypothalamus to the paraventricular nucleus of the thalamus (PVT) are implicated in drug addiction. Specifically, the posterior section of the PVT (pPVT) innervates brain structures that modulate motivated behavior. This study investigated the role of pPVTOrx/Hcrt transmission in cocaine-seeking behavior. Because the effects of Orx/Hcrt are mediated by two Orx/Hcrt receptors (Hcrt-r1 and Hcrt-r2), we examined the extent to which Hcrt-r1 and Hcrt-r2 are involved in Orx/Hcrt-induced cocaine seeking. Male Wistar rats were made cocaine dependent by selfadministering cocaine 6 hours/day (long access) for 21 days. After self-administration training, the rats underwent daily extinction training, during which cocaine was withheld. After extinction, the rats were injected into the pPVT with Orx-A/Hcrt-1 (0-2 mg) alone or, using a single dose of 0.5 mg, in combination with an Hcrt-r1 antagonist (SB334867; 0-15 mg) or an Hcrt-r2 antagonist (TCSOX229; 0-15 mg). Orx-A/Hcrt-1 alone reinstated (primed) cocaine seeking. Unexpectedly, coadministration of Orx-A/Hcrt-1 with SB334867 did not have any effects on Orx-A/Hcrt-1-induced reinstatement, whereas when coadministered with Orx-A/Hcrt-1, TCSOX229 prevented cocaine-seeking behavior. These results indicate that Hcrt-r2 in the pPVT mediates the reinstating effect of Orx-A/Hcrt-1 in animals with a history of cocaine dependence and further identify Hcrt-r2 as a possible molecular target that can guide future therapeutic approaches for the prevention of drug-seeking behavior.

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“…A prior study showed an involvement of orexin receptors in LC in somatic signs of opiate withdrawal (Azizi et al, 2010). However, in our study LH orexin neurons that project to LC were not significantly Fos-activated after preference testing.…”

Section: Discussionmentioning

confidence: 99%

Lateral Hypothalamic Orexin/Hypocretin Neurons That Project to Ventral Tegmental Area Are Differentially Activated with Morphine Preference

Richardson

Aston‐Jones²

2012

J. Neurosci.

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Orexin (or hypocretin) is synthesized exclusively in dorsomedial, perifornical, and lateral hypothalamus (LH). These neurons are implicated in several functions, including reward processing. We examined ventral tegmental area (VTA) as a possible site of orexin action for drug preference during protracted morphine abstinence, and studied functional topography of orexin projections to VTA. Male Sprague Dawley rats were used to investigate whether orexin cells that project to VTA exhibit Fos activation with morphine conditioned place preference (CPP), and whether these cells exhibit increased Fos with morphine CPP during protracted abstinence. Unilateral injections of a retrograde tracer (WGA-Au, 350–400nl) were made into VTA or a non-reward area, locus coeruleus (LC), and morphine or placebo pellets were implanted for 14 d. Approximately 2 wk after pellet removal (post-dependence), CPP conditioning and testing were conducted. Triple labeling for WGA-Au, Fos and orexin revealed that the percentage of VTA-projecting orexin neurons Fos activated on the CPP test day significantly increased in post-dependent (versus non-dependent) rats, and was exclusive to LH orexin neurons (not dorsomedial or perifornical). Post-dependent animals showed a positive correlation between CPP scores and percentages of Fos-activated, caudal VTA-projecting LH orexin cells. Unlike afferents to caudal VTA, percentages of rostral VTA-projecting LH orexin cells that were Fos-activated showed a positive correlation with CPP only in non-dependent animals. Fos in LC-projecting orexin cells was not correlated with CPP in any group. These results indicate that VTA is a heterogeneous and functionally significant target of orexin neurons for morphine reward during protracted abstinence.

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Antagonism of orexin type 1 receptors in the locus coeruleus attenuates signs of naloxone-precipitated morphine withdrawal in rats

Cited by 46 publications

References 41 publications

Hypothalamic Orexin-A Neurons Are Involved in the Response of the Brain Stress System to Morphine Withdrawal

Hypothalamic Orexin-A Neurons Are Involved in the Response of the Brain Stress System to Morphine Withdrawal

Orexin-A/Hypocretin-1 Mediates Cocaine-Seeking Behavior in the Posterior Paraventricular Nucleus of the Thalamus via Orexin/Hypocretin Receptor-2

Lateral Hypothalamic Orexin/Hypocretin Neurons That Project to Ventral Tegmental Area Are Differentially Activated with Morphine Preference

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