The unconditioned fear produced by morphine withdrawal is regulated by μ- and κ-opioid receptors in the midbrain tectum

Ross, Jas; Ávila, Milton A.V.; Ruggiero, Rafael Naime; Nobre, Manoel Jorge; Brandão, Marcus Lira; Castilho, V.M.

doi:10.1016/j.bbr.2009.05.033

Cited by 8 publications

(2 citation statements)

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“…In this study, we analyzed epigenetic changes in response to acute and chronic morphine induction in 10 regions of the rat brain reported to be implicated in response to opiates and the formation of addiction: the midbrain contains the VTA that has been consistently implicated in addiction 23,24 ; the pons contains the locus coeruleus that is key in the integration of opioid and stress signalling and which is served by innervation from the paraventricular nucleus of the hypothalamus 25 ; the inferior and superior colliculus regulate response to opiate withdrawal through reduced activation of mu-opioid receptor signalling 26,27 ; the cerebral cortex (containing the dorsomedial prefrontal cortex), hippocampus and cerebellum are implicated in reinforcement of drug-seeking beheaviors [28][29][30] ; the medulla oblongata is crucial in pain modulation and opiate withdrawal behaviors 31 ; and the thalamus whose function is disrupted in opiate dependence 32,33 . We measured global 5-methylcytosine and 5-hydroxymethylcytosine levels, and analyzed the DNA methylation of genes previously identified as implicated in morphine tolerance (Bdnf, Comt, Il1b, Il6, Nr3c1…”

Section: Introductionmentioning

confidence: 99%

The effect of morphine upon DNA methylation in ten regions of the rat brain

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et al. 2017

Epigenetics

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A and Guo, L (2017) The effect of morphine upon DNA methylation in ten regions of the rat brain. Epigenetics, 12 (12 AbstractMorphine is one of the most effective analgesics in medicine. However, its use is associated with the development of tolerance and dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided insight into mechanisms possibly underlying addiction. In this study, we sought to identify epigenetic changes in ten regions of the rat brain following acute and chronic morphine exposure. We analyzed DNA methylation of six nuclear-encoded genes implicated in brain function (Bdnf, Comt, Il1b, Il6, Nr3c1 and Tnf) and three mitochondrially-encoded genes (Mtco1, Mtco2 and Mtco3), and measured global 5-methylcytosine (5-mc) and 5-hydroxymethylcytosine (5-hmc) levels. We observed differential methylation of Bdnf and Il6 in the pons, Nr3c1 in the cerebellum, and Il1b in the hippocampus in response to acute morphine exposure (all p<0.05). Chronic exposure was associated with differential methylation of Bdnf and Comt in the pons, Nr3c1 in the hippocampus and Il1b in the medulla oblongata (all p<0.05). Global 5-mc levels significantly decreased in the superior colliculus following both acute and chronic morphine exposure, and increased in the hypothalamus following chronic exposure. Chronic exposure was also associated with significantly increased global 5-hmc levels in the cerebral cortex, hippocampus and hypothalamus, but significantly decreased in the midbrain. Our results demonstrate, for the first time, highly localized epigenetic changes in the rat brain following acute and chronic morphine exposure. Further work is required to elucidate the potential role of these changes in the formation of tolerance and dependence.

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Section: Introductionmentioning

confidence: 99%

The effect of morphine upon DNA methylation in ten regions of the rat brain

Barrow

Byun

et al. 2017

Epigenetics

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“…The periaqueductal gray is a major integration site of nociceptive and fear stimuli and hence is an important driver of fear-induced analgesia (Behbehani, 1995). Indeed, Oprm1 agonist morphine injected into the PAG decrease fear and promotes analgesia, while morphine withdrawal is associated with anxiogenesis (De Ross et al, 2009; Halladay and Blair, 2012; Twardowschy and Coimbra, 2015). In humans, obesity is associated with decreased Oprm1 availability in the brain, which would support the notion that obesity raises fear levels (Karlsson et al, 2015; Pitman and Borgland, 2015).…”

Section: Discussionmentioning

confidence: 99%

How Metabolic State May Regulate Fear: Presence of Metabolic Receptors in the Fear Circuitry

et al. 2018

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Metabolic status impacts on the emotional brain to induce behavior that maintains energy balance. While hunger suppresses the fear circuitry to promote explorative food-seeking behavior, satiety or obesity may increase fear to prevent unnecessary risk-taking. Here we aimed to unravel which metabolic factors, that transfer information about the acute and the chronic metabolic status, are of primary importance to regulate fear, and to identify their sites of action within fear-related brain regions. We performed a de novo analysis of central and peripheral metabolic factors that can penetrate the blood–brain barrier using genome-wide expression data across the mouse brain from the Allen Brain Atlas (ABA). The central fear circuitry, as defined by subnuclei of the amygdala, the afferent hippocampus, the medial prefrontal cortex and the efferent periaqueductal gray, was enriched with metabolic receptors. Some of their corresponding ligands were known to modulate fear (e.g., estrogen and thyroid hormones) while others had not been associated with fear before (e.g., glucagon, ACTH). Additionally, several of these enriched metabolic receptors were coexpressed with well-described fear-modulating genes (Crh, Crhr1, or Crhr2). Co-expression analysis of monoamine markers and metabolic receptors suggested that monoaminergic nuclei have differential sensitivity to metabolic alterations. Serotonergic neurons expressed a large number of metabolic receptors (e.g., estrogen receptors, fatty acid receptors), suggesting a wide responsivity to metabolic changes. The noradrenergic system seemed to be specifically sensitive to hypocretin/orexin modulation. Taken together, we identified a number of novel metabolic factors (glucagon, ACTH) that have the potential to modulate the fear response. We additionally propose novel cerebral targets for metabolic factors (e.g., thyroid hormones) that modulate fear, but of which the sites of action are (largely) unknown.

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