Increased fos-like immunoreactivity in the periaqueductal gray of anaesthetised rats during opiate withdrawal

doi:10.1016/0304-3940(94)11119-4

Neuroscience Letters

Volume 183, Issues 1–2, 2 January 1995, Pages 79-82

https://doi.org/10.1016/0304-3940(94)11119-4 Get rights and content

Abstract

Staining of c-fos-like-immunoreactivity (CFIR) in neurones was used to study neuronal activation within subdivisions of periaqueductal gray (PAG), and in locus coeruleus and ventral tegmental area during opiate withdrawal in awake and anaesthetised, morphine-dependent rats. The number of CFIR containing neurones was significantly increased during naloxone-precipitated withdrawal in lateral and ventrolateral, particularly the caudal ventrolateral PAG. No changes were observed in dorsal-intermediate or dorsal-caudal PAG. In awake rats, a similar but more generalised increase in CFIR was observed in PAG following naloxone-precipitated withdrawal. Increases in ventral tegmental area and locus coeruleus during naloxone-precipitated withdrawal under anaesthesia varied greatly between animals. Induction of c-fos in lateral and ventrolateral PAG during withdrawal is consistent with known functions of these regions, involving the integration of autonomic and somatic components of defensive and escape behaviours which are characteristic signs of opiate withdrawal.

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These studies identified piloerection, chills, severe diarrhea, nausea, vomiting, diaphoresis, myoclonus, and mydriasis as classical symptoms of withdrawal in mammals. Furthermore, naloxone-precipitated withdrawal produced defensive and escape behavior in awake rats [19]. When self-administration of heroin by rats was terminated after several weeks, ongoing food-reinforced behavior and locomotion was disrupted for several days [20].
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Ethanol withdrawal activates nitric oxide-producing neurons in anxiety-related brain areas
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Although the VLPAG has been involved in the occurrence of conditioned freezing behavior, the DLPAG appears to be more associated with the active forms of defensive behavior (Carrive et al., 1997; Vianna et al., 2003). Considering drug withdrawal effects, the VLPAG has been considered one of the possible substrates of the expression of somatic morphine withdrawal (Chieng et al., 1995). Furthermore, abrupt discontinuation of an ethanol diet decreased the stimulation threshold for freezing and escape after electrical stimulation of the DLPAG (Cabral et al., 2006).
The present study investigated whether nitric oxide (NO)–producing neurons localized in brain areas related to anxiety are also activated after ethanol withdrawal. Male Wistar rats were subjected to an oral ethanol self-administration procedure, in which they were offered 6–8% (vol/vol) ethanol solution for a period of 21 days followed by abrupt discontinuation of the treatment. Control animals received control dietary fluid for similar periods of time. Twenty-four or 48 h after ethanol discontinuation, the animals were exposed to the open field for 10 min. Two hours later, their brains were removed and processed for Fos immunohistochemistry and nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry (which is used to detect NO-producing neurons). Decreased exploratory activity was observed in animals subjected to 24-h withdrawal, characterized by a shorter distance traveled in the open field. Additionally, increased Fos expression was detected in brain areas, such as the cingulate and piriform cortices, several hypothalamic nuclei, amygdaloid nuclei, most subdivisions of the periaqueductal gray matter, and dorsal raphe nucleus (DRN). Ethanol withdrawal activated NO-producing neurons in the paraventricular nucleus (PVN) of the hypothalamus, dorsolateral periaqueductal gray matter (DLPAG), and DRN. The results show that ethanol withdrawal activates NO-producing neurons in the PVN, DLPAG, and DRN, which are brain areas implicated in the modulation of emotional, autonomic, and motor expression of anxiety-like behaviors.
Anxiety-like symptoms induced by morphine withdrawal may be due to the sensitization of the dorsal periaqueductal grey
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In the current work, we observed a pronounced increase of Fos-like immunoreactivity in its ventrolateral columns, which is in accordance with the type of behaviour displayed by the withdrawn animals, which was not explosive and resembled more behavioural inhibition, with the avoidance and consequent reduction of the exploration of the light compartment of the testing box. Regarding this point, to date, the PAG has been considered one of the possible substrates of the expression of somatic morphine withdrawal effects [27], supposedly through its ventral subdivision [29]. However, our results also showed elevated neural activation of its dorsal part in morphine withdrawn rats that displayed few physical withdrawal symptoms.
Withdrawal from morphine leads to the appearance of extreme anxiety accompanied of several physical disturbances, most of them linked to the activation of brainstem regions such as the locus coeruleus, ventral tegmental area, hypothalamic nuclei and periaqueductal grey (PAG). As anxiety remains one of the main components of morphine withdrawal the present study aimed to evaluating the influence of the dorsal aspects of the PAG on the production of this state, since this structure is well-known to be involved in defensive behaviour elicited by anxiety-evoking stimuli. Different groups of animals were submitted to 10 days of i.p. morphine injections, challenged 2 h after with an i.p. injection of naloxone (0.1 mg/kg), and submitted to the plus-maze, open-field and light–dark transition tests. The effects of morphine withdrawal on anxiety-induced Fos immunolabelling were evaluated in four animals that passed by the light–dark transition test randomly chosen for Fos-protein analysis. Besides the PAG, Fos neural expression was conducted in other brain regions involved in the expression of anxiety-related behaviours. Our results showed that morphine withdrawn rats presented enhanced anxiety accompanied of few somatic symptoms. Increased Fos immunolabelling was noted in brain regions well-known to modulate these states as the prelimbic cortex, nucleus accumbens, amygdala and paraventricular hypothalamus. Increased Fos labelling was also observed in the ventral and dorsal aspects of the PAG, a region involved in anxiety-related processes suggesting that this region could be a common neural substrate enlisted during anxiety evoked by dangerous stimuli as well as those elicited by opiate withdrawal.
Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain
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The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone-precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pre-treatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional 4 h. At the end of the experiment, animals were transcardially perfused and the brains were removed for verification of probe placement. Low dose naltrexone pre-treatment significantly attenuated withdrawal-induced increases of extracellular norepinephrine in the BNST, with a smaller effect in the FC. These findings suggest that alterations in norepinephrine release associated with withdrawal may be attenuated in forebrain targets of noradrenergic brainstem neurons that may underlie reduced behavioral signs of withdrawal following low dose naltrexone administration.

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^☆: Supported by the National Health and Medical Research Council of Australia (MJC no. 910831). Ms Kirsten Howard is gratefully acknowledged for technical assistance with image analyses. Morphine pellets were generously provided by the National Institute on Drug Abuse (USA).

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Increased fos-like immunoreactivity in the periaqueductal gray of anaesthetised rats during opiate withdrawal☆

Abstract

Eur. J. Pharmacol.

Trends Neurosci.

Life Sci.

Brain Res.

Neurosci. Lett.

Eur. J. Pharmacol.

Brain Res.

Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine

Nature

Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input

J. Neurosci.

Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats

Psychopharmacologia (Berlin)