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Pattern of c-fos mRNA induction in rat brain by acute morphine
H B Gutstein1, J L Thome, J L Fine
1Mental Health Research Institute, University of Michigan, Ann Arbor 48109-0720, USA. gutstein@umich.edu
Abstract:
Initially, opioid signaling had been thought to be mainly inhibitory in nature. However, it has been shown that opioids can activate specific signaling pathways and induce immediate early gene (IEG) transcription in brain. IEGs can then regulate the transcription of other genes, leading to changes in neuronal function in response to extracellular stimuli. This study was designed to identify brain regions that demonstrate specific induction of the IEG c-fos, a component of the AP-1 transcription factor, in response to acute morphine, and to contrast this induction with the stressful effects of the injection itself. Rats received either 10 mg/kg morphine or an equivalent volume of saline injected subcutaneously. Animals were then sacrificed 15, 30, or 60 min after injection. Specific induction of c-fos mRNA by morphine was seen in dorsomedial caudate-putamen, paraventricular nucleus of the thalamus, central and intralaminar thalamic nuclei, dorsal central grey, superior colliculus, lateral parabrachial nucleus, inferior olivary complex, and caudal nucleus tractus solitarius. These findings represent the first complete anatomical mapping of c-fos induction in rat brain, and show that acute morphine administration alters gene expression in several areas related to known functional properties of opioids. However, regions showing c-fos induction are not all classically associated with opioid receptors and opioid-mediated effects. These findings are considered in the context of the effects of opioids on neural circuitry as well as direct, receptor-mediated effects of morphine on neural cells.
Insights
Morphine activates immediate early gene (IEG) c-fos transcription in specific rat brain regions, revealing novel opioid signaling pathways. This study maps c-fos induction, highlighting effects beyond classical opioid receptor associations.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Opioid signaling was initially considered primarily inhibitory.
- Recent findings indicate opioids can activate signaling pathways and induce immediate early gene (IEG) transcription.
- IEGs regulate gene transcription, altering neuronal function in response to stimuli.
Purpose of the Study:
- To identify brain regions with specific induction of the immediate early gene c-fos in response to acute morphine administration.
- To differentiate c-fos induction by morphine from the stress response associated with injection.
Main Methods:
- Rats received subcutaneous injections of morphine (10 mg/kg) or saline.
- Animals were sacrificed at 15, 30, and 60 minutes post-injection.
- Quantification of c-fos mRNA expression in specific brain regions.
Main Results:
- Morphine specifically induced c-fos mRNA in the dorsomedial caudate-putamen, thalamus (paraventricular nucleus, central, and intralaminar nuclei), dorsal central grey, superior colliculus, lateral parabrachial nucleus, inferior olivary complex, and caudal nucleus tractus solitarius.
- This represents the first comprehensive anatomical map of c-fos induction by acute morphine in the rat brain.
- Observed c-fos induction occurred in areas not all classically linked to opioid receptors or opioid-mediated effects.
Conclusions:
- Acute morphine administration alters gene expression in multiple brain areas, some with known opioid functions.
- The findings suggest that morphine's effects on neural circuitry and gene expression extend beyond direct, receptor-mediated actions.
- This study provides a detailed neuroanatomical basis for understanding the complex effects of morphine on brain function.