Corticotropin-releasing hormone increases tonic but not sensory-evoked activity of noradrenergic locus coeruleus neurons in unanesthetized rats

OBJECTIVE: Stress-induced release of noradrenaline (NA) from locus coeruleus (LC) neurons is mainly regulated by corticotropin-releasing hormone (CRH). Tyrosine is a precursor of NA and plays an intriguing role in the regulation of NA release. DESIGN: We studied the effects of injecting CRH into the LC using a novel bilateral approach which relies on the mainly ipsilateral projections of LC neurons allowing stimulation of one hemisphere while using the other as control. To analyze the modification of the CRH effect, tyrosine was given intraperitoneally. A combination of CRH and its antagonist d-Phe was administered for validation of the specificity of CRH effects. METHODS: Wistar rats were used in all experiments. Injections were made through fused silica capillaries implanted into both LCs and microdialysis samples were collected bilaterally from the prefrontal cortex (PFM) every 20 min for 1 h before and 3 h after injections. The effects of LC stimulation were investigated by determining 3-methoxy-4-hydroxyphenylglycol (MHPG) in the dialysates. RESULTS: Following CRH injection into one LC and contralateral infusion of artificial cerebrospinal fluid (aCSF), MHPG levels, which are indicative of NA release, increased only in the ipsilateral PFM. These effects were blocked by d-Phe. Simultaneous administration of tyrosine i.p. led to a significant prolongation of MHPG release. CONCLUSIONS: These data provide the first physiological evidence of unilateral LC projections with the bilateral stimulation design proving to be a very valuable tool for the study of LC firing rate, to decrease number of animals and time expenditure. Prolongation of MHPG release after tyrosine supplementation is most likely due to increased NA synthesis.

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Brain alterations in depression

Acta Neuropsychiatrica ◽

10.1017/s0924270800035717 ◽

2000 ◽

Vol 12 (2) ◽

pp. 54-58 ◽

Cited By ~ 2

Author(s):

Witte J.G. Hoogendijk ◽

Gerben Meynen ◽

Piet Eikelenboom ◽

Dick F. Swaab

Keyword(s):

Locus Coeruleus ◽

Brain Structures ◽

Cell Loss ◽

Corticotropin Releasing Hormone ◽

Strong Decrease ◽

Theoretical Rationale ◽

Releasing Hormone ◽

Brain Noradrenaline ◽

Pituitary Adrenal Axis ◽

Aminergic Systems

SUMMARYThis article describes a number of studies by our research group to find brain structures that may be involved in the symptoms of idiopathic depression, depression in Alzheimer's disease and depression in Parkinson's disease. Until recently, idiopathic depression has generally been related to deficiencies of aminergic systems. In Alzheimer patients we found a strong decrease in the number of neurons in the locus coeruleus and brain noradrenaline concentrations, but in depressed Alzheimer patients we did not find an extra de crease. This is in agreement with the finding that there is no cell loss in the locus coeruleus in idiopathic depression. We did find, however, that the number of corticotropin-releasing hormone-, vasopressin- and oxytocin expressing neurons, the number of corticotropin-releasing hormone neurons co-expressing vasopressin and the amount of corticotropin-releasing hormone -mRNA in idiopathic depression were strongly increased in the paraventricular nucleus of the hypothalamus. This result supports the hypothesis on the pathogenetic involvement of the hypothalamo-pituitary-adrenal axis in depression and is of clinical relevance, since it may provide a theoretical rationale for antidepressive therapy with CRH antagonists.

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Locus coeruleus stimulation by corticotropin-releasing hormone suppresses in vitro cellular immune responses

Journal of Neuroscience ◽

10.1523/jneurosci.14-10-06033.1994 ◽

1994 ◽

Vol 14 (10) ◽

pp. 6033-6040 ◽

Cited By ~ 31

Author(s):

S Rassnick ◽

AF Sved ◽

BS Rabin

Keyword(s):

Immune Responses ◽

Locus Coeruleus ◽

Corticotropin Releasing Hormone ◽

Releasing Hormone ◽

Cellular Immune Responses ◽

Cellular Immune

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An amygdalo-parabrachial pathway regulates pain perception and chronic pain

10.1101/2020.01.10.902205 ◽

2020 ◽

Author(s):

Charles Raver ◽

Olivia Uddin ◽

Yadong Ji ◽

Ying Li ◽

Nathan Cramer ◽

...

Keyword(s):

Chronic Pain ◽

Acute Pain ◽

Pain Perception ◽

Central Nucleus ◽

Infraorbital Nerve ◽

Corticotropin Releasing Hormone ◽

Releasing Hormone ◽

Evoked Activity ◽

Novel Target ◽

Rats And Mice

AbstractThe parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to PB neurons from the central nucleus of the amygdala (CeA). Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges—responses that far outlast the stimulus—compared to controls. PB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that—in both rats and mice—PB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naïve animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain.Significance StatementWe describe a novel pathway, consisting of inhibition by dynorphin, somatostatin and corticotropin-releasing hormone expressing neurons in the central nucleus of the amygdala that project to the parabrachial nucleus (PB). We show that this pathway regulates the activity of pain-related neurons in PB, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

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