Continuous stress-induced dopamine dysregulation augments PAP-I and PAP-II expression in melanotrophs of the pituitary gland

Konishi, Hiroyuki; Ogawa, Tokiko; Kawahara, Shinichi; Matsumoto, Sakiko; Kiyama, Hiroshi

doi:10.1016/j.bbrc.2011.02.064

Cited by 4 publications

(4 citation statements)

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“…In this model, a rat is placed in a cage with a very low level of water (1.5 cm in depth) for 1–5 days to induce a continuous level of stress (i.e., CS). Using this model, researchers have demonstrated that CS induces gene expression in several organs, as well as dramatic changes in the pituitary gland at the molecular and cellular levels [7–9, 11–13]. Rats exposed to CS exhibit significant activation of melanotrophs in the intermediate lobe and suppression of somatotrophs in the anterior lobe, as evidenced by the active secretion of alpha-melanocyte stimulating hormone (α-MSH) and significant decreases in growth hormone levels in sera [9, 10].…”

Section: Introductionmentioning

confidence: 99%

Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome

Yasui

Menjyo

Tokizane

et al. 2019

J Neuroinflammation

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Background Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model. Methods Chronic or continuous stress-loading (CS) model rats, housed in a cage with a thin level of water (1.5 cm in depth), were used. The von Frey test and pressure pain test were employed to measure pain behavior. The neuronal and microglial activations were immunohistochemically demonstrated with antibodies against ATF3 and Iba1. Electromyography was used to evaluate muscle activity. Results The expression of ATF3, a marker of neuronal hyperactivity or injury, was first observed in the lumbar dorsal root ganglion (DRG) neurons 2 days after CS initiation. More than 50% of ATF3-positive neurons simultaneously expressed the proprioceptor markers TrkC or VGluT1, whereas the co-expression rates for TrkA, TrkB, IB4, and CGRP were lower than 20%. Retrograde labeling using fluorogold showed that ATF3-positive proprioceptive DRG neurons mainly projected to the soleus. Substantial microglial accumulation was observed in the medial part of the dorsal horn on the fifth CS day. Microglial accumulation was observed around a subset of motor neurons in the dorsal part of the ventral horn on the sixth CS day. The motor neurons surrounded by microglia were ATF3-positive and mainly projected to the soleus. Electromyographic activity in the soleus was two to three times higher in the CS group than in the control group. These results suggest that chronic proprioceptor activation induces the sequential activation of neurons along the spinal reflex arc, and the neuronal activation further activates microglia along the arc. Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior. Conclusion Our results indicate that proprioceptor-induced microglial activation may be a key player in the initiation and maintenance of abnormal pain in patients with CFS. Electronic supplementary material The online version of this article (10.1186/s12974-019-1456-x) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome

Yasui

Menjyo

Tokizane

et al. 2019

J Neuroinflammation

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“…In this model, a rat is placed in a cage with a very low level of water (1.5 cm in depth) for 1–5 days to supply a continuous multiple stresses (i.e., CS). By using this model, we have investigated alterations in the expression of genes in several organs, and also reported dramatic changes in the pituitary gland at the molecular and cellular levels (Konishi et al, ; Ogawa et al, , 2012; Tokizane et al, ). For instance, the expression levels of metallopeptidases are markedly altered; the damage‐induced neuronal endopeptidase (Kiryu‐Seo et al, ; Nagata et al, ) is downregulated in the anterior lobe (AL; Ogawa et al, ), whereas the Neprilysin (another member of the metallopeptidase family) is upregulated in the intermediate lobe (IL; Ogawa et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, somatotrophs in the AL of pituitary exhibit atrophy, and growth hormone secretion is suppressed (Ogawa et al, ). A DNA microarray analysis in the pituitary gland further demonstrated a list of genes whose expression levels are altered (Konishi et al, ; Tokizane et al, ). Furthermore, rats exposed to CS show significant activation of melanotrophs in the IL, evidenced by the active secretion of alpha‐melanocyte stimulating hormone (α‐MSH), followed by the degeneration of melanotrophs (Ogawa et al, ).…”

Section: Introductionmentioning

confidence: 99%

A Chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation

Yasui

Yoshimura

Takeuchi

et al. 2014

Glia

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Patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) display multiple symptoms, such as chronic widespread pain, fatigue, sleep disturbance, and cognitive dysfunction. Abnormal pain sensation may be the most serious of these symptoms; however, its pathophysiology remains unknown. To provide insights into the molecular basis underlying abnormal pain in CFS and FMS, we used a multiple continuous stress (CS) model in rats, which were housed in a cage with a low level of water (1.5 cm in depth). The von Frey and Randall-Seritto tests were used to evaluate pain levels. Results showed that mechanical allodynia at plantar skin and mechanical hyperalgesia at the anterior tibialis (i.e., muscle pain) were induced by CS loading. Moreover, no signs of inflammation and injury incidents were observed in both the plantar skin and leg muscles. However, microglial accumulation and activation were observed in L4-L6 dorsal horn of CS rats. Quantification analysis revealed a higher accumulation of microglia in the medial part of Layers I-IV of the dorsal horn. To evaluate an implication of microglia in pain, minocycline was intrathecally administrated (via an osmotic pump). Minocycline significantly attenuated CS-induced mechanical hyperalgesia and allodynia. These results indicated that activated microglia were involved in the development of abnormal pain in CS animals, suggesting that the pain observed in CFS and FMS patients may be partly caused by a mechanism in which microglial activation is involved.

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“…Additionally, when rats had CS, melanotrophs in the intermediate lobe (IL) were substantially activated, α‐melanocyte stimulating hormone (α‐MSH) was secreted, and eventually melanotrophs showed a degenerative feature by their over‐activation (3). Furthermore, we found induced expression of the inhibitor of DNA binding/differentiation (6), and pancreatitis‐associated proteins (7) in the IL under CS. Intriguingly, all those changes observed in the IL were caused by changes in the expression level of dopamine in the hypothalamus.…”

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confidence: 86%

The Absence of Somatotroph Proliferation During Continuous Stress is a Result of the Lack of Extracellular Signal‐Regulated Kinase 1/2 Activation

Ogawa

Séi

Konishi

et al. 2012

J Neuroendocrinology

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The integrity of homeostasis can be affected by chronic stress, and hyposomatotropism is evident in chronic stress-associated illnesses. In the present study, we demonstrated that a continuous stress (CS) severely affected somatotrophs among hormone-secreting cells in the anterior lobe (AL) of the pituitary by using a rat CS model. Among AL cells, the proliferation of somatotrophs was almost entirely suppressed in rats that had 3-5 days of CS (5dCS), although other hormone-secreting cells continued to proliferate. The cell size of somatotrophs was reduced at 5dCS (P<0.01), the number of secretory granules was increased at 3dCS (P<0.01) and serum growth hormone (GH) was on declining trend during 1 to 5dCS, suggesting that GH release was inhibited. GH-releasing hormone (GHRH) mRNA level in the arcuate nucleus was transiently decreased, whereas its receptor expression in the AL was significantly increased in CS rats. When 5dCS rats were injected with GHRH, transient GH secretion was observed, whereas proliferation of somatotrophs did not occur. The GHRH administration failed to stimulate extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and the nuclear translocation of ERK in somatotrophs. These results suggest that somatotrophs of 5dCS rats expressed sufficient GHRH receptor, which could transfer a signal for GH release. However, the GHRH-induced proliferation signal was blocked somewhere between the receptor and ERK1/2. Because significant increase of corticosterone in the initial stage (the 1-3dCS) was observed in this model, the corticosterone may affect the signalling. Although the mechanism underlying the blockage of the proliferation signal in somatotrophs under CS remains unclear, these somatotrophic disorder, suggesting that the present animal model may be useful for understanding the molecular mechanisms of chronic stress-associated illnesses.

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Continuous stress-induced dopamine dysregulation augments PAP-I and PAP-II expression in melanotrophs of the pituitary gland

Cited by 4 publications

References 41 publications

Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome

Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome

A Chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation

The Absence of Somatotroph Proliferation During Continuous Stress is a Result of the Lack of Extracellular Signal‐Regulated Kinase 1/2 Activation

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