Faculty Opinions recommendation of Anxiogenic and antinociceptive effects induced by corticotropin-releasing factor (CRF) injections into the periaqueductal gray are modulated by CRF1 receptor in mice.

Upon metamorphosis, amphibian tadpoles lose their tails through programmed cell death induced by thyroid hormone (T3). Before transformation, the tail functions as an essential locomotory organ. The binding protein for the stress neuropeptide corticotropin-releasing factor (CRF; CRF-BP) is strongly up-regulated in the tail of Xenopus tadpoles during spontaneous or T3-induced metamorphosis. This finding led us to investigate physiological roles for CRF and CRF-BP in tadpole tail. We found CRF, CRF-BP, and functional CRF1 receptor in tail and CRF and functional CRF1 receptors, but not CRF-BP, in the tail muscle-derived cell line XLT-15. CRF, acting via the CRF1 receptor, slowed spontaneous tail regression in explant culture and caused a reduction in caspase 3/7 activity. CRF increased, but stable CRF-BP overexpression decreased, [3H]thymidine incorporation in XLT-15 cells. Overexpression of CRF-BP in vivo accelerated the loss of tail muscle cells during spontaneous metamorphosis. Lastly, exposure of tail explants to hypoxia increased CRF and urocortin 1 but strongly decreased CRF-BP mRNA expression. We show that CRF is expressed in tadpole tail, is up-regulated by environmental stressors, and is cytoprotective. The inhibitory binding protein for CRF is regulated by hormones or by environmental stressors and can modulate CRF bioactivity.

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Pro- and Anti-Nociceptive Effects of Corticotropin-Releasing Factor (CRF) in Central Amygdala Neurons Are Mediated Through Different Receptors

Journal of Neurophysiology ◽

10.1152/jn.01148.2007 ◽

2008 ◽

Vol 99 (3) ◽

pp. 1201-1212 ◽

Cited By ~ 74

Author(s):

Guangchen Ji ◽

Volker Neugebauer

Keyword(s):

Protein Kinase ◽

Receptor Antagonist ◽

Background Activity ◽

Pain Modulation ◽

Protein Kinase Inhibitors ◽

Corticotropin Releasing Factor ◽

Evoked Responses ◽

Inhibitory Effects ◽

Crf1 Receptor ◽

Crf2 Receptor

Corticotropin-releasing factor (CRF) is not only a stress hormone but also acts as a neuromodulator outside the hypothalamic-pituitary-adrenocortical axis, playing an important role in anxiety, depression, and pain modulation. The underlying mechanisms remain to be determined. A major site of extra-hypothalamic expression of CRF and its receptors is the amygdala, a key player in affect-related disorders such as anxiety. The latero-capsular division of the central nucleus of the amygdala (CeLC) is also important for pain modulation and pain affect. This study analyzed the effects of CRF on nociceptive processing in CeLC neurons and the contribution of CRF1 and CRF2 receptors and protein kinases A and C. Extracellular single-unit recordings were made from CeLC neurons in anesthetized adult rats. All neurons responded more strongly to noxious than innocuous mechanical stimulation of the knee. Evoked responses and background activity were measured before and during administration of CRF into the CeLC by microdialysis. CRF was administered alone or together with receptor antagonists or protein kinase inhibitors. CRF (0.01–1 μM; concentrations in microdialysis probe; 15 min) facilitated the evoked responses more strongly than background activity; a higher concentration (10 μM) had inhibitory effects. Facilitation by CRF (0.1 μM) was reversed by a selective CRF1 receptor antagonist ( NBI27914 , 10 μM) but not a CRF2 receptor antagonist (astressin-2B, 100 μM) and by a protein kinase A (PKA) inhibitor (KT5720, 100 μM) but not a protein kinase C inhibitor (GF109203X, 100 μM). Inhibitory effects of CRF (10 μM) were reversed by astressin-2B. These data suggest that CRF has dual effects on amygdala neurons: CRF1 receptor-mediated PKA-dependent facilitation and CRF2 receptor-mediated inhibition.

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Functional and anatomical characterization of corticotropin-releasing factor receptor subtypes of the rat spinal cord involved in somatic pain relief

10.21203/rs.3.rs-290650/v1 ◽

2021 ◽

Author(s):

Shaaban Mousa ◽

Mohammed Shaqura ◽

Baled Khalefa ◽

Li Li ◽

Mohammed Al-madol ◽

...

Keyword(s):

Spinal Cord ◽

Western Blot ◽

Opioid Receptor ◽

Radioligand Binding ◽

Corticotropin Releasing Factor ◽

Receptor Subtypes ◽

Inhibitory Interneurons ◽

Rat Spinal Cord ◽

Somatic Pain ◽

Antinociceptive Effects

Abstract Corticotropin-releasing factor (CRF) orchestrates our body’s response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway, although the involvement of the CRF receptors of subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. This study aimed to examine CRF-R1 and CRF-R2 expression within spinal cord of rats with Freund’s complete adjuvant-induced hindpaw inflammation using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis, Western blot, immunohistochemistry, and radioligand binding. Moreover, paw pressure algesiometry examined antinociceptive effects of intrathecal (i.t.) CRF and their possible antagonism through CRF-R1 and/or CRF-R2 selective antagonists as well as opioid receptor antagonist naloxone. Our results demonstrated mainly CRF-R2 mRNA, protein, binding sites and immunoreactivity in dorsal horn of rat spinal cord. In parallel, i.t. CRF as well as CRF-R2 agonists elicited potent antinociceptive effects which are dose-dependent and antagonized exclusively by i.t. CRF-R2 (K41498), but not CRF-R1 (NBI35965) antagonist. Moreover, i.t. CRF elicited inhibition of somatic pain that was dose-dependently reversed by the opioid antagonist naloxone. Consistently, double immunofluorescence confocal microscopy showed CRF-R2 on enkephalin (ENK) containing inhibitory interneurons in close opposition of incoming, mu-opioid receptor-immunoreactive nociceptive neurons but not on pre- nor on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonist inhibits inflammatory somatic pain which occurs most predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons resulting in endogenous opioid-mediated pain inhibition.

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