The CRF(1) receptor antagonist, NBI-35965, abolished the activation of locus coeruleus neurons induced by colorectal distension and intracisternal CRF in rats.
Corticotropin-releasing factor (CRF) receptors have been reported to play a role in tonic colorectal distension (CRD)-induced activation of locus coeruleus (LC) neurons. We examined the influence of repeated phasic CRDs and intracisternal (ic) CRF on the spontaneous discharge rate of LC neurons in chloral hydrate-anesthetized rats and the role of CRF receptors using the nonselective CRF(1)/CRF(2) antagonist, astressin, and the water-soluble CRF(1) receptor antagonist, NBI-35965. Two consecutive phasic CRDs (43.7 +/- 1.1 mm Hg, 30 s each) at a 10-min interval increased LC activity to 184.9 +/- 15% and 171.9 +/- 12.2%, respectively. There was no difference in magnitude, onset (within 1 s), and duration (5-7 min) of the LC responses between the 1st and 2nd CRDs. CRF (300 ng/rat, ic) injected 10 min after the 2nd CRD increased LC activity to 191.1 +/- 11.2%. Astressin (3 mug, ic) completely blocked the 2nd CRD- and ic CRF-induced LC activation. Neither ic vehicle nor astressin influenced basal LC neuronal activity. NBI-35965 (10 mg/kg, iv) prevented the 2nd CRD- and ic CRF-induced LC neuronal activation, while at 5 mg significantly reduced the LC response to the 2nd CRD by 80%, but did not block that of ic CRF injected 30 min later. These findings indicate a primary role of brain CRF interacting with CRF(1) receptors in mediating the activation of LC neurons in response to a phasic CRD within the nociceptive range (>40 mm Hg). This activation may have relevance to irritable bowel syndrome characterized by lower pain threshold to CRD and hypervigilance to colonic input.
Kosoyan
Hovsep P
HP
CURE: Digestive Diseases Research Center and Center for Neurovisceral Sciences and Women's Health, Veterans Affairs Medical Center, Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
Grigoriadis
Dimitri E
DE
Taché
Yvette
Y
D000073:Acenaphthenes / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002097:C-Reactive Protein / Q000187:drug effects*; D003106:Colon / Q000294:innervation* / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage* / Q000494:pharmacology; D004347:Drug Interactions; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008125:Locus Coeruleus / Q000166:cytology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000099052:CRF Receptor, Type 1; D000099153:Pentraxins
D000073:Acenaphthenes; D002097:C-Reactive Protein; D003346:Corticotropin-Releasing Hormone; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000099153:Pentraxins; C504986:6-cyclopropylmethyl-2-(2,4-dichlorophenyl)-7-ethyl-4-methyl-7,8-dihydro-6H-1,3,6,8a-tetraazaacenaphthylene; C104416:astressin