The CRF 1 receptor antagonist, NBI-35965, abolished the activation of locus coeruleus neurons induced by colorectal distension and intracisternal CRF in rats

Abstract

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 μg, 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.