LOCUS-COERULEUS ACTIVATION BY COLON DISTENSION - ROLE OF CORTICOTROPIN-RELEASING FACTOR AND EXCITATORY AMINO-ACIDS

The present study was designed to elucidate the neurotransmitters invo lved in activation of the noradrenergic nucleus, locus coeruleus, by d istention of the distal colon. Locus coeruleus spontaneous discharge r ate was recorded from halothane-anesthetized rats before, during and a fter distention of the colon produced by inflation of a balloon cathet er with varying volumes of water. Locus coeruleus activation by colon distention was volume-dependent and reversible. Activation of cortical electroencephalographic activity was temporally correlated with locus coeruleus activation during colon distention and prolonged distention (greater than 2 min) resulted in tachyphalaxis to both locus coeruleu s and cortical electroencephalagraphic activation. The corricotropin-r eleasing factor antagonist, DPheCRF(12-41), administered intracerebrov entricularly (3 mu g) Or microinfused into the locus coeruleus (10 ng) significantly attenuated locus coeruleus activation produced by lower , but not higher magnitudes of colon distention, implicating corticotr opin-releasing factor afferents to the locus coeruleus in this respons e. Consistent with this, prior exposure to 30 min of footshock stress, which desensitizes locus coeruleus neurons to corticotropin-releasing factor, produced a similar attenuation of locus coeruleus activation by low, but not high magnitudes of distention. Kynurenic acid, adminis tered intracerebroventricularly (5 mu mol), significantly antagonized locus coeruleus activation by all magnitudes of colon distention. Howe ver, this excitatory amino acid antagonist was ineffective when admini stered directly into the locus coeruleus (0.3 nmol). Together, these f indings suggest that low magnitudes of colon distention activate the l ocus coeruleus-noradrenergic system via corticotropin-releasing factor release within the locus coeruleus and that excitatory amino acid neu rotransmission at a site distal to the locus coeruleus is necessary fo r this response. Activation of the locus coeruleus-noradrenergic syste m during colon distention may serve as a cognitive limb of the periphe ral parasympathetic response. This activation may also play a role in disorders characterized by comorbidity of colonic and psychiatric symp toms, such as irritable bowel syndrome.