Elsevier

Brain Research

Volume 756, Issues 1–2, 9 May 1997, Pages 114-124
Brain Research

Research report
Locus coeruleus activation by colon distention: role of corticotropin-releasing factor and excitatory amino acids

https://doi.org/10.1016/S0006-8993(97)00116-9Get rights and content

Abstract

The present study was designed to elucidate the neurotransmitters involved in activation of the noradrenergic nucleus, locus coeruleus, by distention of the distal colon. Locus coeruleus spontaneous discharge rate was recorded from halothane-anesthetized rats before, during and after distention of the colon produced by inflation of a balloon catheter 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 coeruleus and cortical electroencephalographic activation. The corticotropin-releasing factor antagonist, DPheCRF12–41, administered intracerebroventricularly (3 μg) or microinfused into the locus coeruleus (10 ng) significantly attenuated locus coeruleus activation produced by lower, but not higher magnitudes of colon distention, implicating corticotropin-releasing factor afferents to the locus coeruleus in this response. 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, administered intracerebroventricularly (5 μmol), significantly antagonized locus coeruleus activation by all magnitudes of colon distention. However, this excitatory amino acid antagonist was ineffective when administered directly into the locus coeruleus (0.3 nmol). Together, these findings suggest that low magnitudes of colon distention activate the locus coeruleus-noradrenergic system via corticotropin-releasing factor release within the locus coeruleus and that excitatory amino acid neurotransmission at a site distal to the locus coeruleus is necessary for this response. Activation of the locus coeruleus-noradrenergic system during colon distention may serve as a cognitive limb of the peripheral parasympathetic response. This activation may also play a role in disorders characterized by comorbidity of colonic and psychiatric symptoms, such as irritable bowel syndrome.

Introduction

The nucleus locus coeruleus (LC) gives rise to a widespread projection system that provides the major source of norepinephrine in the forebrain [41]. Activation of LC neurons and subsequent norepinephrine release onto forebrain target neurons has been implicated in arousal and attention 4, 20. The LC-noradrenergic (LC-NE) system is activated by sensory stimuli of various modalities, as demonstrated in unanesthetized monkeys [19], rats [5], and cats [1]. Additionally, metabolic 16, 30, cardiovascular 14, 49and visceral stimuli 15, 34increase LC discharge rate and this is often associated with activation of forebrain electroencephalographic (EEG) activity 34, 35, 44, indicating that the magnitude of LC activation produced by these stimuli is sufficient to impact on forebrain targets (see also [40]for review). LC activation by physiological stimuli may be important in initiating the forebrain activation that occurs in parallel with autonomic responses to these physiological stimuli.

Of the physiological stimuli that have been demonstrated to activate the LC, hypotension 14, 35, 44, 49and pelvic visceral stimuli [34]have been studied with regard to the mechanism by which they increase LC discharge rate. The effects of hypotension, produced by nitroprusside infusion, have been demonstrated to be dependent on endogenous corticotropin-releasing factor (CRF) and pharmacological evidence suggests that CRF inputs to the LC are required for these effects 35, 44, 49. In contrast, LC responses to a pelvic visceral stimulus, bladder distention, appear to be independent of CRF, but require activation of excitatory amino acid receptors in the LC [34]. A similar role for excitatory amino acid neurotransmission in the LC has been proposed for LC activation by sciatic nerve stimulation [17]and opiate withdrawal.

Colon distention is another pelvic visceral stimulus that increases LC discharge rate [15]. However, the circuitry and neurotransmitters underlying this activation are unknown. The same neuronal pathways that mediate LC activation by bladder distention could also underlie LC activation by colon distention, as both are pelvic visceral stimuli. Alternatively, a role for CRF in this response is also possible. Recent anatomical studies identified neurons in Barrington's nucleus that were retrogradely labeled from both the LC and lumbosacral spinal cord, some of which were CRF-immunoreactive [45]. As Barrington's projections to the sacral parasympathetic nucleus could influence colon function, it is possible that CRF-Barrington's neurons that diverge to project to the LC and spinal cord could coactivate the brain noradrenergic system and colonic efferents in response to colon distention. Indeed, this would be consistent with the hypothesized role of CRF in irritable bowel syndrome [42], a disorder characterized by both psychiatric and colonic dysfunctions [26].

In the present study single unit LC activity was recorded from halothane-anesthetized rats during distention of the distal colon and the ability of antagonists of CRF or excitatory amino acids to prevent LC responses to colon distention was used to elucidate a role of these putative neurotransmitters in this response.

Section snippets

Surgery

The procedures used for recording LC discharge of halothane-anesthetized rats were similar to those previously reported [46]. Male Sprague-Dawley rats (Taconic Farms; approximately 300 g) were anesthetized with a 1–2% halothane-in-air mixture administered through a nose cone. Rats were positioned in a stereotaxic instrument using blunt ear bars, and the head was oriented at a 15° angle to the horizontal plane (nose down). Body temperature was constantly monitored and maintained at 37°C with a

Effects of colon distention on LC discharge rate and cortical EEG

The mean spontaneous discharge rate recorded from 94 LC neurons prior to colon distention was 1.7±0.1 Hz. Colon distention of 2 min duration resulted in a reversible, volume-dependent increase in LC discharge (F(2,36)=12.4, P<0.001) (Fig. 1). Distention with 0.5, 1.0 and 3.0 ml volumes increased LC discharge by 16.6±2.2%, 34.1±5.2%, and 59.1±6.6% above predistention rates, respectively. This increase was significant for all volumes (P<0.01, Student's t-test for matched pairs; Fig. 1B). Fig. 1,

Discussion

The present study confirms and extends the findings of Elam and coworkers [15], which demonstrated that colon distention increases LC spontaneous discharge rates of halothane-anesthetized rats, by characterizing the neuromediators of this response. The differential pharmacological sensitivity of LC activation elicited by different magnitudes of colon distention suggests that heterogeneous neural pathways are recruited depending on the magnitude of the stimulus. Sensitivity to intracoerulear

Acknowledgements

This work was supported by USPHS Grants MH40008, MH42796, MH00840 (RSDA award to R.J.V.) and MH11312 (an NRSA to S.M.L.). The authors acknowledge the generosity of Dr. Jean Rivier for the gift of DPheCRF12–41. The authors also wish to thank Mr. Bowen Kang for expert technical assistance.

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