Research reportCorticotropin-releasing factor and systemic capsaicin-sensitive afferents are involved in abdominal surgery-induced Fos expression in the paraventricular nucleus of the hypothalamus
Introduction
Fos is a nuclear phosphoprotein product of the immediate–early gene c-fos. Together with c-jun, c-fos regulates the transcription of genes having an AP-1 consensus element and mediates the genomic response to extracellular neuronal stimuli 50, 51, 64. In addition, the induction of Fos protein is increasingly used to identify activated neurons that participate in uni- and multi-synaptic pathways in the central nervous system 24, 50, 51. Numerous stressful stimuli of somato-cutaneous or visceral origin and anesthetics induce Fos expression in a discrete population of spinal and brain neurons and activate hypothalamic corticotropin-releasing factor (CRF) containing neurons 15, 20, 27, 35, 36, 46. We recently defined the pattern of Fos expression in the brain induced 1–3 h after abdominal surgery performed in rats under short enflurane anesthesia 6, 10. In particular, Fos-positive neurons were observed in the nucleus tractus solitarii (NTS) recognized to integrate somato- and viscero-visceral reflexes and the paraventricular nucleus of the hypothalamus (PVN), supraoptic nucleus (SON) and central amygdala known to participate in the endocrine and autonomic responses to stress 45, 52, 55, 65, 66, 70. However, the neuronal pathways and biochemical events whereby abdominal surgery activates these brain nuclei are still unknown.
Compelling studies established that capsaicin-sensitive splanchnic primary afferent fibers and activation of supraspinal CRF receptors play a role in mediating abdominal surgery-induced gastric stasis in rats 6, 7, 33, 34, 57. Systemic capsaicin or capsaicin applied on the celiac/superior mesenteric ganglia, known to alter selectively unmyelinated primary afferent terminals [32], reduced the delay in gastric emptying induced by abdominal surgery 6, 7, 31, 33, 34, 57, 67. Moreover, the CRF antagonists, α-helical CRF9–41, [d-Phe12, Nle21,38, Cα-MeLeu37] and astressin 26, 31, 47, 59, injected intracisternally prevented the delay in gastric emptying induced by abdominal surgery in rats 6, 31, 44, 67. These functional observations suggest that capsaicin-sensitive afferents and CRF receptors may modulate the activity of a subset of neurons in the brain, particularly those which play a role in mediating postoperative gastric ileus in rats. In support of this possibility, there is evidence that the central injection of CRF induced Fos expression in specific hypothalamic, limbic, pontine and medullary nuclei 3, 5, 19, 37, 53. In addition, the CRF antagonist injected intracerebroventricularly (i.c.v.) prevents the activation of locus coeruleus and PVN neurons induced by hemodynamic or psychological (restraint) stress 12, 22, 38, 69. Systemic capsaicin was also found to attenuate Fos expression in the spinal cord and brain neurons in response to chemical nociceptive visceral stimuli 8, 11. Therefore, in the present study we investigated whether capsaicin pretreatment and α-helical CRF9–41 injected i.c.v. influence the activation of specific brain neurons induced by abdominal surgery performed under short anesthesia in rats.
Section snippets
Animals
Adult male Sprague-Dawley albino rats (Harlan, Indianapolis, IN) weighing 250–300 g, were individually housed under standardized conditions of illumination (12:12-h light: dark cycle, starting at 06:00), humidity and temperature (21±2°C) for at least 7 days before the experiments. Rats had ad libitum access to a standard rat diet (Purina Lab Chow) and water except for 17–20 h before the experiments when they were deprived of food, but not water. Experiments were performed between 10:00 and
Effect of capsaicin on abdominal surgery-induced Fos expression
In animals pretreated with vehicle, instillation of 1% NH4OH induced eye wipes during the following 10 s period (7.5±1.2 in the right eye, and 7.3±1.1 in the left eye). Beyond the 10-s period, animals never exhibited additional wiping or any signs of discomfort or damage. In rats pretreated with capsaicin, no corneal chemosensory response was observed either in the right (0.0±0.0) or the left eye (0.0±0.0) after instillation of 1% NH4OH.
One hour after abdominal surgery in vehicle-pretreated
Discussion
Abdominal surgery performed under short enflurane anesthesia in s.c. or i.c.v. vehicle-treated rats induced a similar pattern of Fos expression in the brain as previously reported [10]. Fos-labelled cells were localized in the NTS, A1/C1, caudal ventral medulla and cuneate, spinal trigeminal, and lateral parabrachial nuclei. This procedure also generates considerable labelling in the PVN, SON and central nucleus of the amygdala. However, in rats injected i.c.v. with vehicle, there was, in
Acknowledgements
Supported by the National Institute of Arthritis, Metabolism and Digestive Disease, Grants DK-33061, and the National Institute of Mental Health, Grant MH-00663. The authors wish to thank Paul Kirshbaum for help in the preparation of the manuscript.
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