Long-term alterations of colonic nerve-mast cell interactions induced by neonatal maternal deprivation in rats

Background: Neonatal maternal deprivation induces colonic alterations in adult rats, such as hypersensitivity to distension or an increase in paracellular permeability, characteristics of irritable bowel syndrome (IBS) patients. Recent studies described neuroimmune alterations in the colonic mucosa of IBS patients. Methods: Male Wistar rats were submitted to maternal deprivation for 3 h daily during postnatal days 2-14, and were sacrificed at 4 or 12 weeks of age. Control pups were left undisturbed with their dam. Results: Colonic mast cell hyperplasia was observed at 4 and 12 weeks in maternally deprived rats, and was associated with an increase in protease content. Mucosal nerve fibre density assessed by protein gene product (PGP) 9.5 immunoreactivity was increased at 12 weeks but not at 4 weeks, while calcitonin gene-related protein (CGRP)-immunoreactive fibres remain constant. Synaptogenesis assessed by synaptophysin immunostaining was increased at 4 weeks but not at 12 weeks. The number of mast cells in close proximity to PGP 9.5-or CGRP- immunoreactive fibres was greater at both 4 and 12 weeks. Expression of neurokinin NK1 receptors in the spinal cord was enhanced at 12 weeks. No significant change in total mast cell number, PGP 9.5 immunoreactivity and mast cells associated with PGP 9.5-immunoreactive fibres was observed in the jejunum. Treatment of pups with anti-nerve growth factor (NGF) antibodies abolished the increases in synaptogenesis and in the number of mast cells in close proximity to nerve fibres observed 4 weeks after maternal deprivation. Conclusions: Neonatal maternal deprivation induces closer association of colonic mast cells with nerves, which is similar to that seen in IBS patients. NGF is a possible mediator of this effect.