Functional abdominal pain affects about 17% of high school students and accounts for 2-4% of all pediatric office visits. The factors that lead to symptoms are not well understood. The question of whether adverse events experienced in early life can prime a child to develop chronic pain is one that requires further study. Thoraco-lumbar spinal dorsal horn neurons that receive input from afferents of the superficial skin and deep somatic domain are also excited by visceral afferents. N-methyl-D-aspartate (NMDA) and neurokinin (NK) receptors may contribute to central sensitization and play a major role in the development of somatic and visceral hyperalgesia. The goal of this proposal is to investigate alterations in visceral sensation and underlying neuronal plasticity in the spinal cord that result from painful somatic stimulation early in development. A neonatal rat model of somatic pain induced through low pH saline injections will be used to understand the mechanisms involved in neuroplasticity leading to altered visceral sensation in adulthood. In adult rats, two low pH injections in the gastrocnemius (GN) muscle result in transient visceral hyperalgesia (Gastroenterology 126:1082-9, 2004). It is hypothesized that noxious stimulation early in development results in increased expression of NMDA and NK1 receptors and the neuropeptide substance P in the thoraco-lumbar spinal cord. The neonatal stimulus consequently induces hyperexcitabilty of spinal neurons and permanent alterations in visceral sensation (J Physiol. 572:775-87, 2006). The hypothesis will be tested systematically by first evaluating alterations in visceral sensitivity in awake, adult rats after neonatal noxious somatic stimulation and examining the effects of NMDA or NK receptor antagonists (specific aim 1). In adult sensitized animals, electrophysiological recordings from spinal neurons in areas of viscero-somatic convergence and dorsal roots will be performed and their response to NMDA or NK receptor antagonists will be tested (specific aim 2). Neurochemical changes in the spinal cord and DRG will be evaluated by examining mRNA expression and immunoreactivity of these receptors and substance P at different stages of development (specific aim 3). This study will be the first systematic evaluation of chronic visceral hyperalgesia that results from a non-inflammatory somatic stimulus in early life.
| Miranda, Adrian; Mickle, Aaron; Bruckert, Mitchell et al. (2014) NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation. Eur J Pharmacol 744:28-35 |
| Miranda, A; Mickle, A; Schmidt, J et al. (2011) Neonatal cystitis-induced colonic hypersensitivity in adult rats: a model of viscero-visceral convergence. Neurogastroenterol Motil 23:683-e281 |
| Mickle, Aaron; Sood, Manu; Zhang, Zhihong et al. (2010) Antinociceptive effects of melatonin in a rat model of post-inflammatory visceral hyperalgesia: a centrally mediated process. Pain 149:555-64 |
| Miranda, A; Mickle, A; Medda, B et al. (2009) Altered mechanosensitive properties of vagal afferent fibers innervating the stomach following gastric surgery in rats. Neuroscience 162:1299-306 |
