Sensitization of developing sensory neurons during inflammation

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

ABSTRACT: Numerous pediatric disorders and surgical procedures performed on children lead to pain states yet it is well known that current pharmacological treatments for pain have significant adverse effects in children. Thus in order to develop more appropriate therapies for pediatric pain, a better understanding of how pain states are generated in children is of utmost importance. However, compared to adults, we know relatively little about the mechanisms of pediatric pain development. Patients with growth hormone deficiency (GHD) however, may provide insight into this clinical problem since these patients often display pain at rest in addition to deficits in growth. Moreover, treatment of these pain patients with GH provides analgesia. We have also found in neonatal mice with GHD that they display hyper-responsiveness to mechanical and thermal stimuli and the sensory afferents in these mutants are also sensitized to these stimuli. In addition, we found that cutaneous inflammation in normal mice produces a GHD state in the injured skin and observed sensitization of primary afferents and changes in pain-related behaviors during inflammation were blocked by GH treatment via inhibition of insulin like growth factor 1 receptor (IGFr1) upregulation in the DRGs. Finally, a neonatal GH treatment was also effective in blocking the priming effects of early life insults on young adult hypersensitivity. The main goal of this proposal is to determine the molecular mechanisms of how GH levels regulate sensory neuron development and afferent sensitization during inflammation that may underlie short and long term mechanical and thermal responsiveness. To determine this, we developed an ex vivo hairy skin, saphenous nerve, dorsal root ganglion (DRG), spinal cord recording preparation in neonatal mice that enables us to comprehensively phenotype sensory fibers. In Specific Aim 1, we will determine how GH modulates sensory neuron development by using transgenic mice with GHD or mice with afferent specific GH receptor ablation in conjunction with ex vivo recording. In Specific Aim 2, we will test whether knockdown of the receptor (IGFr1) or transcription factor (SRF) that is thought to mediate the actions of altered GH levels modifies these same changes in afferent function in GHD mice using in vivo siRNA-mediated knockdown of these genes in single peripheral nerves in conjunction with ex vivo recording. Finally, in Specific Aim 3, we will use ex vivo recording to determine the influence of treating neonatally inflamed mice with GH on the priming effects to subsequent adult inflammation. All of these aims will be complemented by behavioral analysis of thermal and mechanical responsiveness. These experiments will enable us to determine if GH levels regulate sensory development and identify unique mechanisms associated with how developing sensory neurons respond to injury. These studies will also facilitate our understanding of the transition from acute to chronic pediatric pain, and will allow us to determine the utility of GH as a pain therapy. This work may also lead to the establishment of more suitable treatments for pain in children that target the correct pain receptor(s) or primary afferent subtype(s).