Pain arising from the viscera is associated with a variety of disorders. In the pelvic viscera, there is often an overlap of pain. There are several clinical reports documenting an overlap between functional gastrointestinal (GI) disorders and chronic pelvic pain (CPP). Approximately 35% of patients with CPP showed significant improvement when treated for functional GI disorders. Patients with functional GI disorders have significantly higher prevalence of urinary bladder dysfunction and CPP. The major goal of this research proposal is to study the underlying neural mechanisms of overlapping pain that is commonly observed in the pelvic structures. Our preliminary data indicates that neonatal chronic cystitis in rats causes significant colonic hyperalgesia later in their life. We hypothesized that - (1) a proportion of pelvic nerve afferent fibers that dichotomize and innervate two pelvic organs (e.g., bladder and colon ) may undergo sensitization following cystitis, (2) hyperexcitation of bladder afferents can produce sensitization of spinal neurons receiving converging input from the colon and bladder (i.e., viscero-visceral convergence) and (3) neonatal cystitis leads to changes in descending neural circuitry from periaqueductal gray (PAG) and rostroventral medulla (RVM) that modulates the spinal nociceptive transmission. Studies will be undertaken to test the contribution of viscero-visceral convergence from colon and urinary bladder in CPP.
Specific aim 1 (behavioral study) involves functional characterization of colonic hyperalgesia in adulthood following neonatal cystitis.
Specific aim 2 (electrophysiology study) will focus to study the functional characters of (a) pelvic and splanchnic nerve afferent fibers innervating the colon or urinary bladder following neonatal cystitis, (b) viscero-visceral convergent neurons in the thoraco-lumbar (T13-L1) and lumbo-sacral (L6-S1) spinal cord and (c) responses of spinal neurons to stimulation of PAG and RVM.
Specific aim 3 To dertermine the expression profile of microRNA (miRNAs, small non-coding RNAs) and their target mRNAs in - a) the thoraco-lumber (T13-L1) and lumbo-sacral (L6-S1) spinal cord, b) PAG, c) RVM, from neonatally zymosan-treated, saline-treated and adult zymosan-treated rats. The experience- dependent plasticity of neural circuits requires a proper balance between the excitatory and inhibitory neurons within effected networks and specific miRNA-target mRNA interaction appears to involve in the maintenance of this synaptic homeostasis. We hypothesize that the development of long-term spinal neuron sensitization and altered descending modulatory pathways are due to differential expression of miRNAs during neuronal development. The long-term sensitization is due to down regulation of miRNAs specifically involved with the transcriptional regulation of various excitatory neurotransmitter receptors (particularly NMDAr)), synapse associated proteins (PSD 95/SAP90, SAP102) and upregulation of miRNAs regulating inhibitory neurotransmitter GABA and its receptors GABAA and GABAB. This proposal represents the first systematic investigation of the possible neurophysiological basis of overlapping pelvic pain.
Project narration Although our understanding of pain mechanism has progressed immensely in last two decades, the infant pain especially the chronic pain due to early-life events is still poorly understood. It should be acknowledged that analgesic protocol for such chronic pain is not very successful, which is primarily due to lack of our understanding in neural signaling pathways that undergo changes during the immature period of central nervous system. Therefore, the neural mechanism of their pain perception could be entirely different from the normal adult. Stress or noxious stimulus in early life induces functional changes in the central neurons affecting the descending modulatory system contributing to such chronic pain. The objective of the proposed application is to systematic evaluation of changes in pain signaling pathways and altered neural processing that occurs during neonatal painful stimulus. Results of the proposed studies will help us in understanding of better treatment strategy in chronic pelvic pain.
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