Gene Expression on Profilling on CNS Regions Implicated in a Mouse Model of Spinal Cord Grant uri icon

abstract

  • There are an estimated 250,000 - 400,000 spinal cord injured (SCI) individuals living in the United States. In addition to the obvious motor complications, 60-80% of SCI patients develop chronic pain, with nearly 40% of these patients reporting severe pain. Characteristics of post-SCI pain include severity, persistence and, most importantly, resistance to currently available therapies. Research to identify the underlying mechanisms responsible for this condition needs to focus on the use of injury models that simulate pathological changes associated with human spinal injuries that lead to clinically relevant, pain-related behaviors. One such experimental model is excitotoxic SCI in which the mixed A1v1P A/metabotropic glutamate receptor agonist, quisqualic acid, is microinjected into the dorsal horn of the spinal cord. This insult, which simulates the increase in endogenous excitatory amino acids after SCI, produces pathological and behavioral changes consistent with those observed after human SCI and is a reliable method in which to study post-SCI pain states and their molecular correlates in rodents. Previous research by the co-investigators has demonstrated that there is an increase in cortical opioid peptide mRNA that positively correlates with the onset of pain-related behaviors in this SCI model, suggesting a possible mechanism for the reduced effectiveness of opiate administration in post-SCI-induced pain. The hypothesis of this proposal is that changes in opioid-related gene and protein expression in the medial pain system of the neuraxis will be greater in SCI-injured mice that exhibit pain-related behaviors than in mice that do not exhibit these behaviors. Changes in gene and protein expression will be identified first by nucleic acid microarray hybridization followed by in situ hybridization, and finally by immunoblotting for the encoded proteins in the cingulate cortex, medial thalamus, and the mesencephalic periaqueductal gray. These areas are key structures in the medial pain system, which is rich in opioid peptides and receptors and mediates the motivational-affective components of pain. Because the mechanisms of chronic pain in general, and in particular after SCI, are far from clear, the study of gene and protein expression in specific components of the CNS of animals that develop post-SCI pain will contribute to a better understanding of both the intrinsic mechanisms underlying chronic pain as well as to future development of novel therapeutic strategies to treat this debilitating condition.

date/time interval

  • August 2002 - December 2003