The Effect of Chronic Constriction Injury on Cellular Systems Within Nociceptive Pathways in the Mouse

Chronic neuropathic pain is often difficult to treat due to its resistance to therapeutic intervention. This is due in part to the poor understanding of the physiological mechanisms involved in the establishment and maintenance of neuropathic pain states. The neuropathic pain model, chronic constriction injury of the sciatic nerve, produced robust pain hypersensitivity in our mice. It also induced significant changes in the mitogen activated protein kinase family, and the cannabinoid and µ-opioid systems in three different brain areas involved in the modulation or regulation of pain states. CCI induced a 2.5 fold increase in mRNA of the kinase Raf-1 in the PAG of mice. Raf-1 is part of the ERK cascade in the MAP kinase family of proteins. The MAPK family of proteins has previously been shown to be involved in the establishment and maintenance of chronic neuropathic pain via central sensitization and the PAG is a critical regulator of nociceptive input and is part of the descending pain pathway, which has also been shown to have a role in central sensitization. CCI also resulted in significant decreases in the µ-opioid receptor agonist DAMGO stimulated [35S] GTPγS binding in the medial thalamus, and the cannabinoid receptor agonist, WIN 55, 212-2 stimulated [35S] GTPγS binding in the anterior cingulate cortex. These effects were not due to an overall decrease in µ-opioid receptor or cannabinoid receptor 1 binding, suggesting that the chronic pain-like condition resulted in a desensitization of these receptors. Both the medial thalamus and the anterior cingulate cortex are brain areas involved in the medial pain pathway which, along with the limbic system, have been shown to be involved in the affective component of pain processing. These data are the first to demonstrate changes in these three cellular systems in the respective brain areas of the mouse in response to chronic neuropathic pain. The novel findings presented in this dissertation provide new areas of investigation for the treatment of this debilitating disease