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Descending noradrenergic control of conditioned pain modulation and postoperative pain trajectory in rats.

Parker RA, Wang F, Hayashida K, Martin TJ, Eisenach JC, Peters CM (2013) Descending noradrenergic control of conditioned pain modulation and postoperative pain trajectory in rats. Neuroscience 2013 Abstracts 461.10. Society for Neuroscience, San Diego, CA.

Summary: Aim of Investigation: Chronic pain after surgery (CPAS) is now recognized as a significant clinical problem that occurs in 10-50% of patients undergoing surgery. Recent clinical studies demonstrate the integrity of endogenous pain inhibitory controls are important for preventing CPAS, however this relationship and underlying mechanisms haven’t been examined in preclinical models. We hypothesized that a causal relationship exists between impaired endogenous analgesia and chronic pain after surgery that is in part dependent on descending noradrenergic pathways. Methods: We examined the integrity of endogenous analgesia in rats preoperatively used a previously described method for assessing conditioned pain modulation (CPM) in rats (Ferrari et al., 2010) involving injection of capsaicin (150μg/50μl) in the forepaw as a conditioning stimulus and detection of hindpaw mechanical thresholds (Randall-Selitto device) as the test stimulus. The partial L5 spinal nerve ligation (pSNL) model and mixed effects growth curve modeling of mechanical withdrawal thresholds assessed for 10 weeks following surgery were used to study resolution of postoperative mechanical hypersensitivity. The role of descending spinal noradrenergic pathways in CPM and postoperative trajectory was assessed by ablating spinal noradrenergic fibers with DβH-saporin or blocking their activity pharmacologically with adrenergic receptor antagonists. Results: Forepaw capsaicin resulted in release of NE in the lumbar spinal cord and this CPM paradigm was partially prevented by spinal idazoxan (30μg, i.t.). CPM assessed preoperatively resulted in pronounced but variable increases in hindpaw mechanical withdrawal thresholds at 30 minutes (range: 60-140g). Within individual rats, we observed a significant correlation between the degree of preoperative CPM and the slope of trajectory (P=0.006, r=0.610) as rats with lower endogenous analgesia had slower resolution of mechanical hypersensitivity. In support of a causal role between endogenous spinal noradrenergic activity and CPAS, depletion of spinal noradrenergic fibers prior to pSNL resulted in a significant reduction in the slope of trajectory within the ipsilateral hindpaw. Conclusions: Collectively, these studies suggest that the ability to engage descending endogenous noradrenergic pathways may be critical in determining whether CPAS develops. Furthermore, the use of growth curve modeling to study CPAS will allow us to examine the ability of socio-environmental conditions or pharmacological interventions to impair or improve aspects of postoperative pain trajectory as part of future studies.

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