Localized Sympathectomy Reduces Mechanical Hypersensitivity by Restoring Normal Immune Homeostasis in Rat Models of Inflammatory Pain

Abstract

Some forms of chronic pain are maintained or enhanced by activity in the sympathetic nervous system (SNS), but attempts to model this have yielded conflicting findings. The SNS has both pro-and anti-inflammatory effects on immunity, confounding the interpretation of experiments using global sympathectomy methods. We performed a "microsympathectomy" by cutting the ipsilateral gray rami where they entered the spinal nerves near the L4 and L5 DRG. This led to profound sustained reductions in pain behaviors induced by local DRG inflammation (a rat model of low back pain) and by a peripheral paw inflammation model. Effects of microsympathectomy were evident within one day, making it unlikely that blocking sympathetic sprouting in the local DRGs or hindpaw was the sole mechanism. Prior microsympathectomy greatly reduced hyperexcitability of sensory neurons induced by local DRG inflammation observed 4 d later. Microsympathectomy reduced local inflammation and macrophage density in the affected tissues (as indicated by paw swelling and histochemical staining). Cytokine profiling in locally inflamed DRG showed increases in pro-inflammatory Type 1 cytokines and decreases in the Type 2 cytokines present at baseline, changes that were mitigated by microsympathectomy. Microsympathectomy was also effective in reducing established pain behaviors in the local DRG inflammation model. We conclude that the effect of sympathetic fibers in the L4/L5 gray rami in these models is pro-inflammatory. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some chronic inflammatory pain conditions.

High-fat diet increases pain behaviors in rats with or without obesity

“…In the peripheral inflammation model (paw injection of CFA), high-fat diet also exacerbated paw swelling. The relatively large effects of diet on cold allodynia contrast with our recent study 34 showing that localized sympathectomy markedly reduced DRG inflammation and mechanical pain behaviors but had much smaller effects on cold allodynia. This suggests that diet-induced modulation of the sympathetic system may not be the major mechanism underlying the effect of high-fat diet.…”

“…Next, we tested the effect of the high-fat diet on another model of inflammatory pain – inflammation of the hindpaw by injection of CFA. In previous studies using the CFA model, in which we injected 50 µL of 50% CFA into the paw, the pain behaviors were near-maximal 34 , which would make it difficult to observe further enhancement of pain by the high-fat diet. We therefore modified the model by reducing the 50% CFA injection volume to 10 µl.…”

“…As for the LID model, the CFA model was modified to be much milder, to avoid giving maximal pain behaviors in normal chow animals. For comparison, our previous study 34 used a much larger (50 µL) volume of 50% CFA-50% artificial cerebrospinal fluid to induce paw inflammation. Hence, the dose used in the present study should not have had systemic effects; in other published studies using this model in rats, a dose of 150 µl CFA at 1 mg/ml, was shown to cause only local tissue and joint inflammation, with arthritic changes occurring only in the local joints and only at later times (30 days) than those measured in our experiments 35 , whereas higher doses (e.g.…”

Lumbar Sympathectomy in an Ankylosing Spondylitis Patient with Vasculitis: A Case Report

“…16 Studies have shown that disruption of lumbar sympathetic nerve can regulate the regeneration of cutaneous vascular cells by inhibiting the proliferation of parietal cells and increasing the expression of angiopoietin-1. 17 It can reduce the inflammatory reaction in the sympathetic nerve denervation area, 18 decrease the adrenergic release in the dorsal root ganglion, inhibit sympathetic activity by stimulating α2-adrenergic receptors and/or upregulating α2-adrenoceptors, 19 inhibit spinal microglia activation, and reduce the expression of inflammatory cytokines [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α]. 20 Therefore, the mechanisms of sympathetic nerve blockade for pain relief are complex and need to be further studied.…”

Evaluation of combined radiofrequency and chemical blockade of multi-segmental lumbar sympathetic ganglia in painful diabetic peripheral neuropathy

“…Since there was no significant difference in skin temperature between the three groups, the symptom relief was not simply attributed to expansion of blood vessels to improve circulation in group C. Studies have shown that disruption of lumbar sympathetic nerve can regulate the regeneration of cutaneous vascular cells by inhibiting the proliferation of parietal cells and increasing the expression of angiopoietin-1. 29 It can reduce the inflammatory reaction in the sympathetic nerve denervation area, 30 decrease the adrenergic release in the dorsal root ganglion, inhibit sympathetic activity by stimulating α2-adrenergic receptors and/or upregulating α2-adrenoceptors, 31 inhibit spinal microglia activation and reduce the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α). 32 Therefore, the mechanisms of sympathetic nerve blockade for pain relief are complex and need to be further studied.…”