Sympathectomy decreases pain behaviors and nerve regeneration by downregulating monocyte chemokine CCL2 in dorsal root ganglia in the rat tibial nerve crush model

ABSTRACT: Peripheral nerve regeneration is associated with pain in several preclinical models of neuropathic pain. Some neuropathic pain conditions and preclinical neuropathic pain behaviors are improved by sympathetic blockade. In this study, we examined the effect of a localized "microsympathectomy," ie, cutting the gray rami containing sympathetic postganglionic axons where they enter the L4 and L5 spinal nerves, which is more analogous to clinically used sympathetic blockade compared with chemical or surgical sympathectomy. We also examined manipulations of CCL2 (monocyte chemoattractant protein 1), a key player in both regeneration and pain. We used rat tibial nerve crush as a neuropathic pain model in which peripheral nerve regeneration can occur successfully. CCL2 in the sensory ganglia was increased by tibial nerve crush and reduced by microsympathectomy. Microsympathectomy and localized siRNA-mediated knockdown of CCL2 in the lumbar dorsal root ganglion had very similar effects: partial improvement of mechanical hypersensitivity and guarding behavior, reduction of regeneration markers growth-associated protein 43 and activating transcription factor 3, and reduction of macrophage density in the sensory ganglia and regenerating nerve. Microsympathectomy reduced functional regeneration as measured by myelinated action potential propagation through the injury site and denervation-induced atrophy of the tibial-innervated gastrocnemius muscle at day 10. Microsympathectomy plus CCL2 knockdown had behavioral effects similar to microsympathectomy alone. The results show that local sympathetic effects on neuropathic pain may be mediated in a large part by the effects on expression of CCL2, which in turn regulates the regeneration process.