Progress in Sympathetically Mediated Pathological Pain

Abstract

Aim of review: Many chronic pain conditions remain difficult to treat, presenting a high burden to society. Conditions such as complex regional pain syndrome may be maintained or exacerbated by sympathetic activity. Understanding the interactions between sympathetic nervous system and sensory system will help to improve the effective management of pathological pain including intractable neuropathic pain and persistent inflammatory pain.

Method: We first described the discovery of abnormal connections between sympathetic and sensory neurons. Subsequently, the functional roles of sympathetic sprouting in altered neuronal excitability and increased pain sensitivity were discussed. The mechanisms of the sympathetic sprouting were focusing on its relationship with neurotrophins, local inflammation, and abnormal spontaneous activity. Finally, we discussed clinical implications and conflicting findings in the laboratory and clinical research with respect to the interaction between sympathetic system and sensory system.

Recent findings: The findings that sprouting of sympathetic fibers into the sensory ganglia (dorsal root ganglion) after peripheral nerve injury, offers a possible explanation of the sympathetic involvement in pain. It is also suggested that releases of adenosine triphosphate (ATP), in addition to norepinephrine, from sympathetic nerve endings play important roles in sympathetic-mediated pain. New evidence indicates the importance of sympathetic innervation in local inflammatory responses.

Summary: Hopefully, this review will reinvigorate the study of sympathetic-sensory interactions in chronic pain conditions, and help to better understand how sympathetic system contributes to this serious clinical problem.

Figure 1. A Schematic Diagram Showing the Relationship between Sympathetic System and the Sensory System under Physiological and Pathological Conditions

The preganglionic sympathetic neurons originate from the lateral dorsal horn and project to the sympathetic ganglia via the white communicating rami at T1-T12, and L1-L3 levels. Sympathetic fibers from the postganglionic neurons join the peripheral nerves via the gray rami. Note that there is no white ramus at the L4 or L5 spinal levels. After nerve injury or local inflammation, sympathetic fibers sprout from the surface of the DRG and penetrate into the ganglion, where a “basket” like structures may be formed around certain sensory neurons.

Figure 2. Composite Whole-Mount Staining of Tyrosine Hydroxylase (TH)-Positive Sympathetic Fibers in a DRG 3 Days after Spinal Nerve Ligation

Neurons are stained with NeuN (green), and tyrosine hydroxylase is in red. Note that extensive TH-fiber sprouting onto the surface of the DRG in the SNL DRG. Scale bar: 200 μm.