Role of Descending Serotonergic Fibers in the Development of Pathophysiology after Spinal Cord Injury (SCI): Contribution to Chronic Pain, Spasticity, and Autonomic Dysreflexia.

Abstract

Simple SummaryFiber pathways that descend from the brain to the spinal cord drive motor behavior and modulate incoming sensory signals and the capacity to change (plasticity). A subset of these fibers release the neurotransmitter serotonin (5-HT), which can affect spinal cord function in alternative ways depending upon the region innervated and the receptor type engaged. The present paper examines the dampening (inhibitory) effect of serotonin and how a disruption in this process contributes to pathophysiology after spinal cord injury (SCI). After briefly reviewing the underlying anatomy and receptor types, we discuss how damage to serotonergic fibers can enable a state of over-excitation that interferes with adaptive learning and contributes to the development of pain, spasticity, and the dysregulation of autonomic function (autonomic dysreflexia). Recent work has shown that these effects arise, in part, because there is a shift in how the neurotransmitter gamma-aminobutyric acid (GABA) affects neural transmission within the spinal cord, a modification that lessens its inhibitory effect. Clinical implications of these results are discussed.As the nervous system develops, nerve fibers from the brain form descending tracts that regulate the execution of motor behavior within the spinal cord, incoming sensory signals, and capacity to change (plasticity). How these fibers affect function depends upon the transmitter released, the receptor system engaged, and the pattern of neural innervation. The current review focuses upon the neurotransmitter serotonin (5-HT) and its capacity to dampen (inhibit) neural excitation. A brief review of key anatomical details, receptor types, and pharmacology is provided. The paper then considers how damage to descending serotonergic fibers contributes to pathophysiology after spinal cord injury (SCI). The loss of serotonergic fibers removes an inhibitory brake that enables plasticity and neural excitation. In this state, noxious stimulation can induce a form of over-excitation that sensitizes pain (nociceptive) circuits, a modification that can contribute to the development of chronic pain. Over time, the loss of serotonergic fibers allows prolonged motor drive (spasticity) to develop and removes a regulatory brake on autonomic function, which enables bouts of unregulated sympathetic activity (autonomic dysreflexia). Recent research has shown that the loss of descending serotonergic activity is accompanied by a shift in how the neurotransmitter GABA affects neural activity, reducing its inhibitory effect. Treatments that target the loss of inhibition could have therapeutic benefit.