Chronic Pain-Associated Cardiovascular Disease: The Role of Sympathetic Nerve Activity

Abstract

Chronic pain affects many people world-wide, and this number is continuously increasing. There is a clear link between chronic pain and the development of cardiovascular disease through activation of the sympathetic nervous system. The purpose of this review is to provide evidence from the literature that highlights the direct relationship between sympathetic nervous system dysfunction and chronic pain. We hypothesize that maladaptive changes within a common neural network regulating the sympathetic nervous system and pain perception contribute to sympathetic overactivation and cardiovascular disease in the setting of chronic pain. We review clinical evidence and highlight the basic neurocircuitry linking the sympathetic and nociceptive networks and the overlap between the neural networks controlling the two.

Keywords: cardiovascular disease; chronic pain; sympathetic nerve activity.

Figure 1

Control of sympathetic preganglionic neurons. Efferent sympathetic nerve activity (SNA) is determined by the net product of excitatory and inhibitory projections to sympathetic preganglionic neurons located within the intermediolateral (IML) cell column of the thoracic spinal cord. The rostral ventrolateral medulla (RVLM) is one of the main sources of descending excitatory drive (green). Additionally, second-order sensory neurons, relaying information from primary sensory afferents, are an important intraspinal source of excitatory drive to sympathetic preganglionic neurons. Descending inhibitory projections to sympathetic preganglionic neurons (red) arise from multiple brain regions including from the locus coeruleus (LC) and the reticular formation (RF). Much of the descending excitatory and inhibitory drive to sympathetic preganglionic neurons is regulated by neurons located within the nucleus of the solitary tract (NTS), which is the primary integrative site for baroreceptor and chemoreceptor afferent fibers which drive autonomic reflexes. Included above is an example of raw (lower tracing) and integrated (upper tracing) SNA recorded from postganglionic renal sympathetic nerve fibers in a rat as described in [63] (lower right).

Figure 2

Baroreceptor loading strongly inhibits sympathetic nerve activity. Responses in arterial pressure (AP) and renal sympathetic nerve activity (RSNA) to intravenous administration of phenylephrine (40 µg/kg) in (A) spinal intact and (B) T4 spinal-transected rats. The red line in the top panel represents the level of recorded activity (zero) at the end of the experiment following ganglionic blockade (hexamethonium, 20 mg/kg). See text for additional information.

Figure 3

Central autonomic network. Depicted is the neural circuitry controlling SNA during emotional stress. PFC, prefrontal cortex; IC, insular cortex; ACC, anterior cingulate cortex; AMY, amygdala; DMH, dorsomedial hypothalamus; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla; CVLM, caudal ventrolateral medulla; NTS, nucleus of the solitary tract; SPN, sympathetic preganglionic neurons. See text for additional information.