Nerve compression activates selective nociceptive pathways and upregulates peripheral sodium channel expression in Schwann cells

Abstract

Chronic nerve compression (CNC) injuries, such as carpal tunnel syndrome, are common musculoskeletal conditions that affect patients with debilitating loss of sensory function and pain. Although early detection and treatment are important, our understanding of pain-related molecular mechanisms remains largely unclear. Here we investigate these mechanisms using an animal model for CNC injury. To confirm that CNC injury induces pain, we assessed expression of c-fos, a gene that is rapidly expressed in spinal sensory afferents in response to painful peripheral stimuli, and TNF-a and IL-6, two proinflammatory cytokines that are crucial to development of inflammatorymediated pain. Results show c-fos upregulation 1-2 weeks postinjury in the absence of TNF-a or IL-6 expression, indicating increased neural sensitivity without an inflammatory response. This is consistent with previous studies that showed no morphologic evidence of inflammation in the CNC model. Surprisingly, we also found de novo expression of Na V 1.8, a sodium channel linked to the development of neuropathic pain, in endoneurial Schwann cells following injury. Until now, Na V 1.8 expression was thought to be restricted to sensory neurons. CNC injury appears to be a unique model of noninflammatory neuropathic pain. Further investigation of the underlying molecular basis could yield promising targets for early diagnosis and treatment. Keywords: carpal tunnel syndrome; Schwann cell; Na V 1.8; TNF-a; IL-6, c-fos Chronic nerve compression (CNC) injuries, such as carpal tunnel syndrome, cubital tunnel syndrome, and spinal nerve root stenosis, are debilitating conditions that affect millions of Americans every year. Peripheral nerves often pass through constrained regions of the body and thus are subject to varied forms of mechanical stimulation, from shear stress to stretching and compression. CNC injuries are caused by narrowing of these nerve tunnels, limiting the nerve's movement and resulting in sustained mechanical forces, including shear stress from the nerve gliding through the restricted canal and acute pressures from direct abutment against neighboring rigid structures, as well as chronic hydrostatic pressures gradients. 1 In the early stages of injury, the most common symptoms are intermittent pain accompanied by paresthesias. As the disease progresses further, muscle atrophy and loss of motor function ensue. Current therapies are effective at ameliorating symptoms if treated early in the disease process; but prolonged nerve compression greatly decreases the chance for maximal functional recovery. [2][3][4][5] As such, early diagnosis and treatment are critical. As sensory symptoms usually present before obvious motor or electrophysiological changes, understanding the source of this pain is critical to devising methods for early-stage diagnosis and treatment. 6,7 Until recently, the molecular and cellular events leading to CNC injuries were poorly understood. This is due, in part, to the fact that excision of human tissue for investigatio...

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

“…A recent study suggested that chronic nerve compression resulted in the up-regulation of NaV1.8 immunoreactivity in Schwann cells (51). Notably, the chronic nerve compression model does not induce mechanical allodynia or thermal hyperalgesia, instead resulting in progressive decreases in mechanical sensitivity (52).…”

Neonatal colonic inflammation sensitizes voltage-gated Na+channels via upregulation of cystathionine β-synthetase expression in rat primary sensory neurons

“…VGSCs are integral membrane glycoproteins that are essential for generation and conduction of electrical impulses in excitable cells, thus playing a fundamental role in controlling neuronal excitability. Many of the most common neurological disorders, such as epilepsy, migraine, neurodegenerative diseases, and chronic pain, involve abnormalities of neuronal excitability (8, 33) and abnormal expression and function of VGSCs (9,11,15). Human and rodent studies have identified several channels as pivotal for enhanced neuronal excitability in peripheral sensory neurons (10, 12), including VGSCs Na V 1.7, Na V 1.8, and Na V 1.9, with the latter two resistant to tetrodotoxin (TTX) (2, 11).…”

Neonatal maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats

“…VGSCs are integral membrane glycol proteins that are essential for generation and conduction of electrical impulses in excitable cells, thus playing a fundamental role in controlling neuronal excitability. Many of the most common neurological disorders, such as epilepsy, migraine, neurodegenerative diseases, and chronic pain, involve abnor-malities of neuronal excitability (10,38) and abnormal expression and function of VGSCs (13,16,19). Human and rodent studies have identified several channels as pivotal for enhanced neuronal excitability in peripheral sensory neurons (15,17), including VGSCs Na V 1.7, Na V 1.8, and Na V 1.9, with the latter two resistant to TTX (6,16).…”