SCI-Induced Hyperexcitability of Nociceptors and Development of Chronic Neuropathic Pain
Abstract
Spinal cord injury (SCI) affects approximately 300,000 people in USA, including 42,000 veterans, with an estimate of 54 new cases per million population each year (National Spinal Cord Injury Statistical Center; Department of Veterans Affairs). Following SCI, up to 80% of patients suffer from chronic neuropathic pain (SCI-pain). SCI-pain is often severe to excruciating, with a major negative impact on quality of life and increased risks for depression, anxiety, and addiction. Our understanding of the basic neuronal mechanisms that promote and maintain SCI-pain is very incomplete, leading to inadequate management of SCI-pain which is often refractory to pharmacological, surgical, and behavioral therapeutic strategies. Experiments in rodent models of SCI have suggested that one potential cause for the development of SCI-pain is a change in the electrical activity of pain-sensing neurons (nociceptors) induced by the injury. Nociceptors are usually silent in the absence of injury, but become hyperexcitable and spontaneously active following SCI, providing a possible underlying mechanism for the development of SCI-pain. Similar to human patients with SCI, rat models of SCI develop chronic neuropathic pain phenotypes, and there is a strong relationship between the severity of pain and the incidence of spontaneous firing of nociceptors. The goal of this research proposal is to determine which ion channels undergo changes following SCI to make nociceptors hyperexcitable and become spontaneously active. Our data support the core hypothesis that, following SCI, the activity of T-type calcium channels is increased in nociceptors, leading to their hyperexcitable state and spontaneous firing. Knowledge of the ion channels responsible for driving spontaneous firing of SCI nociceptors should lead to rational and improved pharmacological approaches to treat SCI-pain and reduce the suffering endured by individuals with SCI, and for preventing secondary physical and psychological consequences that further reduce their quality of life. Anticonvulsant and tricyclic antidepressant drugs, such as gabapentin, pregabalin, and amitriptyline, are first line analgesics to treat neuropathic SCI-pain, but their efficacy is very limited (usually less than 30%). As suggested by our preliminary data, and based on their primary role in driving the spontaneous activity of nociceptors following SCI, T-type calcium channels represent a rational pharmacological target for the treatment of SCI-pain. Selective T-type calcium channel blockers, such as Ethosuximide (Zarontin; Pfizer, approved) and Z944 (Epirus Pharmaceuticals, phase II clinical trial), may represent a new and a better alternative to anticonvulsant and tricyclic antidepressant drugs for the treatment of neuropathic SCI-pain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810746
Entities
People
- Michelino Puopolo
Organizations
- Stony Brook University
- United States Army