Endocannabinoid-Mediated Inhibition of T-Type Calcium Channels to Treat SCI-Induced Neuropathic Pain
Abstract
Spinal cord injury (SCI) affects approximately 300,000 people in United States, including 27,000 wounded Soldiers, with an estimate of 54 new cases per million population each year according to the National Spinal Cord Injury Statistical Center and the U.S. Department of Veterans Affairs (VA). Following SCI, up to 80% of patients suffer from chronic neuropathic pain. SCI-induced neuropathic 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. A 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, but become hyperexcitable and spontaneously active following SCI, providing a possible underlying mechanism for the development of SCI-pain. Similar to human patients affected by SCI, rats subjected to SCI develop chronic neuropathic pain phenotypes. Data collected in preclinical rat models of SCI have shown that nociceptors exhibit a hyperexcitable state and spontaneous activity up to 8 months following the injury, and there is a strong correlation between the increased incidence of spontaneous activity of SCI-nociceptors and the severity of pain. Taken together, these observations suggest that the increased electrical activity of nociceptors induced by the injury may represent a possible underlying cause for the development of chronic neuropathic pain following SCI. Our preliminary data collected in a preclinical rat model of SCI suggest that: (1) following SCI, the activity of T-type calcium channels is increased in nociceptors, leading to their increased electrical activity; (2) pharmacological inhibition of T-type calcium channels reduces spontaneous and evoked pain in rats subjected to SCI in vivo; (3) pharmacological inhibition of monoacylglycerol lipase (the metabolizing enzyme for the endogenous endocannabinoid 2-arachidonoylglycerol) reduces the activity of T-type calcium channels in nociceptors in vitro and the development of SCI-pain in vivo. The goal of this research proposal is to target the endocannabinoid system and its metabolizing enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) to inhibit the activity of T-type calcium channels in nociceptors to reduce their electrical activity and thus, treat SCI-pain. Anticonvulsant and tricyclic antidepressant drugs, such as gabapentin, pregabalin, and amitriptyline, are first line analgesics prescribed to treat 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 increased electrical activity of SCI-nociceptors, down-regulation of T-type calcium channels represents a rational pharmacological strategy for the treatment of SCI-pain. MAGL inhibitors (ABX-1431, Abide Therapeutics) and FAAH inhibitors (PF-04457845, Pfizer) have undergone or are undergoing phase 1/2 clinical trials and are safe, and in contrast to serotonin–norepinephrine reuptake inhibitors and pregabalin are devoid of psychoactive side effects. The outcome of this research proposal will lay the foundations for translating endocannabinoid metabolizing enzyme inhibitors 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.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110544
Entities
People
- Michelino Puopolo
Organizations
- Stony Brook University
- United States Army