Inhibition of endocannabinoid catabolizing enzymes MAGL and FAAH reduces the activity of CaV3 channels in nociceptors and pain hypersensitivity in a rat model of spinal cord injury

Development of chronic neuropathic pain is a severe secondary complication following spinal cord injury (SCI) and affects up to 60–70% of patients. Successful management of SCI-induced neuropathic pain is in many cases insufficient, leading to a severe decline in quality of life and increased risk for depression, anxiety, and addiction. Nociceptors’ hyperexcitability and spontaneous activity contribute to the development/maintenance of SCI-induced neuropathic pain, and studies in rodent models of SCI have shown reduced pain hypersensitivity upon downregulation of nociceptors’ hyperexcitability. Previous reports showed that CaV3 channels contribute, together with other mechanisms, to driving nociceptors’ hyperexcitability and the development/maintenance of SCI-induced neuropathic pain in rodent models of SCI. Endocannabinoids can directly inhibit the activity of CaV3 channels. Accordingly, we hypothesized that inhibition of endocannabinoid catabolizing enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), and subsequent increase in the levels of 2-arachidonoylglycerol and anandamide, could result in inhibition of CaV3 channels and reduced pain hypersensitivity following SCI. Using a combination of patch clamp electrophysiology in nociceptors in vitro and behavioral pharmacology in vivo combined with measurements of mechanical hypersensitivity and spontaneous pain in a rat model of SCI, we found that inhibition of MAGL and FAAH reduced the activity of CaV3 channels in nociceptors and mechanical hypersensitivity, while reduction of spontaneous pain was observed only upon inhibition of FAAH. Taken together, our data suggest that inhibition of MAGL and FAAH, with subsequent inhibition of CaV3 channels in nociceptors, may provide a strategy to reduce chronic neuropathic pain following SCI. Perspective: CaV3 channels contribute to nociceptors’ hyperexcitability and SCI-induced neuropathic pain. Our data demonstrate that inhibition of MAGL and FAAH reduces the activity of CaV3 channels in nociceptors and SCI-induced neuropathic pain, suggesting that inhibition of endocannabinoid catabolizing enzymes may represent a rational approach to reduce pain hypersensitivity following SCI.