Dual Effects of Endocannabinoid Modulation in Nociception

University Of South Dakota Main Campus, Vermillion SD

Investigators

Abstract

Pain is a complex physiological and behavioral process that is still poorly understood. One example of our lack of understanding how pain works is the cannabinoid system. The cannabinoid system consists of signaling molecules and their receptors and are generally thought to reduce pain (i.e., have an analgesic effect). However, the cannabinoid system has both pain-decreasing and pain-increasing effects. How can this be? The goal of this project is to discover how different parts of the nervous system respond to cannabinoids to produce these opposing effects on pain. These experiments will be carried out using the medicinal leech, Hirudo verbana. Leeches use the same cannabinoid signaling molecules found in all animals, including people. Another benefit is that the leech has a well-characterized nervous system, and it is relatively easy to monitor the activity of individually identified neurons from each animal. This makes it possible to discover how cannabinoids affect different parts of the nervous system. In this way the researchers hope to discover the mechanisms by which the cannabinoid system generates pain-increasing versus pain-decreasing effects. This project will also provide mentoring training to faculty and students in STEM, which will promote professional development and enhance the inclusion of people from under-represented groups. The ability to detect and appropriately respond to stimuli that elicit damage or potential damage to the body (nociception) has considerable adaptive significance. The cannabinoid system is generally thought to have anti-nociceptive effects, i.e., is analgesic. However, the cannabinoid system can also have pro-nociceptive, sensitizing effects that increase pain signaling. How does the nervous system selectively engage these pro- vs. anti-nociceptive effects of the cannabinoid system? Researchers for the project found previously that different patterns of afferent stimulation can elicit either pro- or anti-nociceptive effects mediated by endocannabinoids. This project aims to understand how different patterns of activity translate into pro- vs. anti-nociceptive effects of endocannabinoids. Is this due to different patterns of activity producing different amounts of endocannabinoids? Do the afferent pathway triggering endocannabinoid synthesis make a difference? Are there intracellular signaling cascades that regulate endocannabinoid effects? These potential mechanisms of pro- and anti-nociception will be examined by pharmacological manipulations of individually identifiable, synaptically connected neurons in the medicinal leech, Hirudo verbena. As Hirudo uses the same endocannabinoids found in all animals, including humans, 2-arachidonoylglycerol (2-AG) and anandamide, these experiments provide a compelling comparative model that will contribute valuable data to our understanding of pain modulation. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.