The laboratory of Dr. Daniel Morgan focuses on understanding the mechanisms responsible for the different roles of cannabinoid signaling in human health and disease. One of the lab's main areas of interest is to better understand the mechanisms responsible for tolerance to cannabinoids such as delta-9-tetrahydrocannabinol (∆9-THC) in pathological models of pain including agonist-specific differences in the mechanisms responsible for cannabinoid tolerance. Previous studies have shown that receptor desensitization is involved in the development of tolerance for GPCR-directed agonists in vivo. The laboratory’s work utilizes a novel “knock-in” mouse line that expresses a desensitization-resistant form of the cannabinoid receptor 1 (CB1) to investigate tolerance for ∆9-THC and two synthetic cannabinoid agonists, WIN 55,212-2 and CP55,950. Results from the lab show that tolerance to WIN 55,212-2 is mediated exclusively through this classical mechanism of desensitization, whereas tolerance to ∆9-THC is only partially attenuated when this mechanism is disrupted. Interestingly, data strongly suggests that tolerance to ∆9-THC, but not the other two synthetic agonists, is partially mediated through a c-Jun N-terminal kinase (JNK) signaling pathway. The laboratory is currently engaged in work to better understand the molecular mechanisms responsible for this novel form of JNK-mediated ∆9-THC tolerance. The laboratory is also engaged in a second major project to understand the role of CB1 internalization and trafficking in cannabinoid tolerance and dependence. This project involves using a second “knock-in” mouse that expresses an internalization-deficient form of CB1 to study tolerance and physical dependence for ∆9-THC, WIN 55,212-2 and CP55,950.
