Δ⁹-THC and COX-2 Signaling

Humans have been using marijuana or cannabis for a few thousands of years, as a recreational or medicinal drug. Δ⁹-Tetrahydrocannabinol (THC) is the major psychoactive ingredient in marijuana. Because of the undesirable side effects and potential abuse, the medical use of THC has been restricted to a limited number of medical conditions. Cyclooxygenase-2 (COX-2) is an inducible enzyme that converts arachidonic acid to prostanoids. Recent study shows that synaptic and cognitive impairments elicited by THC are associated with COX-2 induction through CB1 receptor-coupled G-protein subunits, and downstream NF-δB signaling pathway. COX-2 inhibition by pharmacological or genetic manipulations maintains integrity of hippocampal synaptic structure and function, and improves long-term synaptic plasticity, spatial learning, and memory in animals repeatedly exposed to THC. This information suggests that the medical use of marijuana would be broadened by concurrent COX-2 inhibition, which eliminates the major adverse effects of THC, while retaining cannabinoid beneficial effects.