Synergistic interactions of endogenous opioids and cannabinoid systems

Cannabinoids and opioids are distinct drug classes historically used in combination to treat pain. Δ⁹-THC, an active constituent in marijuana, releases endogenous dynorphin A and leucine enkephalin in the production of analgesia. The endocannabinoid, anandamide (AEA), fails to release dynorphin A. The synthetic cannabinoid, CP55,940, releases dynorphin B. Neither AEA nor CP55,940 enhances morphine analgesia. The CB1 antagonist, SR141716A, differentially blocks Δ⁹-THC versus AEA. Tolerance to Δ⁹-THC, but not AEA, involves a decrease in the release of dynorphin A. Our preclinical studies indicate that Δ⁹-THC and morphine can be useful in low dose combination as an analgesic. Such is not observed with AEA or CP55,940. We hypothesize the existence of a new CB receptor differentially linked to endogenous opioid systems based upon data showing the stereoselectivity of endogenous opioid release. Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans.