Exploring Opioid and Cannabis Pharmacology: Biased Signaling of Endogenous Opioid Peptides and Cannabimimetic Properties of Cannabis Sativa Terpenes

Abstract

The United States has roughly 100 million people suffering from pain disorders, including chronic pain, which is becoming an ever increasing medical and economic burden. Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are first line drugs for the treatment of acute and post-operative pain, however opioids can be ineffective for long-term treatment due to negative side effects such as tolerance and addiction. Recent efforts have attempted to combat pain pharmacologically through different avenues including biased agonists at the mu opioid receptor (MOR) and non-opioid targets such as cannabinoid receptors. Biased agonists attempt to preferentially activate specific downstream pathways of MOR that are therapeutically beneficial over pathways linked to negative side effects. G protein signaling through the MOR mediates its antinociceptive properties, whereas it has been proposed that barrestin2 (barr2) signaling elicits negative side effects such as tolerance and respiratory depression. Thus, recent efforts have attempted to create G protein biased agonists at MOR that have a greater therapeutic index compared to classic opioids. Although initially promising in preclinical trials, MOR biased ligands have fallen short in clinical trials. Although there is significant preclinical data in support of the therapeutic benefit of biased agonists, most of the work uses exogenous agonists. Biased signaling in terms of endogenous ligands at GPCRs is limited and most is centered on chemokine receptors. The literature is very much lacking in whether endogenous agonists at MOR induce biased signaling, if at all, and what the physiological function of this is. It thus begs the question: do endogenous opioids participate in biased signaling? An understanding of biased signaling, or lack thereof, by endogenous ligands could help resolve the disparity between promising preclinical data and failed clinical applications. While the development of biased ligands appeared auspicious, non-opioid targets were also under investigation. Targets of particular interest in the past decade include cannabinoid receptors. Cannabinoid receptors are positioned in suitable locations for the relief of pain, albeit in many other areas, unlike to opioid receptors. In recent decades the stigma of Cannabis sativa has reduced substantially. Consequently, the plant is now legally used for its medicinal properties including analgesia among other treatments. Cannabis sativa is now also available recreationally in many states. The major pharmacologically active components in Cannabis sativa exploited for both medicinal and recreational purposes are (-trans-tetrahydrocannabinol (9-THC) and cannabidiol (CBD). These compounds are part of a large family of ~150 phytocannabinoids found in Cannabis sativa. The plant also contains hundreds of terpenes: small, lipophilic hydrocarbons causing the distinct smells and tastes of Cannabis sativa chemovars. Anecdotal reports have suggested that differing cannabis strains, differing in terpene content, can induce different subjective effects. Reports also show differing therapeutic benefit of cannabinoid/terpene combinations versus just 9-THC alone. This concept is called the entourage effect and suggests interactions of terpenes and cannabinoids at some level In these studies, we have examined whether endogenous opioids participate in biased signaling, and attempted to determine mechanisms for those compounds which do. Furthermore, we sought to characterize the cannabimimetic properties of selected terpenes both in vitro and in vivo, and how these terpenes modulate the function of a cannabinoid agonist.