PROJECT SUMMARY
Chronic pain affects up to one third of the United States population, and the reliance on opioids to treat chronic
pain has contributed substantially to the opioid epidemic. Developing alternative pain therapies is critical to
reducing the use of opioids, and the phyto-cannabinoid cannabidiol (CBD) is a promising candidate. We have
shown that CBD has the ability to reduce chronic neuropathic pain-like responses in mice over 3 weeks.
Terpenoids (eg beta-caryophyllene), also found in the cannabis plant, are a potential second class of
pharmacologically active compounds in cannabis with possible analgesic benefits, although their
pharmacodynamic properties in vitro and in vivo are poorly understood. Likewise, there is an incomplete
understanding of how CBD and terpenoids produce anti-nociception, by themselves or combined (“entourage”),
and their supraspinal neuropharmacological mechanisms of “pain control” remain unknown. The proposed
experiments will first test whether specific combinations of CBD and terpenoids can produce short-term
inflammatory and long-term neuropathic antinociception without tolerance. We will then establish the
action of CBD and terpenoids in a critical brain nucleus for pain, the basolateral amygdala. Finally, we will
determine the pharmacological and biochemical signaling profiles of CBD and terpenoids in vitro and in
vivo. In Aim 1, we will use mixtures of CBD and terpenoids, investigator administered as well as in our gelatin
self-administration model, and measure both consumption and pain scores after partial sciatic nerve ligation to
determine if CBD and/or terpenoids provide analgesic benefit over protracted periods of pain. We will also verify
that these mixtures are not inherently rewarding, which is critical for substance abuse liability. In Aim 2, we will
test whether the amygdala is a critical brain circuit site for CBD/terpenoid analgesic action using single cell
calcium imaging of amygdalar neurons during pain states, in parallel with local injections of CBD and terpenoids
into the amygdala to produce analgesia. Further, we will knock out cannabinoid receptors and other putative
sites of CBD/terpenoid action within the BLA to establish necessity of each in producing behavioral and
physiological responses. In Aim 3, we will use in vitro and in vivo systems to determine the important biochemical
features of CBD and terpenoid action at their putative receptor targets. We will measure cellular signaling activity
via dynamic mass redistribution (DMR), MAP Kinase signaling, and the generation of reactive oxygen species.
These aims will inform public health about the benefits and risks of long-term cannabidiol/terpenoid usage, as
well as providing crucial mechanistic insight that will help develop and understand whether tailored medicinal
cannabis approaches for chronic pain can be harnessed for therapeutic benefit.