Summary
Approximately 50% of HIV-infected patients suffer from intractable pain and many individuals self-report the
consumption of cannabis for alleviating their symptoms. However, data are still limited on the effects of cannabis
in the HIV-infected, cART-treated population. The compound most studied is ¿9-THC, which exerts psychoactive
and addictive effects that limit therapeutic potential. Yet, there are over 120 minor cannabinoids and 200 terpenes
in cannabis and our renowned Marijuana Research Laboratory has found many of them hold non-psychoactive,
therapeutic effects. We identified cannabis constituents that reduce HIV-mediated inflammation/astrogliosis in
cell culture and HIV-protein mediated visceral pain in mice. We hypothesize that several minor cannabinoids and
terpenes will complement cART to ameliorate viremia, inflammation, and cytotoxicity caused by infectious HIV-
1. Moreover, we anticipate several of these compounds to ameliorate the inflammatory, mechanical, visceral,
and neuropathic pain states promoted by cART or HIV-1 proteins. Aim 1 will determine the important cannabis
constituents and targets that modulate HIV-mediated viremia and inflammation in vitro. Utilizing our extensive
library of cannabinoids, terpenes, and volatile oils, we will screen a high-cannabidiol (CBD) mixture and 44 pure
minor cannabinoids and terpenes against human peripheral blood mononuclear cells or microglia that are mock-
infected or infected with HIV-1IIIB or HIV-1BaL. Viremia, cytokine production, and cytotoxicity will be assessed and
the pharmacodynamic mechanisms will be subsequently examined using antagonists to CB1, CB2, and GPR55.
Aim 2 will determine the in vivo anti-nociceptive and analgesic effects of minor cannabinoids and terpenes in
rodent models of HIV-1 protein/cART-related inflammatory, thermal, visceral, and neuropathic pain. Dose-
dependent anti-inflammatory, anti-hyperalgesic, and anti-nociceptive effects of cannabichromene, 10ß-hydroxy-
8-tetrahydrocannabinol, and ß–caryophyllene will be the pure compounds of focus, along with High-CBD extract
(and other anti-inflammatory leads identified in Aim 1). These constituents will be assessed in male and female
transgenic mice that express (or do not express) the HIV-1 Tat or gp120 proteins. Mice will be maintained on
cART to assess potential improvements or interactions with cannabinoid-related outcomes. Aim 3 will determine
the important central and enteric nervous system inflammatory mechanisms that are influenced by cannabinoids
and terpenes following HIV-1 protein/cART exposure. Pain-related brain regions, spinal cord, dorsal root
ganglion, ileum, edema, and plasma collected in Aim 2 will be assessed for cytokine production. Brain and ileum
will be assessed for CB1 or CB2 G-protein activity via [35S]GTP¿S assay as well as neuron morphology and
monocyte-derived cell and astrogliosis. TThese studies will provide insight into the mechanisms by which minor
cannabinoids and terpenes act, will reveal the anti-viremic, anti-inflammatory, and antinociceptive potential of
non-psychoactive cannabis constituents, and will elucidate therapeutics for HIV-related and non-HIV-related,
intractable pain states.
