Substantial evidence indicates that cannabis is effective for the treatment of chronic pain in adults, but medical use of cannabis is restricted by its main psychoactive component tetrahydrocannabinol (THC). Minor cannabinoids, such as cannabidiol (CBD), do not have psychotropic activity. However, their analgesic effects are not as potent as THC and the neural mechanisms by which minor cannabinoids-mediated analgesia may be optimized remain largely unknown. Accordingly, the overall objective of this project is to identify neural mechanisms involved in minor cannabinoids signaling in order to optimize their analgesic effects. In light of compelling evidence that CBD acts on a1 and a3-glycine receptors (GlyRs), which are only a part of molecular players in neuropathic pain, we will investigate the effects and mechanisms of the combination of CBD or other minor cannabinoids with manipulations based on KCC2, a neuron-specific chloride extruder expressed in most neurons. Our test hypothesis is that CBD's mechanistic effects may be modulated by KCC2 dose-dependently and increasing KCC2 activity in spinal cord and/or cortex may enhance CBD analgesia. Specifically, we will determine whether modulating KCC2 activity will alter CBD analgesia in a dose-dependent manner, and define circuit mechanisms by which KCC2 modulates CBD analgesia. In addition to CBD, we will also examine whether KCC2 activity will regulate the analgesic effects of a family of CBD-related minor cannabinoids. Identifying the novel circuit targets and mechanisms of minor cannabinoids-mediated analgesia will not only help optimize non- psychoactive cannabinoid-based therapies but also provide routes to develop effective new treatments with minimal side-effects.

Public Health Relevance

This proposed study aims to identify neural mechanisms involved in minor cannabinoids signaling in order to optimize their analgesic effects. The insights obtained should be useful in designing novel strategies for treating neuropathic pain.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
1R01AT010779-01
Application #
9895134
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Belfer, Inna
Project Start
2019-09-15
Project End
2024-08-31
Budget Start
2019-09-15
Budget End
2020-08-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115