Synthetic and naturally occurring cannabinoids (CBs) have demonstrated effectiveness in numerous chronic inflammatory and neuropathic disorders in humans and in animal models. However, major impediments to the widespread use of CB-based therapies are their psychotropic side-effects, mediated by the activation of central nervous system (CNS) CB1 receptors (CB1Rs). Recently, we developed a series of synthetic peripherally-restricted CBs (PRCBs), and demonstrated potent reversible and repeated suppression of chronic inflammatory and neuropathic pain symptoms in the absence of CNS-mediated side effects. The therapeutic utility of PRCBs may include many other indications where brain-permeant CBs have been shown to be effective. Cancer pain and chemotherapy-induced neuropathy are particularly attractive targets since brain-permeant CBs possess antitumorigenic properties and have been shown to ameliorate the pain symptoms of cancer and chemotherapy-induced neuropathies mainly by peripheral mechanisms. Therefore, this proposal focuses on establishing effectiveness and mechanisms of action of PRCBs against: a) human oral carcinoma proliferation, b) oral carcinoma-induced pain, and c) chemotherapy-induced peripheral neuropathies (CIPNs). We will achieve these aims through the use of innovative and validated operant assays that provide a measure of cerebral processing and orofacial function in mouse oral cancer and rat CIPN models. Gender differences in cancer and CIPN pain sensitivity and their responsiveness to PRCBs will be determined. To further characterize PRCBs we will perform pharmacokinetic studies and determine their receptor targets with tissue-specific transgenic mice. To assess potential off-target actions and peripheral side effects of PRCBs we will use a suite of invasive and non-invasive physiological tools. We will also assess the potential development of tolerance to PRCBs after chronic administration and determine if pre-treatment with PRCBs may actually prevent the onset and maintenance of CIPN symptoms. Successful completion of the proposed studies would allow us to translate pre- clinical findings to a clinical trial; this work would improve outcome for cancer patients.

Public Health Relevance

Chronic pain affects >50 million adults in the U.S. population and represents a major socioeconomic and clinical challenge because the side-effects of existing treatments greatly limit their effectiveness. We have developed a novel class of drugs free of central nervous system side-effects for treating chronic pain and propose to determine their antitumor potential, effectiveness against cancer pain, and chemotherapy-induced neuropathic pain.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA196263-04
Application #
9608720
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
O'Mara, Ann M
Project Start
2016-01-15
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York University
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Zhang, Hong; Lund, Dominique M; Ciccone, Haley A et al. (2018) Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain 159:1814-1823
Mulpuri, Yatendra; Marty, Vincent N; Munier, Joseph J et al. (2018) Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. Neuropharmacology 139:85-97