Principal Investigator

Brian L
Schmidt
Awardee Organization

New York University
United States

Fiscal Year
2020
Activity Code
R01
Project End Date

Peripherally-restricted cannabinoids for cancer and chemotherapy-induced pain

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.

Publications

  • Mulpuri Y, Yamamoto T, Nishimura I, Spigelman I. Role of voltage-gated sodium channels in axonal signal propagation of trigeminal ganglion neurons after infraorbital nerve entrapment. Neurobiology of pain (Cambridge, Mass.). 2022 Jan 21;11:100084. doi: 10.1016/j.ynpai.2022.100084. eCollection 2022 Jan-Jul. PMID: 35128176
  • Wiese BM, Liktor-Busa E, Couture SA, Nikas SP, Ji L, Liu Y, Makriyannis A, Spigelman I, Vanderah TW, Largent-Milnes TM. Brain Penetrant, but not Peripherally Restricted, Synthetic Cannabinoid 1 Receptor Agonists Promote Morphine-Mediated Respiratory Depression. Cannabis and cannabinoid research. 2022 Oct;7(5):621-627. Epub 2021 Dec 17. PMID: 34935460
  • Yamamoto T, Mulpuri Y, Izraylev M, Li Q, Simonian M, Kramme C, Schmidt BL, Seltzman HH, Spigelman I. Selective targeting of peripheral cannabinoid receptors prevents behavioral symptoms and sensitization of trigeminal neurons in mouse models of migraine and medication overuse headache. Pain. 2021 Aug 1;162(8):2246-2262. PMID: 33534356
  • Seki S, Yamamoto T, Quinn K, Spigelman I, Pantazis A, Olcese R, Wiedau-Pazos M, Chandler SH, Venugopal S. Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1G93A Mouse Model for ALS. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019 Oct 30;39(44):8798-8815. Epub 2019 Sep 17. PMID: 31530644
  • Mulpuri Y, Marty VN, Munier JJ, Mackie K, Schmidt BL, Seltzman HH, Spigelman I. Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. Neuropharmacology. 2018 Sep 1;139:85-97. Epub 2018 Jul 5. PMID: 29981335
  • Zhang H, Lund DM, Ciccone HA, Staatz WD, Ibrahim MM, Largent-Milnes TM, Seltzman HH, Spigelman I, Vanderah TW. Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain. 2018 Sep;159(9):1814-1823. PMID: 29781960