Among the millions of patients who receive chemotherapy for cancer, many develop painful peripheral neuropathy. In fact, pain is the principal dose-limiting side effect of chemotherapy, and patients often will receive smaller doses or forego treatment which impacts survival. It is critical to manage this neuropathic pain so that treatment can be optimized. This is a proposal to determine whether cannabinoids may be beneficial for the treatment of chemotherapy-associated pain. Cannabinoid receptors (CB1 and CB2) are located in the periphery, as well as the central nervous system, and modulate nociception. We will investigate whether increased activation of peripheral cannabinoid receptors, or increasing the bioavailability of endogenous cannabinoids (endocannabinoids), will reduce neuropathic pain from chemotherapy. We developed a murine model of neuropathic pain using the chemotherapeutic agent cisplatin, the most widely used chemotherapeutic agent which is often associated with neuropathy. Preliminary data show that mechanical hyperalgesia develops following cisplatin, and cannabinoids given into the hindpaw reduce the hyperalgesia. A multidisciplinary approach employing parallel behavioral, electrophysiological, and cellular studies in mice will be used to investigate changes in endocannabinoid signaling in the periphery that may contribute to cisplatin-evoked hyperalgesia and mechanisms by which cannabinoids may attenuate hyperalgesia. Specifically, we will determine whether injection of cannabinoids or drugs that block degradation of endocannabinoids into the hindpaw attenuate cisplatin-evoked hyperalgesia and sensitization of cutaneous nociceptors. In cellular studies of primary sensory neurons isolated from cisplatin-treated mice, we will determine whether cisplatin alters cannabinoid signaling and receptor expression that may contribute to the hyperalgesia or to the antihyperalgesic effects of cannabinoids. Results from these studies will provide new information on the mechanisms underlying pain from chemotherapy, and will provide a rationale for exploring the use of peripherally-acting cannabinoids in managing pain associated with chemotherapy.

Public Health Relevance

Among the millions of patients who receive chemotherapy for cancer, many develop painful peripheral neuropathy which is the principal dose-limiting side effect of chemotherapy. Patients often will receive smaller doses of chemotherapy or forego treatment which impacts survival. This is a proposal to investigate whether peripheral administration of cannabinoids reduces pain and hyperalgesia from chemotherapy and to determine the underlying mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011471-13
Application #
8233536
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Thomas, David A
Project Start
2000-02-03
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
13
Fiscal Year
2012
Total Cost
$351,505
Indirect Cost
$118,720
Name
University of Minnesota Twin Cities
Department
Dentistry
Type
Schools of Dentistry
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Khasabova, Iryna A; Yao, Xu; Paz, Justin et al. (2014) JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. Pharmacol Res 90:67-75
Khasabova, Iryna A; Holman, Michelle; Morse, Tim et al. (2013) Increased anandamide uptake by sensory neurons contributes to hyperalgesia in a model of cancer pain. Neurobiol Dis 58:19-28
Khasabov, S G; Simone, D A (2013) Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia. Neuroscience 250:151-65
Boyette-Davis, Jessica A; Eng, Cathy; Wang, Xin S et al. (2012) Subclinical peripheral neuropathy is a common finding in colorectal cancer patients prior to chemotherapy. Clin Cancer Res 18:3180-7
Brink, Thaddeus S; Pacharinsak, Cholawat; Khasabov, Sergey G et al. (2012) Differential modulation of neurons in the rostral ventromedial medulla by neurokinin-1 receptors. J Neurophysiol 107:1210-21
Cain, David M; Vang, Derek; Simone, Donald A et al. (2012) Mouse models for studying pain in sickle disease: effects of strain, age, and acuteness. Br J Haematol 156:535-44
Khasabova, Iryna A; Chandiramani, Anisha; Harding-Rose, Catherine et al. (2011) Increasing 2-arachidonoyl glycerol signaling in the periphery attenuates mechanical hyperalgesia in a model of bone cancer pain. Pharmacol Res 64:60-7
Simone, Donald A; Khasabov, Sergey G; Cain, David M et al. (2011) Changes in response properties of nociceptors and dorsal horn neurons in a murine model of cancer pain. Fiziol Zh 57:75-7
Khasabova, Iryna A; Gielissen, James; Chandiramani, Anisha et al. (2011) CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. Behav Pharmacol 22:607-16
Kohli, Divyanshoo R; Li, Yunfang; Khasabov, Sergey G et al. (2010) Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids. Blood 116:456-65

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