Cancer chemotherapy frequently causes a painful peripheral neuropathy that is dose-limiting and can be irreversible. Gabapentin is clinically used to treat diverse forms of neuropathic pain. However, the mechanism(s) responsible for its antinociceptive effects remain poorly understood. Unpublished work from our groups suggests that gabapentin suppresses neuropathic pain induced by the chemotherapeutic agent paclitaxel in rodents through interactions with CB2 cannabinoid receptors. At the cellular level, gabapentin selectively increases ability of the endocannabinoid 2-arachidonoylglycerol (2-AG) to recruit ?-arrestin to CB2 receptors. These observations suggest a previously unrecognized interaction between CB2 receptors, ?- arrestin/ERK1/2 signaling and gabapentin-induced antinociception. We postulate that gabapentin analgesic efficacy is due (at least in part) to a CB2-specific mechanism that involves increased ?-arrestin signaling in microglia or neurons. We will thoroughly test this hypothesis by completing three Specific Aims:
Aim 1 will characterize the impact of gabapentin on CB2 receptor signaling using transfected cells lines, cell lines natively expressing CB2 receptors and primary cultures of CB2-expressing cells. In addition, potential allosteric interactions between gabapentin and CB2 will be probed.
Aim 2 will use conditional deletion of CB2 from neurons, microglia, and astrocytes to determine which cell type(s) express the CB2 receptors mediating gabapentin antinociception during the development and maintenance phases of paclitaxel neuropathy. Since CB2 agonists efficaciously relieve paclitaxel-induced allodynia and hyperalgesia, this approach will also be used to determine the cell type(s) mediating antinociception elicited by direct acting CB2-agonists.
Aim 3 will extend the findings of the first two aims to determine if gabapentin efficacy is also CB2-mediated in other nerve injury and inflammatory pain models. The relevant cell type(s) will be determined using conditional deletion of CB2 as warranted and as described in the second specific aim.
This aim will also investigate the mechanism of direct-acting CB2 agonists in these pain models using the above conditional deletion approach. Our research team combines expertise in (1) CB2 receptor binding, signaling, trafficking, and regulation, (2) cannabinoid pharmacology and antinociceptive mechanisms, and (3) mouse preclinical models of pain. Our studies suggest a highly novel and previously unrecognized intersection between CB2 receptors, endocannabinoids, and arrestin signaling that underlies the therapeutic efficacy of gabapentin. Understanding the cross-talk between these pathways is critical both for elucidating the mechanism of action of gabapentin to exploit and optimize its therapeutic efficacy and for identifying novel therapeutic targets for drug development that lack unwanted side effects of conventional treatments. Lastly, our studies will also identify the cellular targets of CB2 agonist as they relieve a variety of pathological pain states.

Public Health Relevance

While it can be lifesaving, cancer chemotherapy with agents such as paclitaxel can produce pathological pain adversely affecting many of cancer survivors. In this work we will test and validate a novel mechanism of action of a widely used neuropathic pain medication by exploring a previously unrecognized contribution of endocannabinoid signaling to its antinociceptive efficacy. Completion of the proposed work will promote a better understanding of how a commonly used medication for neuropathic pain works and will improve analgesic drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA041229-02
Application #
9259986
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (04)S)
Program Officer
Rapaka, Rao
Project Start
2016-04-15
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$315,900
Indirect Cost
$113,400
Name
Indiana University Bloomington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Panoz-Brown, Danielle; Iyer, Vishakh; Carey, Lawrence M et al. (2018) Replay of Episodic Memories in the Rat. Curr Biol 28:1628-1634.e7
Lin, Xiaoyan; Dhopeshwarkar, Amey S; Huibregtse, Megan et al. (2018) Slowly Signaling G Protein-Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence. Mol Pharmacol 93:49-62
Slivicki, Richard A; Saberi, Shahin A; Iyer, Vishakh et al. (2018) Brain-Permeant and -Impermeant Inhibitors of Fatty Acid Amide Hydrolase Synergize with the Opioid Analgesic Morphine to Suppress Chemotherapy-Induced Neuropathic Nociception Without Enhancing Effects of Morphine on Gastrointestinal Transit. J Pharmacol Exp Ther 367:551-563
Slivicki, Richard A; Xu, Zhili; Kulkarni, Pushkar M et al. (2018) Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. Biol Psychiatry 84:722-733
Li, Ai-Ling; Carey, Lawrence M; Mackie, Ken et al. (2017) Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice. J Pharmacol Exp Ther 362:296-305
Carey, Lawrence M; Gutierrez, Tannia; Deng, Liting et al. (2017) Inflammatory and Neuropathic Nociception is Preserved in GPR55 Knockout Mice. Sci Rep 7:944
Smith, Alexandra E; Slivicki, Richard A; Hohmann, Andrea G et al. (2017) The chemotherapeutic agent paclitaxel selectively impairs learning while sparing source memory and spatial memory. Behav Brain Res 320:48-57
Dhopeshwarkar, Amey; Murataeva, Natalia; Makriyannis, Alex et al. (2017) Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists. J Pharmacol Exp Ther 360:300-311
Woodhams, Stephen G; Chapman, Victoria; Finn, David P et al. (2017) The cannabinoid system and pain. Neuropharmacology 124:105-120
Carey, Lawrence M; Lee, Wan-Hung; Gutierrez, Tannia et al. (2017) Small molecule inhibitors of PSD95-nNOS protein-protein interactions suppress formalin-evoked Fos protein expression and nociceptive behavior in rats. Neuroscience 349:303-317

Showing the most recent 10 out of 11 publications