Pain is a multi-faceted, complex disease that affects all humans. Unfortunately, progress in pain management has been met with limited success. However, considerations of the multiple components of pain have suggested that targeting non-conventional sites could strongly impact the pain management field. The endocannabinoid (eCB) system is one of several lipid signaling systems in the brain and in the body. Verified components of this system include two G-protein coupled receptors, their signaling pathways, two predominant endogenous ligands [anandamide (AEA) and 2-arachidonyl glycerol (2-AG)], and their synthetic and metabolic pathways. The system plays an important modulatory role in many crucial CNS processes (e.g., brain reward, appetite regulation, cognition). Consequently, it is not surprising that this system has been implicated in the pathophysiology of a variety of health problems related to these processes, including pain management. This application is largely based on the idea that a clinically significant component of pain is behavioral depression (i.e., pain-depressed behaviors). In humans, this is indicated by absences from work or school, lack of interest in customary activities, overall decreases in motor activity, and is most often associated with clinical depression. In animals clinical approximation of pain is through decreases in locomotion or grooming and interest in feeding or social interaction. Given these, a promising new strategy for comprehensive treatment of pain is an adjunct focus on pain-depressed behaviors and depressed mood. With this application we plan to evaluate eCB modulation of pain-depressed behaviors using intracranial self-stimulation (ICSS) and drug discrimination (DD) in mice. ICSS has been widely used to study modulation of motivated behavior (i.e. reward) and affect by drugs whereas DD is primarily used to model the subjective/intoxicating effects of drugs. We propose utilizing these well-established operant procedures to evaluate the eCB's effects on pain-induced behavioral depression, affect and intoxication. To complement these behavioral measures, we will determine mechanistic characteristics of affective cannabinoid analgesia versus reward in selected brain regions such as the nucleus accumbens, a brain area implicated in reward and affective pain, through the use of well- established neurochemical analyses such as mass spectrometry and [35S]GTPgS G-protein binding studies. Given the clear need to explore novel therapeutic targets, improve upon existing preclinical pain assays, and incorporate the affective component of pain, we propose that studying the eCB system's modulation of pain-depressed behavior will meet these needs. We feel these studies have significant public health implications and offer a large degree of innovation while relying upon well-established behavioral and neurochemical measures. In summary, considering the paramount public health concern regarding effective pain management this application promises to establish whether the eCB system is a viable and attractive therapeutic means to effectively reduce the great societal burdens associated with pain management.

Public Health Relevance

concern of utmost importance and is typicaly accompanied by behavioral depression that results in absences from work/school, lack of interest in customary activities, overall decreases in activity, and is most often associated with depresion. Given the clear need to explore novel therapeutic targets, improve upon existing preclinical pain assays, and incorporate the affective component of pain, we propose a thorough evaluation of the endogenous cannabinoid system's ability to ameliorate pain-depressed behavior, while taking into account critical factors relevant to this system such as modulation of reward and intoxication.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA030404-04
Application #
8653551
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Rapaka, Rao
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$336,375
Indirect Cost
$111,375
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Bagdas, Deniz; Muldoon, Pretal P; AlSharari, Shakir et al. (2016) Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice. Neuropharmacology 102:236-43
Grim, T W; Morales, A J; Gonek, M M et al. (2016) Stratification of Cannabinoid 1 Receptor (CB1R) Agonist Efficacy: Manipulation of CB1R Density through Use of Transgenic Mice Reveals Congruence between In Vivo and In Vitro Assays. J Pharmacol Exp Ther 359:329-339
Leitl, Michael D; Negus, S Stevens (2016) Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and [INCREMENT]9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats. Behav Pharmacol 27:364-76
Owens, Robert A; Ignatowska-Jankowska, Bogna; Mustafa, Mohammed et al. (2016) Discriminative Stimulus Properties of the Endocannabinoid Catabolic Enzyme Inhibitor SA-57 in Mice. J Pharmacol Exp Ther 358:306-14
Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A et al. (2015) Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice. J Pharmacol Exp Ther 352:195-207
Ghosh, Sudeshna; Kinsey, Steven G; Liu, Qing-Song et al. (2015) Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice. J Pharmacol Exp Ther 354:111-20
Viader, Andreu; Blankman, Jacqueline L; Zhong, Peng et al. (2015) Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action. Cell Rep 12:798-808
Nass, Sara R; Long, Jonathan Z; Schlosburg, Joel E et al. (2015) Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge. J Neuroimmune Pharmacol 10:364-70
Grim, Travis W; Wiebelhaus, Jason M; Morales, Anthony J et al. (2015) Effects of acute and repeated dosing of the synthetic cannabinoid CP55,940 on intracranial self-stimulation in mice. Drug Alcohol Depend 150:31-7
Lazenka, Matthew F; Tomarchio, Aaron J; Lichtman, Aron H et al. (2015) Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in Δ9-Tetrahydrocannabinol-Mediated Induction of ΔFosB in the Mouse Forebrain. J Pharmacol Exp Ther 354:316-27

Showing the most recent 10 out of 20 publications