Main content

Modulation of the Endocannabinoid System Attenuates Naloxone-Precipitated Morphine Withdrawal-Induced Place Aversions in Acutely Dependent Rats

Show full item record

Title: Modulation of the Endocannabinoid System Attenuates Naloxone-Precipitated Morphine Withdrawal-Induced Place Aversions in Acutely Dependent Rats
Author: Wills, Kiri L.
Department: Department of Psychology
Program: Psychology
Advisor: Parker, Linda A.
Abstract: Modulation of the endocannabinoid system is effective in reducing somatic symptoms of opioid withdrawal, however, much less is known regarding its ability to reduce affective opioid withdrawal. Given that the brain regions mediating somatic and affective opioid withdrawal are dissociable, this dissertation aimed to evaluate the ability of CB1 receptor modulation to reduce affective opioid withdrawal in acutely dependent Sprague Dawley rats. Affective opioid withdrawal can be quantified using a naloxone-precipitated morphine withdrawal (MWD) induced conditioned place aversion (CPA). Rats are made acutely dependent with a single high dose of morphine and withdrawal is precipitated 24 hours later with naloxone. Using this paradigm, the ability of systemically administered CB1 receptor antagonists/neutral antagonists (AM251, AM4113, AM6527) and inhibitors of endocannabinoid hydrolysis (fatty acid amide hydrolase, FAAH; monoacylglercerol lipase, MAGL) were evaluated to prevent the establishment of the MWD CPA. All CB1 receptor antagonists tested and the MAGL inhibitor (elevates 2-arachidonoylglycerol; 2-AG), MJN110, interfered with the MWD CPA. The two FAAH inhibitors tested (elevates anandamide; AEA), PF3845 and URB597, were without significant effect. An evaluation of the brain regions mediating the systemic effects of these compounds revealed a double dissociation of CB1 receptor antagonism and agonism to reduce establishment of the MWD CPA in the extended amygdala and associated regions. Specifically, the CB1 receptor antagonist, AM251, interfered with the CPA when microinfused into the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), whereas the MAGL inhibitor, MJN110, interfered with the CPA when microinfused into the basolateral amygdala (BLA) and the interoceptive insular cortex (IC). The ability of endocannabinoid modulation to reduce affective opioid withdrawal is discussed. Ultimately, the findings presented suggest that modulation of the endocannabinoid system may have therapeutic potential in the treatment of affective opioid withdrawal.
URI: http://hdl.handle.net/10214/11392
Date: 2017-07-25


Files in this item

Files Size Format View Description
Wills_Kiri_201707_PhD.pdf 1.450Mb PDF View/Open Thesis

This item appears in the following Collection(s)

Show full item record

Attribution-ShareAlike 2.5 Canada Except where otherwise noted, this item's license is described as Attribution-ShareAlike 2.5 Canada