Defense Date

2021

Document Type

Thesis

Degree Name

Master of Science

Department

Pharmacology & Toxicology

First Advisor

Aron Lichtman, Ph.D.

Second Advisor

Keith Shelton, Ph.D.

Third Advisor

Joseph Porter, Ph.D.

Fourth Advisor

Dana Selley, Ph.D.

Abstract

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model of neuropathic pain (Rahn & Hohmann, 2009). More recently CB1 positive allosteric modulators (PAMs) have shown antinociceptive efficacy in CCI with ZCZ011 and its analogs, GAT211 and ABD1236, producing dose and time-dependent reversal of allodynia (Ignatowska-Jankowska et al. 2015; Slivicki et al. 2018; Tseng et al. 2019). This study reports the activity of the 2-phenyl indole class of CB1 PAMs represented by ZCZ011 in behavioral paradigms for overt and subjective cannabimimetic side effects, and neuropathic pain. The goal of the study was to examine the relationship between the antiallodynic effects, overt and subjective cannabimimetic effects of CB1 PAMs. Overt cannabimimetic activity was assessed in the tetrad assay which consists of the measures: locomotor activity, catalepsy, antinociception, and hypothermia). Subjective cannabimimetic effects were measured in the drug discrimination paradigm. ZCZ011 analogs were either tested alone in these assays to screen for agonist activity or in combination with CB1 orthosteric agonist CP55,940 to screen for PAM effects. ZCZ011 analogs did not exhibit CB1 agonist activity as measured in the tetrad assay and drug discrimination paradigm when administered alone. ZCZ011 was the only PAM to potentiate all three measures of the triad assay (catalepsy, antinociception, hypothermia) whereas the remaining analogs potentiated only a subset of those effects. ZCZ011, GAT211, LDK1747, and LDK1752 were evaluated in the drug discrimination paradigm. Of these compounds only ZCZ011 and LDK1752 had a potentiating effect on subjective responding to CP55,940. Lastly ZCZ011 analogs were tested for antiallodynic activity in a chronic constriction injury (CCI) model of neuropathic pain. ZCZ011, ABD1236, and GAT211 produced full reversal of allodynia in CCI-mice whereas the remaining analogs had no effect. Comparing results from this study, ZCZ011 is the only compound which exhibits PAM activity in each of the three behavioral paradigms. The remaining analogs show disparate effects with respect to overt and/or subjective cannabimimetic effects and antiallodynic activity. The results of this study indicate that there is no correlation for CB1 PAM activity between the three behavioral paradigms and that it is possible for CB1 PAMs to affect only a subset of cannabinoid-related behaviors.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-9-2021

Share

COinS