DOI
https://doi.org/10.25772/9JSP-2K81
Author ORCID Identifier
https://orcid.org/0000-0002-3188-1061
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Dr. Steve Negus
Abstract
Pain is a major public health concern that is commonly associated with behavioral depression, and a major goal in pain treatment is alleviation of pain-related behavioral depression. High-efficacy mu opioid receptor (MOR) agonists (e.g. fentanyl, morphine, oxycodone) are effective to treat pain, but their use is limited by side effects that not only endanger the patient but may also obscure analgesic rescue of pain-depressed behavior. The ongoing epidemic of opioid abuse and overdose deaths has stimulated research to discover non-opioid alternative analgesics; however, this search neglects the clinical potential of safer intermediate-efficacy MOR agonists (e.g. buprenorphine). The objective of the work presented in this dissertation was to test the hypothesis that intermediate- and low-efficacy MOR agonists would be more effective than high-efficacy MOR agonists to produce antinociception in assays of pain-depressed behavior at doses that do not produce motor disruption. To accomplish this, two main goals were achieved. First, we sought out to determine the effects of three classes of opioids to study MOR efficacy [listed from high- to low-efficacy] (1) clinically available single-molecule opioids [methadone, fentanyl, morphine, hydrocodone, buprenorphine, nalbuphine, naltrexone], (2) fentanyl/naltrexone (FENT/NTX) mixtures [100:1, 56:1, 32:1, 10:1, 3.2:1, 1:1], and (3) novel single-molecule opioids [DC-01-128.1, DC-01-76.2, EWB-3-14, JL-02-0039, NAQ, DC-01-76.1, EG-1-203, EG-1-230]. Second, we sought out to validate and establish two novel assays of pain-depressed behavior as a means of better preclinical-to-clinical translational outcomes (1) climbing, and (2) horizontal locomotor + vertical barrier behavior. The work accomplished in this dissertation can be split into three parts. First, in Part I, we studied MOR efficacy as a determinant of horizontal locomotor activity as a “pain-independent” behavior and results determined an efficacy-, dose-, and time- dependent opioid effect on locomotor activity in female and male ICR mice. Second, in Part II, we studied MOR efficacy as a determinant of antinociception in two assays of pain-depressed behavior by using the acute pain stimulus intraperitoneal (IP) lactic acid. Results determined that mouse climbing is a low efficacy requiring assay because it was too sensitive to mu-agonist induced effects to determine alleviation of the pain-depressed behavior; however, the locomotor + barrier assay was a high efficacy requiring assay because alleviation of the pain-depressed behavior was determined with intermediate- and low-efficacy opioids. In particular, a better window of opportunity to determine alleviation of the pain-depressed behavior at doses that did not alter behavior on their own was with opioids that had much lower efficacy than buprenorphine. Third, in Part III, we studied the expression of experimental chronic pain models (complete Freund’s Adjuvant (CFA), laparotomy, and spared nerve injury (SNI)) in the locomotor + barrier assay and results determined that each chronic pain model produced different magnitude and duration of behavioral depression. Overall, the work presented in this dissertation supports the hypothesis that (1) intermediate- to low-efficacy opioids provide the greatest window of opportunity to determine alleviation of the pain-depressed behavior, and (2) pain-depressed behaviors should be considered when studying novel analgesics.
Rights
© Edna Santos
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-4-2023