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Identifier 000426885
Title Cannabinoid modulation of neurochemical and behavioral effects of opioids
Alternative Title Κανναβινοειδική ρύθμιση νευροχημικών και συμπεριφορικών επιδράσεων των οπιοειδών
Author Σολακίδου, Ελεάνα
Thesis advisor Χαραλαμπόπουλος, Ιωάννης
Reviewer Μακρυγιάννης, Αλέξανδρος
Abstract Chronic pain remains one of the most challenging conditions to treat, primarily because the opioid class of drugs, while effective in relieving pain, also activate reward circuitry and are highly reinforcing. Recent studies in human and nonhuman subjects have highlighted the ability of cannabis or cannabinoids (CBs), which also have analgesic effects, to enhance some antinociceptive effects of prescription opioids without similarly enhancing their adverse effects. However, this line of research has not yet yielded a clinically successful candidate. While research to date highlights pharmacological, behavioral, and physiological overlap between the cannabinoid and opioid systems, the neurochemical mechanisms through which cannabinoids modulate the behavioral effects of opioids remains uncertain. The present research begins to address this research gap by evaluating how pharmacological agents targeting the cannabinoid system may influence the neurochemical and behavioral effects of opioids in laboratory animals. By utilizing in vivo microdialysis techniques coupled with LC-MS/MS, extracellular drug levels and neurochemical changes in brain regions that are known to be involved in pain/reward were evaluated. Results from these studies show that: a) extracellular concentrations of oxycodone increased in a dose- and time-dependent manner in dialysates samples collected from nAcc shell; b) increases in extracellular dopamine (DA) followed oxycodone’s pattern of increase in dialysates from nAcc shell of female but not male subjects; c) in male subjects, only HVA increased after a cumulative dose of 3 mg/kg (i.p.) was administered; d) the cannabinoid CB1 agonist, AM11245 was detected in brain dialysates from prefrontal cortex 140min after a single dose of 1.0 mg/kg, i.p., and WIN55-212.2 was detected in dialysates from cerebellum 40 min after 3 mg/kg, while 60 min after 30 mg/kg was present in dialysates from prefrontal cortex; no extracellular drug was found in 4 nAcc core. Data from behavioral studies show that: a) locomotor activity increased in a dose- and time-dependent manner after cumulatively administration of fentanyl, while the CB1 agonist, AM2201 produced a profound decrease in motor activity; and b) oxycodone produced a dose-dependent increase in tail withdrawal latencies with maximum antinociceptive effects occurring following administration of a cumulative dose of 32 mg/kg. Similarly, cumulative administration of the CB1 agonist AM8936 also produced a dose-dependent increase in tail withdrawal latencies. Maximum antinociceptive effects were observed after a cumulative dose of 0.32 mg/kg of AM8936. Together, these neurochemical and behavioral data provide a strong foundation for future studies that will examine how the cannabinoid system influences the neurochemical and behavioral effects of opioids
Language English
Subject LC-MS/MS
Issue date 201912-11
Collection   Faculty/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
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