The effect of novel kappa opioid peptide receptor agonists on learning and memory in rats

Kappa opioid peptide receptors (KOPrs) are a class of opioid receptors which shown analgesic and anti-addictive properties. Nonaddictive analgesics would be beneficial as morphine, one of the most commonly prescribed opioids for chronic pain, activates the brain reward system and can lead to addiction. Although medical research is progressing rapidly, there is still no treatment for psychostimulant abuse. KOPr agonists show promise in this regard but display undesirable side effects and could negatively affect memory. Salvinorin A (Sal A), a structurally unusual KOPr agonist, has a reduced side effect profile compared to the more traditional KOPr agonists such as U50,488. The effect of Sal A and U50,488 on memory is controversial as they have both been shown to induce a memory impairment and also to improve memory impairments. Sal A also has a poor pharmacokinetic profile with a short duration of action. Structural analogues of Sal A have improved pharmacokinetic and side effect profiles compared to Sal A yet retain the analgesic and anti-addiction properties. This thesis will investigate whether Sal A analogues, namely Ethynyl Sal A (Ethy Sal A), Mesyl Salvinorin B (Mesyl Sal B), and Bromo Salvinorin A (Bromo Sal A), produce a memory impairment.  Male Sprague-Dawley rats were evaluated in the novel object recognition (NOR) task to determine whether novel Sal A analogues impair long term recognition memory. The degree of novelty was also investigated on a cellular basis through quantifying c-Fos immunoreactive neurons within the perirhinal cortex, an area of the brain shown to respond to novelty.  Acute administration of Sal A (0.3 and 1 mg/kg) and novel analogues Ethy Sal A (0.3 and 1 mg/kg), Mesyl Sal B (0.3 and 1 mg/kg), and Bromo Sal A (1 mg/kg) showed no significant differences compared to vehicle when tested in the NOR task. The prototypical KOPr agonist, U50,488 (10 mg/kg), produced a significant decrease in recognition index compared to vehicle when tested in the same task as the novel analogues. Correlating the recognition indices calculated from U50,488 in the NOR to c-Fos counts in the perirhinal cortex showed a strong positive correlation with an increase in RI relating to an increase in c-Fos activation. U50,488 (10 mg/kg) showed a non-significant trend compared to vehicle in the number of c-Fos immunoreactive cells within the perirhinal cortex.  Neither Sal A nor novel analogues affected NOR, suggesting no impairment of long term recognition memory. The lack of this side-effect, among others, demonstrates that the development of potent KOPr agonists with reduced side-effect profiles is feasible. These novel analogues show improvement over the traditional KOPr agonists.