Effects of the δ opioid agonist AZD2327 upon operant behaviors and assessment of its potential for abuse.

AZD2327 is a brain-penetrant agonist at δ opioid receptors which has antidepressant and anxiolytic properties in a wide array of animal models. As part of the preclinical safety pharmacology assessment, a number of studies were conducted in order to characterize its behavioral effects and its potential for abuse, in order to enable testing in humans. AZD2327 produced only modest effects when tested in a multiple fixed-ratio differential reinforcement of low rate schedule in rats, and did not enhance the rate-suppressing effects of ethanol in the procedure. In a suppressed responding test, AZD2327 only reduced rates of unpunished responding. In drug discrimination studies, AZD2327 produced partial or no generalization from known drugs of abuse. In primates trained to self-administer cocaine, substitution with AZD2327 did not result in appreciable self-administration of AZD2327, indicating that it does not behave as a positive reinforcer under the present conditions. Following termination of repeated administration of AZD2327, no signs of physical dependence (withdrawal) were noted. Overall, the data suggest that AZD2327 does not possess a high potential for abuse, and appears to have only subtle behavioral effects as measured by operant behaviors.

Assessment of relative intrinsic activity of mu-opioid analgesics in vivo by using beta-funaltrexamine.

Morphine is the prototypic mu-opioid analgesic; however, in certain situations in vitro, morphine behaves as a partial agonist. To assess the relative intrinsic activity of morphine and three other mu-opioid analgesics in vivo, beta-funaltrexamine (beta-FNA), an irreversible antagonist selective for the mu receptor, was used to reduce the effective receptor reserve. By using a stereotaxic device, 1.25 to 20 micrograms of beta-FNA was infused into the lateral ventricle of rats. Twenty-four hours later, animals were tested in the tail-flick assay with cumulative doses of morphine, levorphanol, methadone or fentanyl. Pretreatment with 2.5 micrograms of beta-FNA induced parallel rightward shifts of both the morphine and levorphanol dose-effect curves and 5.0 micrograms of beta-FNA reduced the maximum analgesic effect of these agonists. Methadone surmounted the antagonism of 5.0 micrograms of beta-FNA; 10 micrograms was required to reduce the maximum analgesic effect of methadone. Fentanyl overcame the blockade induced by both 5.0 and 10 micrograms of beta-FNA. Only with a pretreatment dose of 20 micrograms of beta-FNA was the maximum analgesic effect of fentanyl reduced. Thus, when a certain proportion of mu receptors is inactivated, i.e., with 5.0 micrograms of beta-FNA, fentanyl and methadone have the capacity to surmount the blockade, whereas morphine and levorphanol do not. This suggests that fentanyl and methadone have higher intrinsic efficacies than do morphine and levorphanol. Thus, a strategy used widely in vitro was applied successfully in vivo to assess relative intrinsic activities of a series of mu-opioid agonists.