Evaluation of Dual-Activity Opioid-NPFF Ligands for Antinociception

Opioids have become a staple in the medical world as an analgesic used to treat acute and chronic pain. However, there are many issues associated with the frequent use of opioids including tolerance, constipation, and opioid-induced hyperalgesia. Fortunately, recent discoveries of neuropeptide FF (NPFF) antagonists, have led to the understanding that tolerance and hyperalgesia caused by opioids can be greatly reduced. This discovery eventually led to the creation of dual ligands with both opioid agonist and NPFF antagonist activity. These dual ligands have been shown to prevent tolerance and opioid-induced hyperalgesia while maintain analgesic qualities in mice. However, these studies have involved injecting the drug directly into the brain due to their inability to cross the blood brain barrier, which makes them unfit to be converted into drugs fit for clinical use. Intravenous or intraperitoneal injection routes can be used but, oral administration would be the best option for therapeutic use. With this goal in mind, we are met with the task of having the drug penetrate the blood-brain barrier so that it may reach the appropriate recepetors. In this study, we had modified the lead small molecule (non-4,5α-epoxymorphinan derived) designated multiple ligands to hopefully have such blood-brain barrier penetration capabilities. We will evaluate the antinociception of these compounds to determine if they have successfully reached their target receptors from peripheral administration. These compounds tested represent only a portion of the compounds created by our lab